生信网-文献期刊

Front Immunol

2023 Jul 7

Yang H, Cham J, Neal BP

2. Robust spike-specific CD4(+) and CD8(+) T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study.

Front Immunol

2023 Jul 7

Federico L, Tvedt THA, Gainullin M

3. The role of fibromodulin in inflammatory responses and diseases associated with inflammation.

Front Immunol

2023 Jul 7

Zhao F, Bai Y, Xiang X

4. Integrated analyses of single-cell transcriptomics identify metastasis-associated myeloid subpopulations in breast cancer lung metastasis.

Front Immunol

2023 Jul 7

Huang Z, Bu D, Yang N

5. Efficacy and safety of Lenvatinib-based combination therapies for patients with unresectable hepatocellular carcinoma: a single center retrospective study.

Front Immunol

2023 Jul 7

Huang J, Wang ZG, Tao QF

BACKGROUND: Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies. METHODS: This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR). RESULTS: Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE. CONCLUSION: Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.

6. ARID5B regulates fatty acid metabolism and proliferation at the Pre-B cell stage during B cell development.

Front Immunol

2023 Jul 7

Chalise JP, Ehsani A, Lemecha M

7. The structure of songbird MHC class I reveals antigen binding that is flexible at the N-terminus and static at the C-terminus.

Front Immunol

2023 Jul 7

Eltschkner S, Mellinger S, Buus S

8. Identification of immune activation-related gene signature for predicting prognosis and immunotherapy efficacy in lung adenocarcinoma.

Front Immunol

2023 Jul 7

Zeng W, Wang J, Yang J

BACKGROUND: Lung adenocarcinoma (LUAD) is a major subtype of non-small cell lung cancer (NSCLC) with a highly heterogeneous tumor microenvironment. Immune checkpoint inhibitors (ICIs) are more effective in tumors with a pre-activated immune status. However, the potential of the immune activation-associated gene (IAG) signature for prognosis prediction and immunotherapy response assessment in LUAD has not been established. Therefore, it is critical to explore such gene signatures. METHODS: RNA sequencing profiles and corresponding clinical parameters of LUAD were extracted from the TCGA and GEO databases. Unsupervised consistency clustering analysis based on immune activation-related genes was performed on the enrolled samples. Subsequently, prognostic models based on genes associated with prognosis were built using the last absolute shrinkage and selection operator (LASSO) method and univariate Cox regression. The expression levels of four immune activation related gene index (IARGI) related genes were validated in 12 pairs of LUAD tumor and normal tissue samples using qPCR. Using the ESTIMATE, TIMER, and ssGSEA algorithms, immune cell infiltration analysis was carried out for different groups, and the tumor immune dysfunction and rejection (TIDE) score was used to evaluate the effectiveness of immunotherapy. RESULTS: Based on the expression patterns of IAGs, the TCGA LUAD cohort was classified into two clusters, with those in the IAG-high pattern demonstrating significantly better survival outcomes and immune cell infiltration compared to those in the IAG-low pattern. Then, we developed an IARGI model that effectively stratified patients into different risk groups, revealing differences in prognosis, mutation profiles, and immune cell infiltration within the tumor microenvironment between the high and low-risk groups. Notably, significant disparities in TIDE score between the two groups suggest that the low-risk group may exhibit better responses to ICIs therapy. The IARGI risk model was validated across multiple datasets and demonstrated exceptional performance in predicting overall survival in LUAD, and an IARGI-integrated nomogram was established as a quantitative tool for clinical practice. CONCLUSION: The IARGI can serve as valuable biomarkers for evaluating the tumor microenvironment and predicting the prognosis of LUAD patients. Furthermore, these genes probably provide valuable guidance for establishing effective immunotherapy regimens for LUAD patients.

9. Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation.

Front Immunol

2023 Jul 7

Salvato I, Ricciardi L, Dal Col J

INTRODUCTION: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RESULTS: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. DISCUSSION: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.

10. Real-world treatment patterns, discontinuation and clinical outcomes in patients with B-cell lymphoproliferative diseases treated with BTK inhibitors in China.

Front Immunol

2023 Jul 7

Yan Y, Lv R, Wang T

INTRODUCTION: Bruton tyrosine kinase inhibitor (BTKi) has demonstrated substantial efficacy in treating B-cell lymphoproliferative diseases (BLPD). Nonetheless, the significant discontinuation rates due to toxicity or financial reasons cannot be overlooked. In China, empirical evidence on the usage of BTKi remains scarce. METHODS: To address this, a retrospective cohort study was conducted focused on 673 Chinese patients with BLPD who underwent at least one month of BTKi therapy. RESULTS: Median age at BTKi initiation was 60 years. The median duration on BTKi treatment of the whole cohort was 36.4 months. The median post-BTK survival was not reach. BTKi-based treatment was permanently discontinued in 288 (43.8%) patients during follow-up, mostly attributed to progressive disease. Within the first 6 months of BTKi treatment, 76 patients (26.3%) had early treatment discontinuation. Patients with early discontinuation had extreme worse outcome with a median post-discontinuation survival of only 6.9 months. On multivariate analysis, withdrawal BTKi by toxicity and withdrawal BTKi within 6 months retained to be independent predictors of post-BTK survival, after taking account of the response depth, lines of therapy and baseline cytogenetics including 17p deletion. The decision between BTKi monotherapy and combination therapy, along with the preference for first or second-generation BTKi, exerted no significant impact on survival. DISCUSSIONS: These observations contribute valuable real-world insights into the utilization of BTKi in China. We concluded that BTKi is an effective and well-tolerated treatment for long-term use in Chinese patient population. However, it is imperative to stress that a proportion of patients discontinue BTKi early, leading to suboptimal outcomes. This study underscores the importance of adherence to BTKi therapy for improved clinical outcomes in real-world patients.

11. Diabetic complications and prospective immunotherapy.

Front Immunol

2023 Jul 7

Reynolds L, Luo Z, Singh K.

12. A network approach to define the predictive role of immune profile on tumor response and toxicity of anti PD-1 single agent immunotherapy in patients with solid tumors.

Front Immunol

2023 Jul 7

Mezi S, Pomati G, Fiscon G

13. Muscle fiber necroptosis in pathophysiology of idiopathic inflammatory myopathies and its potential as target of novel treatment strategy.

Front Immunol

2023 Jul 7

Kamiya M, Kimura N, Umezawa N

Idiopathic inflammatory myopathies (IIMs), which are a group of chronic and diverse inflammatory diseases, are primarily characterized by weakness in the proximal muscles that progressively leads to persistent disability. Current treatments of IIMs depend on nonspecific immunosuppressive agents (including glucocorticoids and immunosuppressants). However, these therapies sometimes fail to regulate muscle inflammation, and some patients suffer from infectious diseases and other adverse effects related to the treatment. Furthermore, even after inflammation has subsided, muscle weakness persists in a significant proportion of the patients. Therefore, the elucidation of pathophysiology of IIMs and development of a better therapeutic strategy that not only alleviates muscle inflammation but also improves muscle weakness without increment of opportunistic infection is awaited. Muscle fiber death, which has been formerly postulated as "necrosis", is a key histological feature of all subtypes of IIMs, however, its detailed mechanisms and contribution to the pathophysiology remained to be elucidated. Recent studies have revealed that muscle fibers of IIMs undergo necroptosis, a newly recognized form of regulated cell death, and promote muscle inflammation and dysfunction through releasing inflammatory mediators such as damage-associated molecular patterns (DAMPs). The research on murine model of polymyositis, a subtype of IIM, revealed that the inhibition of necroptosis or HMGB1, one of major DAMPs released from muscle fibers undergoing necroptosis, ameliorated muscle inflammation and recovered muscle weakness. Furthermore, not only the necroptosis-associated molecules but also PGAM5, a mitochondrial protein, and reactive oxygen species have been shown to be involved in muscle fiber necroptosis, indicating the multiple target candidates for the treatment of IIMs acting through necroptosis regulation. This article overviews the research on muscle injury mechanisms in IIMs focusing on the contribution of necroptosis in their pathophysiology and discusses the potential treatment strategy targeting muscle fiber necroptosis.

14. γδ T cell-intrinsic IL-1R promotes survival during Staphylococcus aureus bacteremia.

Front Immunol

2023 Jul 7

Wang Y, Ahmadi MZ, Dikeman DA

15. CD93 overexpresses in liver hepatocellular carcinoma and represents a potential immunotherapy target.

Front Immunol

2023 Jul 7

Jiang Q, Kuai J, Jiang Z

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is one of the malignant tumors with high incidence as well as high death, which is ranked as the sixth most common tumor and the third highest mortality worldwide. CD93, a transmembrane protein, has been widely reported to play an important role in different types of diseases, including many types of cancer by mainly functioning in extracellular matrix formation and vascular maturation. However, there are few researches focusing on the role and potential function of CD93 in LIHC. METHODS: In this study, we comprehensively analyzed the relationship between CD93 and LIHC. We not only discovered transcriptional expression of CD93 in LIHC by using the TIMER, GEPIA and UALCAN database, but also performed WB and IHC to verify the protein expression of CD93 in LIHC. Meantime, Kaplan-Meier Plotter Database Analysis were used to assess the prognosis of CD93 in LIHC. After knowing close correlation between CD93 expression and LIHC, there were STRING, GeneMania and GO and KEGG enrichment analyses to find how CD93 functions in LIHC. We further applied CIBERSORT Algorithm to explore the correlation between CD93 and immune cells and evaluate prognostic value of CD93 based on them in LIHC patients. RESULTS: The transcriptional and protein expression of CD93 were both obviously increased in LIHC by above methods. There was also a significant and close correlation between the expression of CD93 and the prognosis of LIHC patients by using Kaplan-Meier Analysis, which showed that LIHC patients with elevated expression of CD93 were associated with a predicted poor prognosis. We found that the functions of CD93 in different cancers are mainly related to Insulin like growth factor binding protein 7 Gene (IGFBP7)/CD93 pathway via STRING, GeneMania and functional enrichment analyses. Further, our data obtained from CIBERSORT Algorithm suggested CD93 was also associated with the immune response. There is a close positive correlation between CD93 expression and the infiltration levels of all six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Importantly, CD93 can affect the prognosis of patients with LIHC partially due to immune infiltration. CONCLUSION: Our results demonstrated CD93 may be a candidate predictor of clinical prognosis and immunotherapy response in LIHC.

16. Interrogation of human microglial phagocytosis by CRISPR genome editing.

Front Immunol

2023 Jul 7

Chang JC, Wang CY, Lin S.

BACKGROUND: Microglia are an integral part of central nervous system, but our understanding of microglial biology is limited due to the challenges in obtaining and culturing primary human microglia. HMC3 is an important cell line for studying human microglia because it is readily accessible and straightforward to maintain in standard laboratories. Although HMC3 is widely used for microglial research, a robust genetic method has not been described. Here, we report a CRISPR genome editing platform, by the electroporation of Cas9 ribonucleoproteins (Cas9 RNP) and synthetic DNA repair templates, to enable rapid and precise genetic modifications of HMC3. For proof-of-concept demonstrations, we targeted the genes implicated in the regulation of amyloid beta (Aβ) and glioblastoma phagocytosis in microglia. We showed that CRISPR genome editing could enhance the phagocytic activities of HMC3. METHODS: We performed CRISPR gene knockout (KO) in HMC3 by the electroporation of pre-assembled Cas9 RNP. Co-introduction of DNA repair templates allowed site-specific knock-in (KI) of an epitope tag, a synthetic promoter and a fluorescent reporter gene. The editing efficiencies were determined genotypically by DNA sequencing and phenotypically by immunofluorescent staining and flow cytometry. The gene-edited HMC3 cells were examined in vitro by fluorescent Aβ and glioblastoma phagocytosis assays. RESULTS: Our platform enabled robust single (>90%) and double (>70%) KO without detectable off-target editing by high throughput DNA sequencing. We also inserted a synthetic SFFV promoter to efficiently upregulate the expression of endogenous CD14 and TREM2 genes associated with microglial phagocytosis. The CRISPR-edited HMC3 showed stable phenotypes and enhanced phagocytosis of fluorescence-labeled Aβ1-42 peptides. Confocal microscopy further confirmed the localization of Aβ1-42 aggregates in the acidified lysosomes. HMC3 mutants also changed the phagocytic characteristic toward apoptotic glioblastoma cells. CONCLUSION: CRISPR genome editing by Cas9 RNP electroporation is a robust approach to genetically modify HMC3 for functional studies such as the interrogation of Aβ and tumor phagocytosis, and is readily adoptable to investigate other aspects of microglial biology.

17. Primary oxidative phosphorylation defects lead to perturbations in the human B cell repertoire.

Front Immunol

2023 Jul 7

Gordon-Lipkin EM, Banerjee P, Franco JLM

18. Monocyte-endothelial cell interactions in vascular and tissue remodeling.

Front Immunol

2023 Jul 7

Medrano-Bosch M, Simón-Codina B, Jiménez W

19. Immune responses in the uterine mucosa: clues for vaccine development in pigs.

Front Immunol

2023 Jul 7

Choudhary P, Magloire D, Hamonic G

20. Induction of humoral and cell-mediated immunity to the NS1 protein of TBEV with recombinant Influenza virus and MVA affords partial protection against lethal TBEV infection in mice.

Front Immunol

2023 Jul 7

Beicht J, Kubinski M, Zdora I

21. Dimethyl fumarate-related immune and transcriptional signature is associated with clinical response in multiple sclerosis-treated patients.

Front Immunol

2023 Jul 7

Sánchez-Sanz A, García-Martín S, Sabín-Muñoz J

BACKGROUND AND OBJECTIVE: Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response. MATERIAL AND METHODS: PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively. RESULTS: In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes). CONCLUSIONS: Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.

22. Risk factors for relapse in non-infectious cryoglobulinemic vasculitis, including type I cryoglobulinemia: a systematic review.

Front Immunol

2023 Jul 7

Rajendran N, Rameli PM, Awad H.

23. Genetic support of the causal association between gut microbiome and COVID-19: a bidirectional Mendelian randomization study.

Front Immunol

2023 Jul 7

Li Z, Zhu G, Lei X

BACKGROUND: The association between gut microbiome and coronavirus disease 2019 (COVID-19) has attracted much attention, but its causality remains unclear and requires more direct evidence. METHODS: In this study, we conducted the bidirectional Mendelian randomization (MR) analysis to assess the causal association between gut microbiome and COVID-19 based on the summary statistics data of genome-wide association studies (GWASs). Over 1.8 million individuals with three COVID-19 phenotypes (severity, hospitalization and infection) were included. And 196 bacterial taxa from phylum to genus were analyzed. The inverse-variance weighted (IVW) analysis was chosen as the primary method. Besides, false discovery rate (FDR) correction of p-value was used. To test the robustness of the causal relationships with p-FDR < 0.05, sensitivity analyses including the secondary MR analyses, horizontal pleiotropy test, outliers test, and "leave-one-out" analysis were conducted. RESULTS: In the forward MR, we found that 3, 8, and 10 bacterial taxa had suggestive effects on COVID-19 severity, hospitalization and infection, respectively. The genus Alloprevotella [odds ratio (OR) = 1.67; 95% confidence interval (95% CI), 1.32-2.11; p = 1.69×10-5, p-FDR = 2.01×10-3] was causally associated with a higher COVID-19 severity risk. In the reverse MR, COVID-19 severity, hospitalization and infection had suggestive effects on the abundance of 4, 8 and 10 bacterial taxa, respectively. COVID-19 hospitalization causally increased the abundance of the phylum Bacteroidetes (OR = 1.13; 95% CI, 1.04-1.22; p = 3.02×10-3; p-FDR = 2.72×10-2). However, secondary MR analyses indicated that the result of COVID-19 hospitalization on the phylum Bacteroidetes required careful consideration. CONCLUSION: Our study revealed the causal association between gut microbiome and COVID-19 and highlighted the role of "gut-lung axis" in the progression of COVID-19.

24. HBV-associated DLBCL of poor prognosis: advance in pathogenesis, immunity and therapy.

Front Immunol

2023 Jul 7

Wan X, Young KH, Bai O.

25. Targeting LSD1 in tumor immunotherapy: rationale, challenges and potential.

Front Immunol

2023 Jul 7

Bao L, Zhu P, Mou Y

26. Intracellular DNA sensing by neutrophils and amplification of the innate immune response.

Front Immunol

2023 Jul 7

Mankan AK, Czajka-Francuz P, Prendes M

27. NK cells from COVID-19 positive patients exhibit enhanced cytotoxic activity upon NKG2A and KIR2DL1 blockade.

Front Immunol

2023 Jul 7

Lee G, Schauner R, Burke J

28. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders.

Front Immunol

2023 Jul 7

Gonzalez Caldito N.

29. Case Report: Chemoimmunotherapy in microsatellite-instability-high advanced goblet cell carcinoma of the colon.

Front Immunol

2023 Jul 7

Mutlu AU, Aytaç E, Gülmez M

30. Vitamin D supplementation reduced blood inflammatory cytokines expression and improved graft function in kidney transplant recipients.

Front Immunol

2023 Jul 6

Bai YJ, Li YM, Hu SM

31. Sirtuin family in autoimmune diseases.

Front Immunol

2023 Jul 6

Tao Z, Jin Z, Wu J

32. Advances in attractive therapeutic approach for macrophage activation syndrome in COVID-19.

Front Immunol

2023 Jul 6

Chen S, Zhang C, Chen D

33. Efficacy and safety of innate and adaptive immunotherapy combined with standard of care in high-grade gliomas: a systematic review and meta-analysis.

Front Immunol

2023 Jul 6

Guo B, Zhang S, Xu L

BACKGROUND: Malignant glioma is the most common intracranial malignant tumor with the highest mortality. In the era of immunotherapy, it is important to determine what type of immunotherapy provides the best chance of survival. METHOD: Here, the efficacy and safety of immunotherapy in high-grade glioma (HGG) were evaluated by systematic review and meta-analysis. The differences between various types of immunotherapy were explored. Retrieved hits were screened for inclusion in 2,317 articles. We extracted the overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) as two key outcomes for examining the efficacy of immunotherapy. We also analyzed data on the reported corresponding adverse events to assess the safety of immunotherapy. This study was registered with PROSPERO (CRD42019112356). RESULTS: We included a total of 1,271 patients, of which 524 received a combination of immunotherapy and standard of care (SOC), while 747 received SOC alone. We found that immunotherapy extended the OS (HR = 0.74; 95% confidence interval [CI], 0.56-0.99; Z = -2.00, P = 0.0458 < 0.05) and PFS (HR = 0.67; 95% CI, 0.45-0.99; Z = -1.99, P = 0.0466 < 0.05), although certain adverse events occurred (proportion = 0.0773, 95% CI, 0.0589-0.1014). Our data have demonstrated the efficacy of the dendritic cell (DC) vaccine in prolonging the OS (HR = 0.38; 95% CI, 0.21-0.68; Z = -3.23; P = 0.0012 < 0.05) of glioma patients. Oncolytic viral therapy (VT) only extended patient survival in a subgroup analysis (HR = 0.60; 95% CI, 0.45-0.80; Z = -3.53; P = 0.0004 < 0.05). By contrast, immunopotentiation (IP) did not prolong OS (HR = 0.69; 95% CI, 0.50-0.96; Z = -2.23; P = 0.0256). CONCLUSION: Thus, DC vaccination significantly prolonged the OS of HGG patients, however, the efficacy of VT and IP should be explored in further studies. All the therapeutic schemes evaluated were associated with certain side effects. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=112356.

34. Network proteomic analysis identifies inter-alpha-trypsin inhibitor heavy chain 4 during early human Achilles tendon healing as a prognostic biomarker of good long-term outcomes.

Front Immunol

2023 Jul 6

Wu X, Chen J, Sun W

35. Effect of early initiation of steroid-sparing drugs in patients with bullous pemphigoid.

Front Immunol

2023 Jul 6

Fenne IJ, Askildsen Oftebro G, Vestergaard C

INTRODUCTION: Bullous pemphigoid (BP) can be treated using systemic and topical glucocorticoids and/or other immunomodulatory agents. However, the long-term use of systemic glucocorticoids causes severe adverse side effects. This study was aimed at investigating whether the early initiation of corticosteroid-sparing therapy (CST) in BP patients results in better outcomes than late or no CST. METHOD: We retrospectively identified all BP patients referred to the tertiary center, of the Department of Dermatology and Venerology, Aarhus University Hospital, Denmark, from 2015 to 2021. Patients' demographics, comorbidities, treatment, remission of BP, length of admission, relapse, and 1-year mortality were recorded. All patients who received CST were dichotomised into two groups: initiated with CST <28 or >28 days. The groups were compared using t-tests. Additionally, all patients who received CST were compared with those who received systemic glucocorticoids alone. Our cohort was compared with that of a previous study (2006-2013) performed in our department. In 2015, we revised our BP treatment guidelines to include the early initiation of CST. RESULTS: On comparing the group of patients initiated with CST <28 versus >28 days, we found no significant differences in the complications or mortality between the groups (p = 0.63 and p=0.79, respectively). The <28 days group had a lower rate of relapse (p < 0.05). On comparing data from this study with those from the previous study, conducted before we revised our treatment guideline, we found a reduced initial dose of prednisolone and reduced admission time in this study. No significant differences were found between patients treated with CST and those treated with systemic glucocorticoids alone. CONCLUSION: The rate of complications and 1-year mortality did not differ significantly between the two subgroups in this study. The relapse rate was lower in the CST <28 days group than in the CST >28 days group. The initial dose of prednisolone and admission time were reduced in this study compared with those in the previous study performed before the implementation of a local treatment guideline recommending the early initiation of CST.

36. Eosinophils as potential biomarkers in respiratory viral infections.

Front Immunol

2023 Jul 6

Macchia I, La Sorsa V, Urbani F

37. Engineering cytokines for cancer immunotherapy: a systematic review.

Front Immunol

2023 Jul 6

Fu Y, Tang R, Zhao X.

38. Effect of antiviral and immunomodulatory treatment on a cytokine profile in patients with COVID-19.

Front Immunol

2023 Jul 6

Martonik D, Parfieniuk-Kowerda A, Starosz A

BACKGROUND: The severity of COVID-19 is associated with an elevated level of a variety of inflammatory mediators. Increasing evidence suggests that the Th17 response contributes to the severity of COVID-19 pneumonia, whereas Th22 response plays a regulatory role in SARS-CoV-2 infection. Two main types of available COVID-19 treatments are antivirals and immunomodulatory drugs; however, their effect on a cytokine profile is yet to be determined. METHODS: This study aim to analyse a cytokine profile in peripheral blood from patients with COVID-19 (n=44) undergoing antiviral or/and immunomodulatory treatment and healthy controls (n=20). Circulating CD4+ and CD8+ T cells and their intracellular expression of IL-17A and IL-22 were assessed by flow cytometry. RESULTS: Initial results showed an overexpression of IL-17F, IL-17A, CCL5/RANTES, GM-CSF, IL-4, IL-10, CXCL-10/IP-10 and IL-6 in COVID-19 patients compared to healthy controls. Treatment with remdesivir resulted in a significant decline in concentrations of IL-6, IL-10, IFN-alpha and CXCL10/IP-10. Immunomodulatory treatment contributed to a significant downregulation of IL-10, IFN-alpha, CXCL10/IP-10 and B7-H3 as well as upregulation of IL-22 and IL-1 beta. A combination of an antiviral and immunomodulatory treatment resulted in a significant decrease in IL-17F, IL-10, IFN-alpha, CXCL10/IP-10 and B7-H3 levels as well as an increase in IL-17A and IL-1 beta. We found significantly higher percentage of both CD4+ and CD8+ T cells producing IL-17A and CD4+ T cells producing IL-22 in patients with COVID-19. CONCLUSION: Administration of antiviral or/and immunomodulatory treatment resulted in a significant downregulation of pro-inflammatory cytokine expression and an upregulation of T cell absolute counts in most cases, thus showing effectiveness of treatment in COVID-19. SARS-CoV-2 infection induced cytokine overexpression in hospitalized patients with COVID-19 as well as lymphopenia, particularly a decrease in CD4+ and CD8+ T cell counts. Moreover, despite the reduced counts of CD4+ and CD8+ T cells, both subsets showed overactivation and increased expression of IL-17A and IL-22, thus targeting Th17 response might alleviate inflammatory response in severe disease.

39. TLR7/TLR8 activation and susceptibility genes synergize to breach gut barrier in a mouse model of lupus.

Front Immunol

2023 Jul 6

Ma L, Terrell M, Brown J

BACKGROUND: Mounting evidence suggests that increased gut permeability, or leaky gut, and the resulting translocation of pathobionts or their metabolites contributes to the pathogenesis of Systemic Lupus Erythematosus. However, the mechanisms underlying the induction of gut leakage remain unclear. In this study, we examined the effect of a treatment with a TLR7/8 agonist in the B6.Sle1.Sle2.Sle3 triple congenic (TC) mouse, a spontaneous mouse model of lupus without gut leakage. MATERIALS AND METHODS: Lupus-prone mice (TC), TC.Rag1-/- mice that lack B and T cells, and congenic B6 healthy controls were treated with R848. Gut barrier integrity was assessed by measuring FITC-dextran in the serum following oral gavage. Claudin-1 and PECAM1 expression as well as the extent of CD45+ immune cells, B220+ B cells, CD3+ T cells and CD11b+ myeloid cells were measured in the ileum by immunofluorescence. NKp46+ cells were measured in the ileum and colon by immunofluorescence. Immune cells in the ileum were also analyzed by flow cytometry. RESULTS: R848 decreased gut barrier integrity in TC but not in congenic control B6 mice. Immunofluorescence staining of the ileum showed a reduced expression of the tight junction protein Claudin-1, endothelial cell tight junction PECAM1, as well as an increased infiltration of immune cells, including B cells and CD11b+ cells, in R848-treated TC as compared to untreated control mice. However, NKp46+ cells which play critical role in maintaining gut barrier integrity, had a lower frequency in treated TC mice. Flow cytometry showed an increased frequency of plasma cells, dendritic cells and macrophages along with a decreased frequency of NK cells in R848 treated TC mice lamina propria. In addition, we showed that the R848 treatment did not induce gut leakage in TC.Rag1-/- mice that lack mature T and B cells. CONCLUSIONS: These results demonstrate that TLR7/8 activation induces a leaky gut in lupus-prone mice, which is mediated by adaptive immune responses. TLR7/8 activation is however not sufficient to breach gut barrier integrity in non-autoimmune mice.

40. Genetically predicted ankylosing spondylitis is causally associated with psoriasis.

Front Immunol

2023 Jul 6

Tian D, Zhou Y, Chen Y

41. The potential of activator protein 1 (AP-1) in cancer targeted therapy.

Front Immunol

2023 Jul 6

Song D, Lian Y, Zhang L.

42. Assessment of BoHV-4-based vector vaccine intranasally administered in a hamster challenge model of lung disease.

Front Immunol

2023 Jul 6

Park SC, Conti L, Franceschi V

43. Insight of a lipid metabolism prognostic model to identify immune landscape and potential target for retroperitoneal liposarcoma.

Front Immunol

2023 Jul 6

Wang Z, Tao P, Fan P

INTRODUCTION: The exploration of lipid metabolism dysregulation may provide novel perspectives for retroperitoneal liposarcoma (RPLS). In our study, we aimed to investigate potential targets and facilitate further understanding of immune landscape in RPLS, through lipid metabolism-associated genes (LMAGs) based prognostic model. METHODS: Gene expression profiles and corresponding clinical information of 234 cases were enrolled from two public databases and the largest retroperitoneal tumor research center of East China, including cohort-TCGA (n=58), cohort-GSE30929 (n=92), cohort-FD (n=50), cohort-scRNA-seq (n=4) and cohort-validation (n=30). Consensus clustering analysis was performed to identify lipid metabolism-associated molecular subtypes (LMSs). A prognostic risk model containing 13 LMAGs was established using LASSO algorithm and multivariate Cox analysis in cohort-TCGA. ESTIMATE, CIBERSORT, XCELL and MCP analyses were performed to visualize the immune landscape. WGCNA was used to identify three hub genes among the 13 model LMAGs, and preliminarily validated in both cohort-GSE30929 and cohort-FD. Moreover, TIMER was used to visualize the correlation between antigen-presenting cells and potential targets. Finally, single-cell RNA-sequencing (scRNA-seq) analysis of four RPLS and multiplexed immunohistochemistry (mIHC) were performed in cohort-validation to validate the discoveries of bioinformatics analysis. RESULTS: LMS1 and LMS2 were characterized as immune-infiltrated and -excluded tumors, with significant differences in molecular features and clinical prognosis, respectively. Elongation of very long chain fatty acids protein 2 (ELOVL2), the enzyme that catalyzed the elongation of long chain fatty acids, involved in the maintenance of lipid metabolism and cellular homeostasis in normal cells, was identified and negatively correlated with antigen-presenting cells and identified as a potential target in RPLS. Furthermore, ELOVL2 was enriched in LMS2 with significantly lower immunoscore and unfavorable prognosis. Finally, a high-resolution dissection through scRNA-seq was performed in four RPLS, revealing the entire tumor ecosystem and validated previous findings. DISCUSSION: The LMS subgroups and risk model based on LMAGs proposed in our study were both promising prognostic classifications for RPLS. ELOVL2 is a potential target linking lipid metabolism to immune regulations against RPLS, specifically for patients with LMS2 tumors.

44. A new method for oral cancer biomarkers detection with a non-invasive cyto-salivary sampling and rapid-highly sensitive ELISA immunoassay: a pilot study in humans.

Front Immunol

2023 Jul 6

Rebaudi F, De Rosa A, Greppi M

INTRODUCTION: Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of oral malignancies and has a 5-year mortality rate close to 50%. A consistent part (70%) of all oral cancers is diagnosed at an advanced stage since available screening techniques are ineffective. Therefore, it would be urgent to improve them. The diagnostic gold standard is tissue biopsy with histological and immunohistochemical assessment. This method presents some limitations. Biopsy is invasive and the histopathological evaluation is semi-quantitative, and the absolute abundance of the target cannot be reliably determined. In addition, tissue is highly processed and may lead to loss of information of the natural state. The search for classical and new clinical biomarkers on fragments of tissue/cells collected with a cytobrush is a highly hopeful technique for early detection and diagnosis of OSCC, because of its non-invasive sampling and easy collection method. METHODS: Here we analyzed cytobrush biopsies samples collected from the oral cavity of 15 patients with already diagnosed OSCC by applying an innovative high-sensitivity ELISA technique, in order to verify if this approach may provide useful information for detection, diagnosis, and prognosis of OSCC. To this end, we selected six biomarkers, already used in clinical practice for the diagnosis of OSCC (EGFR, Ki67, p53) or selected based on recent scientific and clinical data which indicate their presence or over-expression in cells undergoing transformation and their role as possible molecular targets in immunecheckpoints blockade therapies (PD-L1, HLA-E, B7-H6). RESULTS: The selected tumor biomarkers were highly expressed in the tumor core, while were virtually negative in healthy tissue collected from the same patients. These differences were highly statistically significant and consistent with those obtained using the gold standard test clearly indicating that the proposed approach, i.e. analysis of biomarkers by a custom ELISA technique, is strongly reliable. DISCUSSION: These preliminary data suggest that this non-invasive rapid phenotyping technique could be useful as a screening tool for phenotyping oral lesions and support clinical practice by precise indications on the characteristics of the lesion, also with a view to the application of new anti-tumor treatments, such as immunotherapy, aimed at OSCC patients.

45. Modulation of innate lymphoid cells by enteric bacterial pathogens.

Front Immunol

2023 Jul 6

Sah P, Zenewicz LA.

46. E protein binding at the Tcra enhancer promotes Tcra repertoire diversity.

Front Immunol

2023 Jul 6

Mihai A, Roy S, Krangel MS

47. Sequence variants contributing to dysregulated inflammatory responses across keratoconic cone surface in adolescent patients with keratoconus.

Front Immunol

2023 Jul 6

Jaskiewicz K, Maleszka-Kurpiel M, Kabza M

48. Identification and characterisation of anti-IL-13 inhibitory single domain antibodies provides new insights into receptor selectivity and attractive opportunities for drug discovery.

Front Immunol

2023 Jul 6

Walker K, Baravalle R, Holyfield R

49. β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in Braf(V600E)-driven thyroid cancer cells.

Front Immunol

2023 Jul 6

Zou M, Al-Yahya S, Al-Alwan M

50. An immune-related gene prognostic index for predicting prognosis in patients with colorectal cancer.

Front Immunol

2023 Jul 6

Li C, Wirth U, Schardey J

BACKGROUND: Colorectal cancer (CRC) is one of the most common solid malignant burdens worldwide. Cancer immunology and immunotherapy have become fundamental areas in CRC research and treatment. Currently, the method of generating Immune-Related Gene Prognostic Indices (IRGPIs) has been found to predict patient prognosis as an immune-related prognostic biomarker in a variety of tumors. However, their role in patients with CRC remains mostly unknown. Therefore, we aimed to establish an IRGPI for prognosis evaluation in CRC. METHODS: RNA-sequencing data and clinical information of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases as training and validation sets, respectively. Immune-related gene data was obtained from the ImmPort and InnateDB databases. The weighted gene co-expression network analysis (WGCNA) was used to identify hub immune-related genes. An IRGPI was then constructed using Cox regression methods. Based on the median risk score of IRGPI, patients could be divided into high-risk and low-risk groups. To further investigate the immunologic differences, Gene set variation analysis (GSVA) studies were conducted. In addition, immune cell infiltration and related functional analysis were used to identify the differential immune cell subsets and related functional pathways. RESULTS: We identified 49 immune-related genes associated with the prognosis of CRC, 17 of which were selected for an IRGPI. The IRGPI model significantly differentiates the survival rates of CRC patients in the different groups. The IRGPI as an independent prognostic factor significantly correlates with clinico-pathological factors such as age and tumor stage. Furthermore, we developed a nomogram to improve the clinical utility of the IRGPI score. Immuno-correlation analysis in different IRGPI groups revealed distinct immune cell infiltration (CD4+ T cells resting memory) and associated pathways (macrophages, Type I IFNs responses, iDCs.), providing new insights into the tumor microenvironment. At last, drug sensitivity analysis revealed that the high-risk IRGPI group was sensitive to 11 and resistant to 15 drugs. CONCLUSION: Our study established a promising immune-related risk model for predicting survival in CRC patients. This could help to better understand the correlation between immunity and the prognosis of CRC providing a new perspective for personalized treatment of CRC.

51. RIG-I agonist SLR10 promotes macrophage M1 polarization during influenza virus infection.

Front Immunol

2023 Jul 5

Wu W, Zhang W, Alexandar JS

RATIONALE: A family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection. METHODS: Mice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV. RESULTS: SLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. In vitro testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization. CONCLUSIONS: Our data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.

52. Vimentin: from a cytoskeletal protein to a critical modulator of immune response and a target for infection.

Front Immunol

2023 Jul 5

Arrindell J, Desnues B.

53. Multi-omics analyses of glucose metabolic reprogramming in colorectal cancer.

Front Immunol

2023 Jul 5

Huang M, Wu Y, Cheng L

54. B cell abnormalities and autoantibody production in patients with partial RAG deficiency.

Front Immunol

2023 Jul 5

Min Q, Csomos K, Li Y

55. The role of neutrophils in chorioamnionitis.

Front Immunol

2023 Jul 5

Zhang C, Cao J, Xu M

56. A unique maternal and placental galectin signature upon SARS-CoV-2 infection suggests galectin-1 as a key alarmin at the maternal-fetal interface.

Front Immunol

2023 Jul 5

Zhao F, Tallarek AC, Wang Y

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic imposed a risk of infection and disease in pregnant women and neonates. Successful pregnancy requires a fine-tuned regulation of the maternal immune system to accommodate the growing fetus and to protect the mother from infection. Galectins, a family of β-galactoside-binding proteins, modulate immune and inflammatory processes and have been recognized as critical factors in reproductive orchestration, including maternal immune adaptation in pregnancy. Pregnancy-specific glycoprotein 1 (PSG1) is a recently identified gal-1 ligand at the maternal-fetal interface, which may facilitate a successful pregnancy. Several studies suggest that galectins are involved in the immune response in SARS-CoV-2-infected patients. However, the galectins and PSG1 signature upon SARS-CoV-2 infection and vaccination during pregnancy remain unclear. In the present study, we examined the maternal circulating levels of galectins (gal-1, gal-3, gal-7, and gal-9) and PSG1 in pregnant women infected with SARS-CoV-2 before vaccination or uninfected women who were vaccinated against SARS-CoV-2 and correlated their expression with different pregnancy parameters. SARS-CoV-2 infection or vaccination during pregnancy provoked an increase in maternal gal-1 circulating levels. On the other hand, levels of PSG1 were only augmented upon SARS-CoV-2 infection. A healthy pregnancy is associated with a positive correlation between gal-1 concentrations and gal-3 or gal-9; however, no correlation was observed between these lectins during SARS-CoV-2 infection. Transcriptome analysis of the placenta showed that gal-1, gal-3, and several PSG and glycoenzymes responsible for the synthesis of gal-1-binding glycotopes (such as linkage-specific N-acetyl-glucosaminyltransferases (MGATs)) are upregulated in pregnant women infected with SARS-CoV-2. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies the SARS-CoV-2 infection and vaccination in pregnancy, and they highlight a potentially significant role for gal-1 as a key pregnancy protective alarmin during virus infection.

57. Insights into immuno-oncology drug development landscape with focus on bone metastasis.

Front Immunol

2023 Jul 5

Kähkönen TE, Halleen JM, MacRitchie G

58. Interplay between RNA interference and transposable elements in mammals.

Front Immunol

2023 Jul 5

Cornec A, Poirier EZ.

59. A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies.

Front Immunol

2023 Jul 5

Sentis G, Loukogiannaki C, Malissovas N

60. Growth hormone remodels the 3D-structure of the mitochondria of inflammatory macrophages and promotes metabolic reprogramming.

Front Immunol

2023 Jul 5

Soler Palacios B, Villares R, Lucas P

61. T cell receptor β repertoires in patients with COVID-19 reveal disease severity signatures.

Front Immunol

2023 Jul 5

Xu J, Li XX, Yuan N

62. Potential value of neuroimmunotherapy for COVID-19: efficacies and mechanisms of vagus nerve stimulation, electroacupuncture, and cholinergic drugs.

Front Immunol

2023 Jul 5

Yu X, Kong Q.

63. Prognostic value of complement serum C3 level and glomerular C3 deposits in anti-glomerular basement membrane disease.

Front Immunol

2023 Jul 5

Caillard P, Vigneau C, Halimi JM

BACKGROUND AND OBJECTIVES: Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease. METHODS: We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival. RESULTS: Of the 150 patients included, 89 (65%) were men. The median [interquartile range (IQR)] age was 45 [26-64]. At diagnosis, kidney involvement was characterized by a median [IQR] peak serum creatinine (SCr) level of 578 [298-977] µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% [25-76], vs. 91% [78-100] in the C3- group; p=0.01), with a hazard ratio [95% confidence interval] of 5.71 [1.13-28.85] (p=0.04, after adjusting for SCr). CONCLUSION: In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.

64. Uncovering the potential role of oxidative stress in the development of periodontitis and establishing a stable diagnostic model via combining single-cell and machine learning analysis.

Front Immunol

2023 Jul 5

Song G, Peng G, Zhang J

BACKGROUND: The primary pathogenic cause of tooth loss in adults is periodontitis, although few reliable diagnostic methods are available in the early stages. One pathological factor that defines periodontitis pathology has previously been believed to be the equilibrium between inflammatory defense mechanisms and oxidative stress. Therefore, it is necessary to construct a model of oxidative stress-related periodontitis diagnostic markers through machine learning and bioinformatic analysis. METHODS: We used LASSO, SVM-RFE, and Random Forest techniques to screen for periodontitis-related oxidative stress variables and construct a diagnostic model by logistic regression, followed by a biological approach to build a Protein-Protein interaction network (PPI) based on modelled genes while using modelled genes. Unsupervised clustering analysis was performed to screen for oxidative stress subtypes of periodontitis. we used WGCNA to explore the pathways correlated with oxidative stress in periodontitis patients. Networks. Finally, we used single-cell data to screen the cellular subpopulations with the highest correlation by scoring oxidative stress genes and performed a proposed temporal analysis of the subpopulations. RESULTS: We discovered 3 periodontitis-associated genes (CASP3, IL-1β, and TXN). A characteristic line graph based on these genes can be helpful for patients. The primary hub gene screened by the PPI was constructed, where immune-related and cellular metabolism-related pathways were significantly enriched. Consistent clustering analysis found two oxidative stress categories, with the C2 subtype showing higher immune cell infiltration and immune function ratings. Therefore, we hypothesized that the high expression of oxidative stress genes was correlated with the formation of the immune environment in patients with periodontitis. Using the WGCNA approach, we examined the co-expressed gene modules related to the various subtypes of oxidative stress. Finally, we selected monocytes for mimetic time series analysis and analyzed the expression changes of oxidative stress genes with the mimetic time series axis, in which the expression of JUN, TXN, and IL-1β differed with the change of cell status. CONCLUSION: This study identifies a diagnostic model of 3-OSRGs from which patients can benefit and explores the importance of oxidative stress genes in building an immune environment in patients with periodontitis.

65. CD4(+) T-cell-dependent differentiation of CD23(+) follicular B cells contributes to the pulmonary pathology in a primary Sjögren's syndrome mouse model.

Front Immunol

2023 Jul 5

Sato-Fukuba M, Arakaki R, Ushio A

66. A modified perioperative regimen for deceased donor kidney transplantation in presensitized recipients without prior desensitization therapy.

Front Immunol

2023 Jul 5

Guo Z, Zhao D, Sa R

67. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review.

Front Immunol

2023 Jul 5

Xu J, Yu L, Liu F

68. An oncolytic adenovirus coding for a variant interleukin 2 cytokine improves response to chemotherapy through enhancement of effector lymphocyte cytotoxicity, fibroblast compartment modulation and mitotic slippage.

Front Immunol

2023 Jul 5

Pakola S, Quixabeira DCA, Kudling TV

Pancreatic ductal adenocarcinoma (PDAC) is a highly treatment-resistant cancer. Currently, the only curative treatment for PDAC is surgery, but most patients are diagnosed with metastatic disease and thus outside the scope of surgery. The majority of metastatic patients receive chemotherapy, but responses are limited. New therapeutics are thus urgently needed for PDAC. One major limitation in treating PDAC has been the highly immunosuppressive tumor microenvironment (TME) which inhibits anti-cancer immune responses. We have constructed an oncolytic adenovirus coding for a variant the interleukin 2 molecule, Ad5/3-E2F-d24-vIL2 (also known as TILT-452, and "vIL-2 virus"), with preferential binding to IL-2 receptors on the surface of effector lymphocytes over T regulatory cells (T regs). In the present study this virus was evaluated in combination with nab-paclitaxel and gemcitabine chemotherapy in Panc02 mouse model. Ad5/3-E2F-d24-vIL2 showed marked PDAC cell killing in vitro, alongside induction of mitotic slippage and immunogenic cell death in PDAC cell lines, when combined with chemotherapy. Increased survival was seen in vivo with 80% of animals surviving long term, when compared to chemotherapy alone. Moreover, combination therapy mediated enhanced tumor growth control, without observable toxicities in internal organs or external features. Survival and tumor control benefits were associated with activation of tumor infiltrating immune cells, downregulation of inhibitory signals, change in fibroblast populations in the tumors and changes in intratumoral cytokines, with increased chemokine amounts (CCL2, CCL3, CCL4) and anti-tumor cytokines (IFN-γ and TNFα). Furthermore, vIL-2 virus in combination with chemotherapy efficiently induced tumor protection upon rechallenge, that was extended to a previously non-encountered cancer cell line. In conclusion, Ad5/3-E2F-d24-vIL2 is a promising immunotherapy candidate when combined with nab-paclitaxel and gemcitabine.

69. A novel murine model of pyoderma gangrenosum reveals that inflammatory skin-gut crosstalk is mediated by IL-1β-primed neutrophils.

Front Immunol

2023 Jul 5

Jatana S, Ponti AK, Johnson EE

70. Exploration of prognosis and immunometabolism landscapes in ER+ breast cancer based on a novel lipid metabolism-related signature.

Front Immunol

2023 Jul 4

Shen L, Huang H, Li J

INTRODUCTION: Lipid metabolic reprogramming is gaining attention as a hallmark of cancers. Recent mounting evidence indicates that the malignant behavior of breast cancer (BC) is closely related to lipid metabolism. Here, we focus on the estrogen receptor-positive (ER+) subtype, the most common subgroup of BC, to explore immunometabolism landscapes and prognostic significance according to lipid metabolism-related genes (LMRGs). METHODS: Samples from The Cancer Genome Atlas (TCGA) database were used as training cohort, and samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Gene Expression Omnibus (GEO) datasets and our cohort were applied for external validation. The survival-related LMRG molecular pattern and signature were constructed by unsupervised consensus clustering and least absolute shrinkage and selection operator (LASSO) analysis. A lipid metabolism-related clinicopathologic nomogram was established. Gene enrichment and pathway analysis were performed to explore the underlying mechanism. Immune landscapes, immunotherapy and chemotherapy response were further explored. Moreover, the relationship between gene expression and clinicopathological features was assessed by immunohistochemistry. RESULTS: Two LMRG molecular patterns were identified and associated with distinct prognoses and immune cell infiltration. Next, a prognostic signature based on nine survival-related LMRGs was established and validated. The signature was confirmed to be an independent prognostic factor and an optimal nomogram incorporating age and T stage (AUC of 5-year overall survival: 0.778). Pathway enrichment analysis revealed differences in immune activities, lipid biosynthesis and drug metabolism by comparing groups with low- and high-risk scores. Further exploration verified different immune microenvironment profiles, immune checkpoint expression, and sensitivity to immunotherapy and chemotherapy between the two groups. Finally, arachidonate 15-lipoxygenase (ALOX15) was selected as the most prominent differentially expressed gene between the two groups. Its expression was positively related to larger tumor size, more advanced tumor stage and vascular invasion in our cohort (n = 149). DISCUSSION: This is the first lipid metabolism-based signature with value for prognosis prediction and immunotherapy or chemotherapy guidance for ER+ BC.

71. Macrophage death in atherosclerosis: potential role in calcification.

Front Immunol

2023 Jul 4

Neels JG, Gollentz C, Chinetti G.

72. Extracellular vesicles in renal cell carcinoma: challenges and opportunities coexist.

Front Immunol

2023 Jul 4

Lu Y, Zhang M, Zhou J

73. Low cross reactivity between wild type and deamidated AAV can lead to false negative results in immune monitoring T-cell assays.

Front Immunol

2023 Jul 4

Bing SJ, Warrington S, Mazor R.

74. Case Report: Immunotherapy for low-grade myofibroblastic sarcoma of the pharynx.

Front Immunol

2023 Jul 4

Sun B, Luo Z, Liu P

75. Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant.

Front Immunol

2023 Jul 4

Cao XY, Zhang JP, Zhao YL

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. METHODS: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. RESULTS: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). CONCLUSIONS: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

76. The role of macrophage ion channels in the progression of atherosclerosis.

Front Immunol

2023 Jul 31

Wu X, Singla S, Liu JJ

77. The interplay of oxidative stress and immune dysfunction in Hashimoto's thyroiditis and polycystic ovary syndrome: a comprehensive review.

Front Immunol

2023 Jul 31

Batóg G, Dołoto A, Bąk E

78. Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma.

Front Immunol

2023 Jul 31

Patra-Kneuer M, Chang G, Xu W

79. Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Front Immunol

2023 Jul 31

Koudriavtseva T, Lorenzano S, Cellerino M

OBJECTIVES: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. METHODS: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. RESULTS: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. CONCLUSION: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04380220.

80. Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis.

Front Immunol

2023 Jul 31

Chen Y, Bian H, Lv J

81. Ferroptosis of CD163(+) tissue-infiltrating macrophages and CD10(+) PC(+) epithelial cells in lupus nephritis.

Front Immunol

2023 Jul 31

Cheng Q, Mou L, Su W

BACKGROUND: Dysregulation of cell death and defective clearance of dying cells are closely related to the pathogenesis of lupus nephritis (LN). However, the contribution of a recently discovered form of programmed cell death (PCD) called ferroptosis to LN has not been explored in detail. The purpose of this study was to investigate the role of ferroptosis and its associated metabolic pathways in the pathogenesis of LN. METHODS: The composite gene expression scores were calculated by averaging the z-scored transformed log2 expressed genes within each form of PCD and pathway. Immunohistochemistry and immunofluorescence assays were used to verify the bioinformatics results. RESULTS: We determined that ferroptosis is prominently and specifically elevated in the glomerular compartment of LN patients compared to other forms of PCD and kidney disease. This finding was then verified by immunohistochemical staining of 4-HNE (a key indicator for ferroptosis) expression in our own cohort (P < 0.0001). Intercorrelation networks were observed between 4-HNE and blood urea nitrogen, SLE disease activity index, serum creatinine, and complement 4, and negatively correlated with glomerular filtration rate in our own LN cohort (P < 0.05). Furthermore, enhanced iron metabolism and reduced fatty acid synthesis may be the most important factors for ferroptosis within the glomerulus. Through analysis of a single cell sequencing dataset and verification of immunohistochemical and immunofluorescence staining, aberrantly activated lipid peroxidation in CD163+ macrophages and CD10+ PC+ (pyruvate carboxylase) epithelial cells indicated that they may be undergoing ferroptosis in the glomerular compartment. CONCLUSIONS: Two dysregulated genes, CD163 and PC, were identified and verified that were significantly associated with lipid peroxidation. Targeting ferroptosis in CD163+ macrophages and CD10+ PC+ epithelial cells may provide novel therapeutic approaches in LN.

82. Identification of novel clusters of co-expressing cytokines in a diagnostic cytokine multiplex test.

Front Immunol

2023 Jul 31

Polley DJ, Latham P, Choi MY

83. IL-6 and IL-27 play both distinct and redundant roles in regulating CD4 T-cell responses during chronic viral infection.

Front Immunol

2023 Jul 31

Harker JA, Greene TT, Barnett BE

84. Antibody responses to an inactivated SARS-CoV-2 vaccine in individuals aged from 50 to 102 years.

Front Immunol

2023 Jul 31

Zhu HH, Sun GQ, Wu JY

85. Identification of novel gene signature for lung adenocarcinoma by machine learning to predict immunotherapy and prognosis.

Front Immunol

2023 Jul 31

Shu J, Jiang J, Zhao G.

BACKGROUND: Lung adenocarcinoma (LUAD) as a frequent type of lung cancer has a 5-year overall survival rate of lower than 20% among patients with advanced lung cancer. This study aims to construct a risk model to guide immunotherapy in LUAD patients effectively. MATERIALS AND METHODS: LUAD Bulk RNA-seq data for the construction of a model, single-cell RNA sequencing (scRNA-seq) data (GSE203360) for cell cluster analysis, and microarray data (GSE31210) for validation were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We used the Seurat R package to filter and process scRNA-seq data. Sample clustering was performed in the ConsensusClusterPlus R package. Differentially expressed genes (DEGs) between two groups were mined by the Limma R package. MCP-counter, CIBERSORT, ssGSEA, and ESTIMATE were employed to evaluate immune characteristics. Stepwise multivariate analysis, Univariate Cox analysis, and Lasso regression analysis were conducted to identify key prognostic genes and were used to construct the risk model. Key prognostic gene expressions were explored by RT-qPCR and Western blot assay. RESULTS: A total of 27 immune cell marker genes associated with prognosis were identified for subtyping LUAD samples into clusters C3, C2, and C1. C1 had the longest overall survival and highest immune infiltration among them, followed by C2 and C3. Oncogenic pathways such as VEGF, EFGR, and MAPK were more activated in C3 compared to the other two clusters. Based on the DEGs among clusters, we confirmed seven key prognostic genes including CPA3, S100P, PTTG1, LOXL2, MELTF, PKP2, and TMPRSS11E. Two risk groups defined by the seven-gene risk model presented distinct responses to immunotherapy and chemotherapy, immune infiltration, and prognosis. The mRNA and protein level of CPA3 was decreased, while the remaining six gene levels were increased in clinical tumor tissues. CONCLUSION: Immune cell markers are effective in clustering LUAD samples into different subtypes, and they play important roles in regulating the immune microenvironment and cancer development. In addition, the seven-gene risk model may serve as a guide for assisting in personalized treatment in LUAD patients.

86. Effects of Atrazine exposure on human bone marrow-derived mesenchymal stromal cells assessed by combinatorial assay matrix.

Front Immunol

2023 Jul 31

Uwazie CC, Pirlot BM, Faircloth TU

INTRODUCTION: Mesenchymal Stromal/Stem cells (MSCs) are an essential component of the regenerative and immunoregulatory stem cell compartment of the human body and thus of major importance in human physiology. The MSCs elicit their beneficial properties through a multitude of complementary mechanisms, which makes it challenging to assess their phenotype and function in environmental toxicity screening. We here employed the novel combinatorial assays matrix approach/technology to profile the MSC response to the herbicide Atrazine, which is a common environmental xenobiotic, that is in widespread agricultural use in the US and other countries, but banned in the EU. Our here presented approach is representative for screening the impact of environmental xenobiotics and toxins on MSCs as an essential representative component of human physiology and well-being. METHODS: We here employed the combinatorial assay matrix approach, including a panel of well standardized assays, such as flow cytometry, multiplex secretome analysis, and metabolic assays, to define the phenotype and functionality of human-donor-derived primary MSCs exposed to the representative xenobiotic Atrazine. This assay matrix approach is now also endorsed for characterization of cell therapies by leading regulatory agencies, such as FDA and EMA. RESULTS: Our results show that the exposure to Atrazine modulates the metabolic activity, size, and granularity of MSCs in a dose and time dependent manner. Intriguingly, Atrazine exposure leads to a broad modulation of the MSCs secretome (both upregulation and downmodulation of certain factors) with the identification of Interleukin-8 as the topmost upregulated representative secretory molecule. Interestingly, Atrazine attenuates IFNγ-induced upregulation of MHC-class-II, but not MHC-class-I, and early phosphorylation signals on MSCs. Furthermore, Atrazine exposure attenuates IFNγ responsive secretome of MSCs. Mechanistic knockdown analysis identified that the Atrazine-induced effector molecule Interleukin-8 affects only certain but not all the related angiogenic secretome of MSCs. DISCUSSION: The here described Combinatorial Assay Matrix Technology identified that Atrazine affects both the innate/resting and cytokine-induced/stimulated assay matrix functionality of human MSCs, as identified through the modulation of selective, but not all effector molecules, thus vouching for the great usefulness of this approach to study the impact of xenobiotics on this important human cellular subset involved in the regenerative healing responses in humans.

87. Crosstalk between hypoxic cellular micro-environment and the immune system: a potential therapeutic target for infectious diseases.

Front Immunol

2023 Jul 31

Akinsulie OC, Shahzad S, Ogunleye SC

88. Transitioning from pediatric to adult healthcare with an inborn error of immunity: a qualitative study of the lived experience of youths and their families.

Front Immunol

2023 Jul 31

Ouimet F, Fortin J, Bogossian A

INTRODUCTION: Transition from pediatric to adult healthcare is a multifaceted and consequential process with important health implications for youth. Although research on transition has grown significantly, research on transition for patients living with an inborn error of immunity (IEI) is scarce. We undertook a qualitative study to better understand the perspectives of youths and parents in an outpatient immunology clinic. METHDOS: Semi-structured interviews were conducted with 9 youths, 6 parents and 5 clinicians, all recruited from the same clinic. All youths recently transferred to adult care with or without an established diagnosis of IEI. Interviews were transcribed verbatim and thematic analysis was conducted. Two sets of themes were generated. The first set captured the positive and negative aspects experienced during transition, as well as recommendations to facilitate the process. The second set focused on key topics discussed in the interviews that were merged into overarching themes. RESULTS: Perspectives of participants were clustered into 6 overarching themes: (1) lack of knowledge about IEIs; (2) scattered transitions; (3) changing healthcare teams; (4) approaching an unknown environment; (5) transitioning to adulthood; (6) assuming responsibility for the management of the condition. Overall, the challenges encountered with respect to these themes had profound clinical and humanistic implications for patients such as generating significant distress. DISCUSSION: We discuss the unique challenges of the youths in our study in comparison to common problems reported by youths with chronic illness in the broader transition literature (for example: the change of healthcare team, the lack of information about the transition process and navigating the adult care system, growth towards self-management and the co-occurring developmental transition to adulthood). There is an urgency to attend to the specific problems created by the rarity of IEIs and related lack of knowledge about them as well as the need for multidisciplinary cross-clinic care during transition and beyond.

89. Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha.

Front Immunol

2023 Jul 31

Sailliet N, Mai HL, Dupuy A

90. Gene loss and co-option of toll-like receptors facilitate paternal immunological adaptation in the brood pouch of pregnant male seahorses.

Front Immunol

2023 Jul 31

Zhang B, Xiao W, Qin G

91. Machine learning-based on cytotoxic T lymphocyte evasion gene develops a novel signature to predict prognosis and immunotherapy responses for kidney renal clear cell carcinoma patients.

Front Immunol

2023 Jul 31

Chen M, Nie Z, Huang D

BACKGROUND: Immunotherapy resistance has become a difficult point in treating kidney renal clear cell carcinoma (KIRC) patients, mainly because of immune evasion. Currently, there is no effective signature to predict immunotherapy. Therefore, we use machine learning algorithms to construct a signature based on cytotoxic T lymphocyte evasion genes (CTLEGs) to predict the immunotherapy responses of patients, so as to screen patients effective for immunotherapy. METHODS: In public data sets and our in-house cohort, we used 10 machine learning algorithms to screen the optimal model with 89 combinations under the cross-validation framework, and 101 published signatures were collected. The relationship between the CTLEG signature (CTLEGS) and clinical variables was analyzed. We analyzed the role of CTLES in other types of cancer by pan-cancer analysis. The immune cell infiltration and biological characteristics were evaluated. Moreover, the response to immunotherapy and drug sensitivity of different risk groups were investigated. The key gene closely related to the signature was identified by WGCNA. We also conducted cell functional experiments and clinical tissue validation of key gene. RESULTS: In public data sets and our in-house cohort, the CTLEGS shows good prediction performance. The CTLEGS can be regard as an independent risk factor for KIRC. Compared with 101 published models, our signature shows considerable superiority. The high-risk group has abundant infiltration of immunosuppressive cells and high expression of T cell depletion markers, which are characterized by immunosuppressive phenotype, minimal benefit from immunotherapy, and resistance to sunitinib and sorafenib. The CTLEGS was also strongly correlated with immunity in pan-cancer. Immunohistochemistry verified that T cell depletion marker LAG3 is highly expressed in high-risk groups in the clinical in-house cohort. The key CTLEG STAT2 can promote the proliferation, migration and invasion of KIRC cell. CONCLUSIONS: CTLEGS can accurately predict the prognosis of patients and their response to immunotherapy. It can provide guidance for the precise treatment of KIRC and help clinicians identify patients who may benefit from immunotherapy.

92. Macrophage targeted polymeric curcumin nanoparticles limit intracellular survival of Mycobacterium tuberculosis through induction of autophagy and augment anti-TB activity of isoniazid in RAW 264.7 macrophages.

Front Immunol

2023 Jul 31

Gupta PK, Jahagirdar P, Tripathi D

Rapid emergence of antibiotic resistance in tuberculosis has left us with limited resources to treat and manage multi drug resistant (MDR) cases of tuberculosis, prompting the development of novel therapeutics. Mycobacterium tuberculosis (MTB) perturbs the host protective pathways for its survival, therefore host directed therapeutic (HDT) interventions offer an attractive alternative strategy. Curcumin (CMN), the principle curcuminoid from Curcuma longa is known to have anti-TB activity against MDR strains of MTB in macrophages. We discovered that treatment of CMN induced autophagy in uninfected and MTB infected macrophages which was evident by conversion of LC3-I to LC3-II and degradation of p62. Inhibition of autophagy by a pharmacological inhibitor 3-MA resulted in significant inhibition of intracellular killing activity of CMN, suggesting the involvement of autophagy in intracellular clearance of MTB. Moreover, annexin v-FITC/PI staining data suggested induction of apoptosis in uninfected and MTB infected macrophages post CMN treatment. This finding was further corroborated by up-regulated expression of pro-apoptotic proteins, Bax, cleaved caspase-3 and PARP and diminished expression of anti-apoptotic protein Bcl-2 as evaluated by immunoblotting. Using GFP-MTB H37Rv and Lysotracker Red staining we demonstrated co-localization of GFP-MTB H37Rv containing phagosome to lysosome after CMN treatment, indicating enhanced phagosome lysosome fusion. Due to poor bioavailability of CMN, its clinical use is limited, therefore to overcome this issue, CMN was encapsulated in Poly(lactic-co-glycolic) acid (PLGA) shell, resulting in polymeric CMN nano particles (ISCurNP). Flow cytometric evaluation suggested >99% uptake of ISCurNP after 3h of treatment. In BALB/c mice, oral dose of ISCurNP resulted in 6.7-fold increase in the bioavailability compared to free CMN. Moreover, ISCurNP treatment resulted in significant decrease in the intracellular survival of MTB H37Rv through induction of autophagy. Adjunct action of ISCurNP and CMN in combination with isoniazid (INH) revealed >99% decrease in intracellular survival of MTB in macrophage as compared to ISCurNP, CMN or INH alone. In conclusion, our findings suggest the role of ISCurNP as novel host directed formulation to combat both sensitive and MDR strains of MTB by induction of autophagy.

93. Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Front Immunol

2023 Jul 31

Greve P, Beishuizen A, Hagleitner M

94. Transarterial chemoembolization combined with molecularly targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma: a retrospective cohort study.

Front Immunol

2023 Jul 31

Jiang N, Zhong B, Huang J

PURPOSE: To retrospectively evaluate and compare treatment effectiveness and safety between transarterial chemoembolization (TACE) combined with molecularly targeted agents plus immune checkpoint inhibitors (TACE+T+I) and TACE combined with molecularly targeted agents (TACE+T) for unresectable hepatocellular carcinoma (uHCC). METHODS: We retrospectively analyzed the data of patients with unresectable HCC from January 2018 to June 2022. The patients were screened based on the inclusion criteria and were divided into the triple combination group (TACE+T+I) and the double combination group (TACE+T). The primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). The secondary outcomes were objective response rate (ORR) and disease control rate (DCR). Risk factors associated with PFS and OS were determined by Cox regression analysis. RESULTS: A total of 87 patients were enrolled in this study, including 42 patients in the TACE+T+I group and 45 patients in the TACE+T group. Over a median follow-up of 29.00 and 26.70 months, patients who received TACE+T+I therapy achieved a significantly longer median OS (24.00 vs. 21.40 months, p = 0.007) and median PFS (9.70 vs. 7.00 months, p = 0.017); no grade 4 AEs or treatment-related death occurred in the two groups. Grade 3 AEs attributed to systemic agents in the two groups showed no significant difference (19.0% vs. 15.6%, p = 0.667). Patients in the TACE+T+I group demonstrated better tumor response when compared with patients in the TACE+T group, with an ORR of 52.4% vs. 17.8% (p = 0.001). No significant difference was observed in DCR between the two groups (83.3% vs. 77.8%, p = 0.514). Cox regression analysis showed that only the treatment method was an independent factor of OS, and both age and treatment method were independent factors related to PFS. CONCLUSION: Compared with TACE plus molecularly targeted agents (TACE+T), the triple therapy (TACE+T+I) could improve survival and tumor response in unresectable HCC with manageable toxicities.

95. Efficacy and safety of pembrolizumab with preoperative neoadjuvant chemotherapy in patients with resectable locally advanced head and neck squamous cell carcinomas.

Front Immunol

2023 Jul 31

Wang K, Gui L, Lu H

96. Vaccination with an in vitro culture attenuated Babesia bovis strain safely protects highly susceptible adult cattle against acute bovine babesiosis.

Front Immunol

2023 Jul 31

Bastos RG, Capelli-Peixoto J, Laughery JM

INTRODUCTION: Live in vivo attenuated Babesia bovis vaccines produced by sequential passages in splenectomized calves have historically been used to control acute bovine babesiosis in endemic areas worldwide. However, several constraints prevent the widespread use of these vaccines, including the need for several splenectomized calves to produce vaccine batches, and potential inconsistent parasite attenuation, which contraindicates their use for highly Babesia-susceptible adult cattle. Thus, the use of vaccines based on well-defined in vitro culture attenuated B. bovis strains emerges as a more sustainable and efficient alternative. Previous work demonstrated that the culture attenuated strain Att-S74-T3Bo is non-tick transmissible and able to safely protect calves against needle challenge with a B. bovis virulent strain. METHODS AND RESULTS: Herein we evaluated safety and efficacy of Att-S74-T3Bo in preventing acute babesiosis in adult (>1.5 year of age) cattle. Results demonstrated that Att-S74-T3Bo vaccination of adult animals (n=5) induced self-limiting signs of acute infection and protected the vaccinated animals against challenge with the homologous virulent B. bovis strain Vir-S74-T3Bo. Att-S74-T3Bo-vaccinated adult cattle developed significant (P<0.05) monocytosis, with concomitant neutropenia and CD4+ leukopenia, in peripheral blood early after vaccination. Also, vaccinated animals developed a specific signature of pro- and anti-inflammatory cytokine expression in peripheral blood and significant levels of IgM, total IgG, IgG1, and IgG2 against the B. bovis immunodominant antigen RAP-1 CT. Strikingly, none of the vaccinated animals showed any signs of acute babesiosis after challenge with Vir-S74-T3Bo. In contrast, control adult cattle (n=5) showed pathognomonic symptoms of acute babesiosis, and significant decrease (P<0.05) in lymphocytes, monocytes, and neutrophils, starting on day 7 post-challenge. All control animals developed severe acute disease and were euthanized on days 10 through 12 days post-challenge. DISCUSSION AND CONCLUSION: Evidence from this study indicates that Att-S74-T3Bo safely protects highly susceptible adult cattle against challenge with a homologous virulent strain of B. bovis. In conclusion, Att-S74-T3Bo may be considered as a potential efficient and sustainable attenuated candidate vaccine strain to control acute bovine babesiosis in highly susceptible adult cattle. Future studies should focus on increasing the number of animals vaccinated, duration of immunity, and efficacy of this attenuated strain against heterologous virulent parasite strains.

97. IRF4 is required for migration of CD4(+) T cells to the intestine but not for Th2 and Th17 cell maintenance.

Front Immunol

2023 Jul 3

Schmidt C, Harberts A, Reimers D

98. The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Front Immunol

2023 Jul 3

Rendina M, Barone M, Lillo C

INTRODUCTION: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. METHODS: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. RESULTS: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. DISCUSSION: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

99. TNF superfamily control of tissue remodeling and fibrosis.

Front Immunol

2023 Jul 3

Steele H, Cheng J, Willicut A

100. Establishment of a porcine bronchial epithelial cell line and its application to study innate immunity in the respiratory epithelium.

Front Immunol

2023 Jul 3

Fukuyama K, Zhuang T, Toyoshi E

101. Cell type- and time-dependent biological responses in ex vivo perfused lung grafts.

Front Immunol

2023 Jul 3

Gouin C, Vu Manh TP, Jouneau L

102. Cyto-IL-15 synergizes with the STING agonist ADU-S100 to eliminate prostate tumors and confer durable immunity in mouse models.

Front Immunol

2023 Jul 3

Papaevangelou E, Esteves AM, Dasgupta P

INTRODUCTION: Prostate cancer is one of the most commonly diagnosed malignancies in men with high mortality rates. Despite the recent therapeutic advances, such as immunotherapies, survival of patients with advance disease remains significantly low. Blockade of immune checkpoints has led to low response rates in these patients probably due to the immunosuppressive microenvironment and low mutation burden of prostate tumors. Combination of multiple immunotherapeutic regimes has also been unsatisfactory due to augmented adverse effects. To activate multiple immune-stimulatory pathways in the hostile prostate cancer microenvironment, we used a combination of cytotopically modified interleukin-15 (cyto-IL-15) with the stimulator of interferon genes (STING) agonist, ADU-S100. METHODS: To determine whether this combination regime could lead to both local and systemic anti-tumor effects, intratumoral administration of these agents was used in murine models of prostate cancer. Tumor growth and mouse survival were monitored, and ex vivo analyses, and RNA sequencing were performed on the tumors. RESULTS: Intratumorally injected ADU-S100 and cyto-IL-15 synergized to eliminate tumors in 58-67% of mice with unilateral tumors and promoted abscopal immunity in 50% of mice with bilateral tumors treated only at one side. Moreover, this combination regime offered immunoprotection against tumor rechallenge in 83% of cured mice. The efficacy of the combination treatment was associated with a strong innate and adaptive immune activation and induction of apoptotic and necrotic cell death. Cytokines, including type I and II interferons, and cytokine signalling pathways were activated, NK and T cell mediated cytotoxicity was increased, and B cells were activated both locally and systemically. While ADU-S100 led to an ulcerative pathology at the injection site, no other adverse effects were observed. DISCUSSION: Localised administration of a STING agonist together with cyto-IL-15 can confer significant systemic benefits and long-lasting immunity against prostate tumors while reducing immune related toxicities.

103. The role of mononuclear phagocyte system in IgA nephropathy: pathogenesis and prognosis.

Front Immunol

2023 Jul 3

Liu Y, Gong Y, Xu G.

104. Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

Front Immunol

2023 Jul 3

Shafqat A, Omer MH, Ahmed EN

105. Identification and validation of immune-associated NETosis subtypes and biomarkers in anti-neutrophil cytoplasmic antibody associated glomerulonephritis.

Front Immunol

2023 Jul 3

Tao M, He Y, Li L

BACKGROUND: NETosis is a new form of cell death, marked by DNA chromatin release from dead neutrophils. While it aids in microbe defense, it may worsen inflammation in autoimmune diseases, causing tissue harm. The impact of NETosis on Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis (ANCA-GN) remains unexplored and requires investigation. METHODS: First, a weighted gene co-expression network analysis (WGCNA) was conducted to uncover differential expression of neutrophil extranuclear trap-associated genes (DE-NETs) in ANCA-GN. The NETosisScore model was established through the single sample gene set enrichment analysis (ssGSEA), which categorized all patients into high-risk and low-risk groups. The accuracy of model was assessed by ROC curve. The biological function of various subgroups was explored through Gene Set Variation Analysis (GSVA), while the abundance of immune cell infiltration was measured with CIBERSORT. Furthermore, the key NETosis-related genes (NRGs) were identified using three machine learning algorithms, and their relationship with renal function was analyzed through the NephroseqV5 database. Through the application of qPCR and immunohistochemical staining techniques, the mRNA and protein expression levels of NRGs were determined in patients with ANCA-GN and control. RESULTS: A NETosisScore model was developed from 18 DE-NETs using the ssGSEA algorithm. The model's ability to predict ANCA-GN patients with a ROC AUC of 0.921. The high-risk group in ANCA-GN showed enrichment of immune-related pathways and greater infiltration of immune cells, as revealed by KEGG enrichment analysis and CIBERSORT. Using three machine learning algorithms, we identified six NRGs. Significant positive correlations were found between NRGs and CCR, macrophages, T-cell co-inhibition, and TIL. Further KEGG analysis revealed that the functions of NRGs may be closely related to the toll-like receptor signaling pathway. The levels of NRGs increased as kidney function declined and were positively correlated with Scr (serum creatinine) and negatively correlated with GFR (glomerular filtration rate), qPCR analysis showed increased expression of most NRGs in ANCA-GN patients. Furthermore, immunohistochemical staining confirmed higher expression of all NRGs in ANCA-GN patients. CONCLUSION: NETosisScore model accurately predicts high-risk patients in ANCA-GN with enriched immune pathways, 6 NRGs identified as potential biomarkers.

106. Lactobacillus plantarum GX17 benefits growth performance and improves functions of intestinal barrier/intestinal flora among yellow-feathered broilers.

Front Immunol

2023 Jul 3

Yin Y, Liao Y, Li J

Lactobacillus plantarum has recently been found to be a natural source feed additive bacteria with great advantages in food safety and animal welfare. Discovering novel strains with commercial application potentiation could benefit the local poultry industry, and in particular support Chinese farmers. In this study, we tested a recently isolated novel strain of Lactobacillus plantarum GX17 as a feed additive on the growth performance and intestinal barrier functions of 1-day-old Chinese yellow-feather chicks. As good as other commercial probiotics, feeding with Lactobacillus plantarum GX17 showed significant improvements in humoral immune responses and enhanced the immune effect after vaccination for either the Newcastle disease vaccine or the avian influenza vaccine. This study also found that feeding with Lactobacillus plantarum GX17 improved the feed-to-weight ratio and caused a significant increase of the villus length to crypt depth ratio. Furthermore, Lactobacillus plantarum GX17 significantly up-regulated the mRNA expression of CLDN, MUC2, and TLR2, all of which are jejunum-associated barrier genes, indicating an improvement of the intestinal barrier functions by enhancing the tight junction between epithelia cells. These results are comparable to the effects of feeding the commercial complex probiotics that improve the expression levels of CLDN, ocludin, MUC2, TLR2, and TLR4. In terms of maintaining intestinal health, commercial complex probiotics increased the relative abundance of Parabacteroides and Romboutsia, while Lactobacillus plantarum GX17 increased the relative abundance of Pseudoflavonifractor. Our data suggest that Lactobacillus plantarum GX17 could enhance the intestinal absorption of nutrients and therefore improve the growth performance of Chinese yellow-feather chicks. In conclusion, compared with the commercial complex probiotics, Lactobacillus plantarum GX17 has more positive effects on the growth performance and intestinal barrier function of yellow-feather chickens, and can be used as a feed additive.

107. Third dose of BNT162b2 improves immune response in liver transplant recipients to ancestral strain but not Omicron BA.1 and XBB.

Front Immunol

2023 Jul 3

Chang ZW, Goh YS, Rouers A

108. Case Report: Kinetics and durability of humoral and cellular response of SARS-CoV-2 messenger RNA vaccine in a lung and kidney transplant recipient.

Front Immunol

2023 Jul 3

Long J, Soni M, Muranski P

109. Comprehensive bioinformatics analysis reveals the crosstalk genes and immune relationship between the systemic lupus erythematosus and venous thromboembolism.

Front Immunol

2023 Jul 3

Yu J, Yang J, He Q

BACKGROUND: It is well known that patients with systemic lupus erythematosus (SLE) had a high risk of venous thromboembolism (VTE). This study aimed to identify the crosstalk genes between SLE and VTE and explored their clinical value and molecular mechanism initially. METHODS: We downloaded microarray datasets of SLE and VTE from the Gene Expression Omnibus (GEO) dataset. Differential expression analysis was applied to identify the crosstalk genes (CGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the shared genes. The shared diagnostic biomarkers of the two diseases were further screened from CGs using least absolute shrinkage and selection operator (Lasso) regression. Two risk scores for SLE and VTE were constructed separately to predict the likelihood of illness according to the diagnostic biomarkers using a logical regression algorithm. The immune infiltration levels of SEL and VTE were estimated via the CIBERSORT algorithm and the relationship of CGs with immune cell infiltration was investigated. Finally, we explored potential phenotype subgroups in SLE and VTE based on the expression level of CGs through the consensus clustering method and studied immune cell infiltration in different subtypes. RESULT: A total of 171 CGs were obtained by the intersection of differentially expressed genes (DEGs) between SLE and VTE cohorts. The functional enrichment shown these CGs were mainly related to immune pathways. After screening by lasso regression, we found that three hub CGs (RSAD2, HSP90AB1, and FPR2) were the optimal shared diagnostic biomarkers for SLE and VTE. Based on the expression level of RSAD2 and HSP90AB1, two risk prediction models for SLE and VTE were built by multifactor logistic regression and systemically validated in internal and external validation datasets. The immune infiltration results revealed that CGs were highly correlated with multiple infiltrated immunocytes. Consensus clustering was used to respectively regroup SLE and VTE patients into C1 and C2 clusters based on the CGs expression profile. The levels of immune cell infiltration and immune activation were higher in C1 than in C2 subtypes. CONCLUSION: In our study, we further screen out diagnostic biomarkers from crosstalk genes SLE and VTE and built two risk scores. Our findings reveal a close relationship between CGs and the immune microenvironment of diseases. This provides clues for further exploring the common mechanism and interaction between the two diseases.

110. Basophils in pruritic skin diseases.

Front Immunol

2023 Jul 3

Wiebe D, Limberg MM, Gray N

111. Prediction of herpes virus infections after solid organ transplantation: a prospective study of immune function.

Front Immunol

2023 Jul 3

Møller DL, Sørensen SS, Rezahosseini O

INTRODUCTION: Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR. METHODS: All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex. RESULTS: We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001). CONCLUSION: In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.

112. Preventing bacterial disease in poultry in the post-antibiotic era: a case for innate immunity modulation as an alternative to antibiotic use.

Front Immunol

2023 Jul 3

Adams JRG, Mehat J, La Ragione R

113. Guianensin, a Simulium guianense salivary protein, has broad anti-hemostatic and anti-inflammatory properties.

Front Immunol

2023 Jul 3

Valenzuela-Leon PC, Campos Chagas A, Martin-Martin I

BACKGROUND: Salivary glands from blood-feeding arthropods secrete several molecules that inhibit mammalian hemostasis and facilitate blood feeding and pathogen transmission. The salivary functions from Simulium guianense, the main vector of Onchocerciasis in South America, remain largely understudied. Here, we have characterized a salivary protease inhibitor (Guianensin) from the blackfly Simulium guianense. MATERIALS AND METHODS: A combination of bioinformatic and biophysical analyses, recombinant protein production, in vitro and in vivo experiments were utilized to characterize the molecula mechanism of action of Guianensin. Kinetics of Guianensin interaction with proteases involved in vertebrate inflammation and coagulation were carried out by surface plasmon resonance and isothermal titration calorimetry. Plasma recalcification and coagulometry and tail bleeding assays were performed to understand the role of Guianensin in coagulation. RESULTS: Guianensin was identified in the sialotranscriptome of adult S. guianense flies and belongs to the Kunitz domain of protease inhibitors. It targets various serine proteases involved in hemostasis and inflammation. Binding to these enzymes is highly specific to the catalytic site and is not detectable for their zymogens, the catalytic site-blocked human coagulation factor Xa (FXa), or thrombin. Accordingly, Guianensin significantly increased both PT (Prothrombin time) and aPTT (Activated partial thromboplastin time) in human plasma and consequently increased blood clotting time ex vivo. Guianensin also inhibited prothrombinase activity on endothelial cells. We show that Guianensin acts as a potent anti-inflammatory molecule on FXa-induced paw edema formation in mice. CONCLUSION: The information generated by this work highlights the biological functionality of Guianensin as an antithrombotic and anti-inflammatory protein that may play significant roles in blood feeding and pathogen transmission.

114. Impact of vaccine platform and BCG vaccination on antibody responses to COVID-19 vaccination.

Front Immunol

2023 Jul 3

Messina NL, Sperotto MG, Puga MAM

115. Research progress of biomarkers in the prediction of anti-PD-1/PD-L1 immunotherapeutic efficiency in lung cancer.

Front Immunol

2023 Jul 3

Wang L, Yang Z, Guo F

116. COVID-19 vaccine induced poor neutralization titers for SARS-CoV-2 omicron variants in maternal and cord blood.

Front Immunol

2023 Jul 3

Govindaraj S, Cheedarla N, Cheedarla S

INTRODUCTION: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and cross-neutralization capacity of maternal and cord antibody responses to SARS-CoV-2 variants following COVID-19 vaccination in pregnancy can inform neonatal immunity. METHODS: Here we characterized the binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants. In addition, we evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. RESULTS: Our results reveal that the current COVID-19 vaccination induced significantly higher RBD-specific binding IgG titers in cord blood compared to maternal blood for both the Wuhan and Omicron BA1 strain. Interestingly, the binding IgG antibody levels for the Omicron BA1 strain were significantly lower when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, and BA4/5 specific neutralizing antibody levels were significantly lower compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not detected in either maternal or cord blood. DISCUSSION: Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for the Wuhan and Delta variants but not for the Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for bivalent boosters as new variants emerge.

117. Immune function of colon cancer associated miRNA and target genes.

Front Immunol

2023 Jul 3

Han L, Chen S, Luan Z

118. Damage-mediated macrophage polarization in sterile inflammation.

Front Immunol

2023 Jul 3

Koncz G, Jenei V, Tóth M

Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile inflammation, either as a cause or a consequence of these conditions. The ability to control the progression of inflammation toward tissue resolution before it becomes chronic holds significant clinical potential. During sterile inflammation, the initiation of inflammation occurs through damage-associated molecular patterns (DAMPs) in the absence of pathogen-associated molecules. Macrophages, which are primarily localized in the tissue, play a pivotal role in sensing DAMPs. Furthermore, macrophages can also detect and respond to resolution-associated molecular patterns (RAMPs) and specific pro-resolving mediators (SPMs) during sterile inflammation. Macrophages, being highly adaptable cells, are particularly influenced by changes in the microenvironment. In response to the tissue environment, monocytes, pro-inflammatory macrophages, and pro-resolution macrophages can modulate their differentiation state. Ultimately, DAMP and RAMP-primed macrophages, depending on the predominant subpopulation, regulate the balance between inflammatory and resolving processes. While sterile injury and pathogen-induced reactions may have distinct effects on macrophages, most studies have focused on macrophage responses induced by pathogens. In this review, which emphasizes available human data, we illustrate how macrophages sense these mediators by examining the expression of receptors for DAMPs, RAMPs, and SPMs. We also delve into the signaling pathways induced by DAMPs, RAMPs, and SPMs, which primarily contribute to the regulation of macrophage differentiation from a pro-inflammatory to a pro-resolution phenotype. Understanding the regulatory mechanisms behind the transition between macrophage subtypes can offer insights into manipulating the transition from inflammation to resolution in sterile inflammatory diseases.

119. Causal association between inflammatory bowel disease and herpes virus infections: a two-sample bidirectional Mendelian randomization study.

Front Immunol

2023 Jul 3

Zou M, Zhang W, Shen L

BACKGROUND: Previous observational or retrospective studies have suggested an association between inflammatory bowel disease (IBD) and herpes virus infections. Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between IBD and herpes virus infections. METHODS: In genome-wide association study (GWAS) datasets of the International Inflammatory Bowel Disease Genetics Consortium, we obtained genetic instrumental variables for three phenotypes from 34,652 participants (12,882 IBD cases and 21,770 controls), 27,432 participants [6,968 ulcerative colitis (UC) cases and 20,464 controls], and 20,883 participants [5,956 Crohn's disease (CD) cases and 14,927 controls], respectively. Summary statistics for herpes virus infections (chickenpox, herpes zoster, and mononucleosis) were obtained from the FinnGen database. MR results were expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: Our study found no evidence of a causal effect of genetically predicted IBD on herpes virus infections [P value for inverse variance weighting (IVW): 0.063 to 0.652]. For the subtypes of IBD, UC had a suggestive association with mononucleosis (P value for IVW: 0.023). It appeared that CD was also weakly associated with mononucleosis (P value for IVW: 0.058; P value for Weighted median: 0.036). In addition, we found a suggestive causality for CD on chickenpox (P value for IVW: 0.038). Neither UC (P value for IVW: 0.574) nor CD (P value for IVW: 0.168) has a causal effect on herpes zoster. The results of the bidirectional MR analysis did not indicate that herpes virus infections were associated with IBD, UC or CD (P value for IVW: 0.239 to 0.888). CONCLUSION: This study showed a suggestive causality for both CD-chickenpox and UC-mononucleosis, despite no associations reaching a statistical significance value after corrections for multiple testing. There was no evidence of a causal association between IBD and its two subtypes on herpes zoster.

120. Immunogenomic profile at baseline predicts host susceptibility to clinical malaria.

Front Immunol

2023 Jul 3

Mbambo G, Dwivedi A, Ifeonu OO

121. Prognostic and immunological significance of an M1 macrophage-related gene signature in osteosarcoma.

Front Immunol

2023 Jul 3

Mao X, Song F, Jin J

As the most abundant infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are pivotal in tumor development and treatment. The present investigation endeavors to explore the potential of M1 macrophage-related genes (MRGs) as biomarkers for assessing risk in individuals with osteosarcoma. RNA-sequence data and clinical data were derived from TCGA and GEO databases. The CIBERSORT method was utilized to discern subtypes of tumor-infiltrating immune cells. Identification of MRGs was achieved through Pearson correlation analysis. A prognostic risk model for MRGs was developed using Cox and LASSO regression analyses. A tripartite gene signature comprising CD37, GABRD, and ARHGAP25 was an independent prognostic indicator and was employed to develop a risk score model. The internal and external validation cohort confirmed the results. The area under the ROC curve (AUC) was determined for survival periods of 1 year, three years, and five years, yielding values of 0.746, 0.839, and 0.850, respectively. The C-index of the risk score was found to be superior to clinicopathological factors. GO/KEGG enrichment showed that the differences between high- and low-risk groups were predominantly associated with immune response pathways. Immune-related analysis related to proportions of immune cells, immune function, and expression levels of immune checkpoint genes all showed differences between the high- and low-risk groups. The qRT-PCR and Western blotting results indicate that CD37 expression was markedly higher in MG63 and U2OS cell lines when compared to normal osteoblast hFOB1.19. In U2OS cell line, GABRD expression levels were significantly upregulated. ARHGAP25 expression levels were elevated in both 143B and U2OS cell lines. In summary, utilizing a macrophage genes signature demonstrates efficacy in predicting both the prognosis and therapy response of OS. Additionally, immune analysis confirms a correlation between the risk score and the tumor microenvironment. Our findings, therefore, provide a cogent account for the disparate prognoses observed among patients and furnish a justification for further inquiry into biomarkers and anti-tumor treatment strategies.

122. Reduning alleviates sepsis-induced acute lung injury by reducing apoptosis of pulmonary microvascular endothelial cells.

Front Immunol

2023 Jul 3

Wang Z, Guo Z, Wang X

123. Hericium erinaceus, in combination with natural flavonoid/alkaloid and B(3)/B(8) vitamins, can improve inflammatory burden in Inflammatory bowel diseases tissue: an ex vivo study.

Front Immunol

2023 Jul 3

Gravina AG, Pellegrino R, Palladino G

124. Immunologic and vascular biomarkers of mortality in critical COVID-19 in a South African cohort.

Front Immunol

2023 Jul 3

Shaw JA, Meiring M, Snyders C

INTRODUCTION: Biomarkers predicting mortality among critical Coronavirus disease 2019 (COVID-19) patients provide insight into the underlying pathophysiology of fatal disease and assist with triaging of cases in overburdened settings. However, data describing these biomarkers in Sub-Saharan African populations are sparse. METHODS: We collected serum samples and corresponding clinical data from 87 patients with critical COVID-19 on day 1 of admission to the intensive care unit (ICU) of a tertiary hospital in Cape Town, South Africa, during the second wave of the COVID-19 pandemic. A second sample from the same patients was collected on day 7 of ICU admission. Patients were followed up until in-hospital death or hospital discharge. A custom-designed 52 biomarker panel was performed on the Luminex® platform. Data were analyzed for any association between biomarkers and mortality based on pre-determined functional groups, and individual analytes. RESULTS: Of 87 patients, 55 (63.2%) died and 32 (36.8%) survived. We found a dysregulated cytokine response in patients who died, with elevated levels of type-1 and type-2 cytokines, chemokines, and acute phase reactants, as well as reduced levels of regulatory T cell cytokines. Interleukin (IL)-15 and IL-18 were elevated in those who died, and levels reduced over time in those who survived. Procalcitonin (PCT), C-reactive protein, Endothelin-1 and vascular cell adhesion molecule-1 were elevated in those who died. DISCUSSION: These results show the pattern of dysregulation in critical COVID-19 in a Sub-Saharan African cohort. They suggest that fatal COVID-19 involved excessive activation of cytotoxic cells and the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome. Furthermore, superinfection and endothelial dysfunction with thrombosis might have contributed to mortality. HIV infection did not affect the outcome. A clinically relevant biosignature including PCT, pH and lymphocyte percentage on differential count, had an 84.8% sensitivity for mortality, and outperformed the Luminex-derived biosignature.

125. Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice.

Front Immunol

2023 Jul 3

Yang G, Tong Y, Wang X

Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer's disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL's anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.

126. Multi-b-values-fitting readout-segmentation of long variable echo-trains diffusion-weighted imaging (RESOLVE DWI) in evaluation of disease activity and curative effect of axial spondyloarthritis (axSpA).

Front Immunol

2023 Jul 3

Chen X, Yang S, Lin M

BACKGROUND: Disease activity is relevant to the treatment and prognosis of axSpA, and methods to quantitatively assess disease activity and efficacy of axSpA are still being explored. OBJECTIVE: The purpose of this study was to find an optimal quantitative indicator for evaluating disease activity and curative effect of axSpA, using multi-b-values-fitting RESOLVE DWI. METHODS: The prospective study included 106 patients divided into axSpA group (n=89) and no-axSpA group (n=17) by Assessment of Spondyloarthritis international Society (ASAS) criteria. The axSpA group were divided into active group and inactive group according to ASDAS-CRP. The active group treated with systematic tumour necrosis factor inhibitors (TNFi) was selected as treatment group (n=20). All patients underwent MRI examination of sacroiliac joints (SIJs), including RESOLVE DWI. The ADC values of subchondral bone marrow in SIJs were measured (ADC50,500 was b=50,500s/mm2 fitting, ADC50,700 was b=50,700s/mm2 fitting, and ADC50,500,700 was b=50,500,700s/mm2 fitting). By comparing the ADC values between different groups, a relatively optimal b-values-fitting sequence was obtained, further evaluating curative effect of the treatment group. RESULTD: The ADC values of axSpA group, inactive group and active group SIJs were all higher than those of no-axSpA group. The ADC values of active group SIJs were all higher than those of inactive group. ADC50,500,700 had the largest AUC, relative higher sensitivity and specificity while taking account of the image quality than ADC50,700 and ADC50,500 between different groups. In the treatment group, there was no significant difference in ADC values between pre-treatment and 3 weeks, 3 weeks and 6 weeks, 6 weeks and 12 weeks (all P>0.0083, Bonferroni-corrected threshold), while the decreased ADC values in the interval of 6 weeks or more were statistically significant (all P<0.0083, Bonferroni-corrected threshold). CONCLUSION: Multi-b-values-fitting (b=50,500,700s/mm2) RESOLVE DWI has a certain advantage in evaluating disease activity of axSpA. It was worth noting that short-term review (3 weeks or less) of RESOLVE DWI was unsatisfactory and review at 6 weeks or later would help to evaluate curative effect of axSpA.

127. MDSCs in breast cancer: an important enabler of tumor progression and an emerging therapeutic target.

Front Immunol

2023 Jul 3

Liu H, Wang Z, Zhou Y

128. Rituximab resistance in ITP and beyond.

Front Immunol

2023 Jul 28

Xiao Z, Murakhovskaya I.

129. The arms race between bacteria CBASS and bacteriophages.

Front Immunol

2023 Jul 28

Wang L, Zhang L.

130. The landscape of the immunoglobulin repertoire in endemic pemphigus foliaceus.

Front Immunol

2023 Jul 28

Calonga-Solís V, Olbrich M, Ott F

INTRODUCTION: Primarily driven by autoreactive B cells, pemphigus foliaceus (PF) is an uncommon autoimmune blistering skin disease of sporadic occurrence worldwide. However, PF reaches a prevalence of 3% in the endemic areas of Brazil, the highest ever registered for any autoimmune disease, which indicates environmental factors influencing the immune response in susceptible individuals. We aimed to provide insights into the immune repertoire of patients with PF living in the endemic region of the disease, compared to healthy individuals from the endemic region and a non-endemic area. METHODS: We characterized the B-cell repertoire in i) nontreated patients (n=5); ii) patients under immunosuppressive treatment (n=5); iii) patients in remission without treatment (n=6); and two control groups iv) from the endemic (n=6) and v) non-endemic areas in Brazil (n=4). We used total RNA extracted from peripheral blood mononuclear cells and performed a comprehensive characterization of the variable region of immunoglobulin heavy chain (IGH) in IgG and IgM using next-generation sequencing. RESULTS: Compared to individuals from a different area, we observed remarkably lower clonotype diversity in the B-cell immune repertoire of patients and controls from the endemic area (p < 0.02), suggesting that the immune repertoire in the endemic area is under geographically specific and intense environmental pressure. Moreover, we observed longer CDR3 sequences in patients, and we identified differential disease-specific usage of IGHV segments, including increased IGHV3-30 and decreased IGHV3-23 in patients with active disease (p < 0.04). Finally, our robust network analysis discovered clusters of CDR3 sequences uniquely observed in patients with PF. DISCUSSION: Our results indicate that environmental factors, in addition to disease state, impact the characteristics of the repertoire. Our findings can be applied to further investigation of the environmental factors that trigger pemphigus and expand the knowledge for identifying new targeted and more effective therapies.

131. Endothelial exosomes work as a functional mediator to activate macrophages.

Front Immunol

2023 Jul 28

Lin W, Huang F, Yuan Y

132. Lipedema stage affects adipocyte hypertrophy, subcutaneous adipose tissue inflammation and interstitial fibrosis.

Front Immunol

2023 Jul 28

Kruppa P, Gohlke S, Łapiński K

133. Machine learning-based integration develops a neutrophil-derived signature for improving outcomes in hepatocellular carcinoma.

Front Immunol

2023 Jul 28

Gong Q, Chen X, Liu F

INTRODUCTION: The heterogeneity of tumor immune microenvironments is a major factor in poor prognosis among hepatocellular carcinoma (HCC) patients. Neutrophils have been identified as playing a critical role in the immune microenvironment of HCC based on recent single-cell studies. However, there is still a need to stratify HCC patients based on neutrophil heterogeneity. Therefore, developing an approach that efficiently describes "neutrophil characteristics" in HCC patients is crucial to guide clinical decision-making. METHODS: We stratified two cohorts of HCC patients into molecular subtypes associated with neutrophils using bulk-sequencing and single-cell sequencing data. Additionally, we constructed a new risk model by integrating machine learning analysis from 101 prediction models. We compared the biological and molecular features among patient subgroups to assess the model's effectiveness. Furthermore, an essential gene identified in this study was validated through molecular biology experiments. RESULTS: We stratified patients with HCC into subtypes that exhibited significant differences in prognosis, clinical pathological characteristics, inflammation-related pathways, levels of immune infiltration, and expression levels of immune genes. Furthermore, A risk model called the "neutrophil-derived signature" (NDS) was constructed using machine learning, consisting of 10 essential genes. The NDS's RiskScore demonstrated superior accuracy to clinical variables and correlated with higher malignancy degrees. RiskScore was an independent prognostic factor for overall survival and showed predictive value for HCC patient prognosis. Additionally, we observed associations between RiskScore and the efficacy of immune therapy and chemotherapy drugs. DISCUSSION: Our study highlights the critical role of neutrophils in the tumor microenvironment of HCC. The developed NDS is a powerful tool for assessing the risk and clinical treatment of HCC. Furthermore, we identified and analyzed the feasibility of the critical gene RTN3 in NDS as a molecular marker for HCC.

134. Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer.

Front Immunol

2023 Jul 28

Lin F, Huang J, Zhu W

BACKGROUND: Treatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy. METHODS: Data relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan-Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC). RESULTS: Six DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (P=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients. CONCLUSION: TERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.

135. Identifying a baicalein-related prognostic signature contributes to prognosis prediction and tumor microenvironment of pancreatic cancer.

Front Immunol

2023 Jul 28

Zhang C, Lei D, Zhou Y

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant and lethal human cancers in the world due to its high metastatic potential, and patients with PDAC have a poor prognosis, yet quite little is understood regarding the underlying biological mechanisms of its high metastatic capacity. Baicalein has a dramatic anti-tumor function in the treatment of different types of cancer. However, the therapeutic effects of baicalein on human PDAC and its mechanisms of action have not been extensively understood. In order to explore the biological characteristic, molecular mechanisms, and potential clinical value of baicalein in inhibiting the metastatic capacity of PDAC. We performed several in vitro, in vivo, and in silico studies. We first examined the potential regulation of baicalein in the metastatic capacity of PDAC cells. We showed that baicalein could dramatically suppress liver metastasis of PDAC cells with highly metastatic potential in mice model. The high-throughput sequencing analysis was employed to explore the biological roles of baicalein in PDAC cells. We found that baicalein might be involved in the infiltration of Cancer-Associated Fibroblasts (CAF) in PDAC. Moreover, a baicalein-related risk model and a lncRNA-related model were built by Cox analysis according to the data set of PDAC from TCGA database which suggested a clinical value of baicalein. Finally, we revealed a potential downstream target of baicalein in PDAC, we proposed that baicalein might contribute to the infiltration of CAF via FGFBP1. Thus, we uncovered a novel role for baicalein in regulation of PDAC liver metastasis that may contribute to its anti-cancer effect. We proposed that baicalein might suppress PDAC liver metastasis via regulation of FGFBP1-mediated CAF infiltration. Our results provide a new perspective on clinical utility of baicalein and open new avenues for the inhibition of liver-metastasis of PDAC.

136. In utero position matters for littermate cell transfer in mice: an additional and confounding source with maternal microchimerism.

Front Immunol

2023 Jul 28

Giassi M, Hemon MF, Martin M

137. Associations of complete blood cell count-derived inflammatory biomarkers with asthma and mortality in adults: a population-based study.

Front Immunol

2023 Jul 28

Ke J, Qiu F, Fan W

OBJECTIVE: This study aims to assess the associations of complete blood cell count (CBC)-derived inflammatory biomarkers with the prevalence of asthma and mortality. METHODS: Data was collected from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). Mortality was identified using the National Death Index until December 31, 2019. The study analyzed the relationship between CBC-derived inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index (SII), and the prevalence of asthma using multiple logistic regressions. To assess the significance of CBC-derived inflammatory biomarkers in predicting all-cause and respiratory disease mortality in asthma patients, Cox proportional regressions and the random survival forest (RSF) analysis were utilized. RESULTS: A total of 48,305 participants were included, with a mean age of 47.27 ± 0.18 years and 49.44% male. Among them, 6,403 participants had asthma, with a prevalence of 13.28%. The all-cause and respiratory disease deaths at a median follow-up of 8.2 (4.5, 12.8) years were 929 and 137 respectively. After adjusting for confounders, the prevalence of asthma was found to be positively associated with NLR, PLR, MLR, SIRI and SII. Compared to the lowest quartile, the highest quartile of NLR (HR=1.765 [1.378-2.262]), MLR (HR=1.717 [1.316-2.241]), SIRI (HR=1.796 [1.353-2.383]) and SII (HR=1.432 [1.141-1.797]) were associated with an increased risk of all-cause mortality. These associations were more pronounced in respiratory disease mortality of asthma patients. RSF analysis showed that MLR had the highest predictive value for all-cause and respiratory disease mortality in adults with asthma. The sensitivity analysis demonstrated the stability of our results. CONCLUSION: The findings suggest that CBC-derived inflammatory biomarkers are associated with a higher risk of all-cause and respiratory disease mortality in adults with asthma.

138. Functional reprogramming of peripheral blood monocytes by soluble mediators in patients with pancreatic cancer and intraductal papillary mucinous neoplasms.

Front Immunol

2023 Jul 28

Eckhoff AM, Brown MC, Landa K

BACKGROUND: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment in patients with intraductal papillary mucinous neoplasm (IPMN), a precursor lesion to PDAC, change during disease progression has not been defined. Here we functionally profiled the peripheral immune system and characterized the tumor microenvironment of patients with both IPMN and PDAC. We also tested if sera from patients with IPMN and PDAC functionally reprogram monocytes relative to that of healthy donors. METHODS: Pancreatic tissue and peripheral blood were collected at the time of resection from 16 patients with IPMN and 32 patients with PDAC. Peripheral blood and pancreatic tissue/tumor were immunophenotyped using flow cytometry. Whole blood was plated and incubated with R848 (a TLR 7/8 agonist) or LPS (a TLR4 agonist) for 6 hours and TNF expression in monocytes was measured by flow cytometry to measure monocyte activation. To test if TLR sensitivity is determined by factors in patient sera, we preconditioned healthy donor monocytes in serum from PDAC (n=23), IPMN (n=15), or age-matched healthy donors (n=10) followed by in vitro stimulation with R848 or LPS and multiplex cytokine measurements in the supernatant. RESULTS: TNF expression in R848-stimulated peripheral blood monocytes was higher in patients with low grade vs high grade IPMN (65% vs 32%, p = 0.03) and stage 1 vs stage 2/3 PDAC (58% vs 42%, p = 0.03), this was not observed after LPS stimulation. TLR activation correlated with increasing grade of dysplasia from low grade IPMN to high grade IPMN. Serum from patients with IPMN and PDAC recapitulated suppression of TNF induction after R848 stimulation in naïve, healthy donor monocytes. CONCLUSION: Peripheral blood monocyte TNF secretion inversely correlates with the degree of dysplasia in IPMN and cancer stage in PDAC, suggesting innate immune reprogramming as IPMNs progress to invasive disease. These effects are, at least in part, mediated by soluble mediators in sera.

139. NR2F6, a new immune checkpoint that acts as a potential biomarker of immunosuppression and contributes to poor clinical outcome in human glioma.

Front Immunol

2023 Jul 28

Miftah H, Naji O, Ssi SA

INTORODUCTION: Nuclear receptor subfamily 2 group F member 6 (NR2F6) is a promising checkpoint target for cancer immunotherapy. However, there has been no investigation of NR2F6 in glioma. Our study systematically explored the clinical characteristics and biological functions of NR2F6 in gliomas. METHODS: We extracted RNA sequencing (RNA-seq) data of 663 glioma samples from The Cancer Genome Atlas (TCGA) as the training cohort and 325 samples from the Chinese Glioma Genome Atlas (CGGA) as the validation cohort. We also confirmed the NR2F6 gene expression feature in our own cohort of 60 glioma patients. R language and GraphPad Prism softwares were mainly used for statistical analysis and graphical work. RESULTS: We found that NR2F6 was significantly related to high tumor aggressiveness and poor outcomes for glioma patients. Functional enrichment analysis demonstrated that NR2F6 was associated with many biological processes that are related to glioma progression, such as angiogenesis, and with multiple immune-related functions. Moreover, NR2F6 was found to be significantly correlated with stromal and immune infiltration in gliomas. Subsequent analysis based on Gliomas single-cell sequencing datasets showed that NR2F6 was expressed in immune cells, tumor cells, and stromal cells. Mechanistically, results suggested that NR2F6 might act as a potential immunosuppression-mediated molecule in the glioma microenvironment through multiple ways, such as the recruitment of immunosuppressive cells, secretion of immunosuppressive cytokines, M2 polarization of macrophages, in addition to combining with other immune checkpoint inhibitors. CONCLUSION: Our findings indicated that intracellular targeting of NR2F6 in both immune cells and tumor cells, as well as stromal cells, may represent a promising immunotherapeutic strategy for glioma. Stromal cells, may represent a promising immunotherapeutic strategy for glioma.

140. Combining deep mutational scanning to heatmap of HLA class II binding of immunogenic sequences to preserve functionality and mitigate predicted immunogenicity.

Front Immunol

2023 Jul 28

Sivelle C, Sierocki R, Lesparre Y

141. Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation.

Front Immunol

2023 Jul 28

Grudzien P, Neufeld H, Ebe Eyenga M

142. The extracellular vesicles targeting tumor microenvironment: a promising therapeutic strategy for melanoma.

Front Immunol

2023 Jul 28

Li Y, Liu F.

143. The role of the CD8+ T cell compartment in ageing and neurodegenerative disorders.

Front Immunol

2023 Jul 28

Terrabuio E, Zenaro E, Constantin G.

144. The impact of exosomes derived from distinct sources on rheumatoid arthritis.

Front Immunol

2023 Jul 27

Zhang S, Duan Z, Liu F

145. Clinical and immunological spectra of human cutaneous leishmaniasis in North Africa and French Guiana.

Front Immunol

2023 Jul 27

Saidi N, Blaizot R, Prévot G

146. Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes.

Front Immunol

2023 Jul 27

Nirenjen S, Narayanan J, Tamilanban T

BACKGROUND: Impaired wound healing is the most common and significant complication of Diabetes. While most other complications of Diabetes have better treatment options, diabetic wounds remain a burden as they can cause pain and suffering in patients. Wound closure and repair are orchestrated by a sequence of events aided by the release of pro-inflammatory cytokines, which are dysregulated in cases of Diabetes, making the wound environment unfavorable for healing and delaying the wound healing processes. This concise review provides an overview of the dysregulation of pro-inflammatory cytokines and offers insights into better therapeutic outcomes. PURPOSE OF REVIEW: Although many therapeutic approaches have been lined up nowadays to treat Diabetes, there are no proper treatment modalities proposed yet in treating diabetic wounds due to the lack of understanding about the role of inflammatory mediators, especially Pro-inflammatory mediators- Cytokines, in the process of Wound healing which we mainly focus on this review. RECENT FINDINGS: Although complications of Diabetes mellitus are most reported after years of diagnosis, the most severe critical complication is impaired Wound Healing among Diabetes patients. Even though Trauma, Peripheral Artery Disease, and Peripheral Neuropathy are the leading triggering factors for the development of ulcerations, the most significant issue contributing to the development of complicated cutaneous wounds is wound healing impairment. It may even end up with amputation. Newer therapeutic approaches such as incorporating the additives in the present dressing materials, which include antimicrobial molecules and immunomodulatory cytokines is of better therapeutic value. SUMMARY: The adoption of these technologies and the establishment of novel therapeutic interventions is difficult since there is a gap in terms of a complete understanding of the pathophysiological mechanisms at the cellular and molecular level and the lack of data in terms of the assessment of safety and bioavailability differences in the individuals' patients. The target-specific pro-inflammatory cytokines-based therapies, either by upregulation or downregulation of them, will be helpful in the wound healing process and thereby enhances the Quality of life in patients, which is the goal of drug therapy.

147. Erratum: The HLA class-II immunopeptidomes of AAV capsids proteins.

Front Immunol

2023 Jul 27

Frontiers Production Office.

148. The role of N-glycosylation in B-cell biology and IgG activity. The aspects of autoimmunity and anti-inflammatory therapy.

Front Immunol

2023 Jul 27

Trzos S, Link-Lenczowski P, Pocheć E.

The immune system is strictly regulated by glycosylation through the addition of highly diverse and dynamically changing sugar structures (glycans) to the majority of immune cell receptors. Although knowledge in the field of glycoimmunology is still limited, numerous studies point to the key role of glycosylation in maintaining homeostasis, but also in reflecting its disruption. Changes in oligosaccharide patterns can lead to impairment of both innate and acquired immune responses, with important implications in the pathogenesis of diseases, including autoimmunity. B cells appear to be unique within the immune system, since they exhibit both innate and adaptive immune activity. B cell surface is rich in glycosylated proteins and lectins which recognise glycosylated ligands on other cells. Glycans are important in the development, selection, and maturation of B cells. Changes in sialylation and fucosylation of cell surface proteins affect B cell signal transduction through BCRs, CD22 inhibitory coreceptor and Siglec-G. Plasmocytes, as the final stage of B cell differentiation, produce and secrete immunoglobulins (Igs), of which IgGs are the most abundant N-glycosylated proteins in human serum with the conserved N-glycosylation site at Asn297. N-oligosaccharide composition of the IgG Fc region affects its secretion, structure, half-life and effector functions (ADCC, CDC). IgG N-glycosylation undergoes little change during homeostasis, and may gradually be modified with age and during ongoing inflammatory processes. Hyperactivated B lymphocytes secrete autoreactive antibodies responsible for the development of autoimmunity. The altered profile of IgG N-glycans contributes to disease progression and remission and is sensitive to the application of therapeutic substances and immunosuppressive agents. In this review, we focus on the role of N-glycans in B-cell biology and IgG activity, the rearrangement of IgG oligosaccharides in aging, autoimmunity and immunosuppressive therapy.

149. Quantifying cellular dynamics in mice using a novel fluorescent division reporter system.

Front Immunol

2023 Jul 27

Lukas E, Hogan T, Williams C

150. FcγR requirements and costimulatory capacity of Urelumab, Utomilumab, and Varlilumab.

Front Immunol

2023 Jul 27

Leitner J, Egerer R, Waidhofer-Söllner P

151. COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Front Immunol

2023 Jul 27

Sun D, Du Q, Wang R

152. Chitinase-3-like 1 regulates T(H)2 cells, T(FH) cells and IgE responses to helminth infection.

Front Immunol

2023 Jul 27

Curtiss ML, Rosenberg AF, Scharer CD

153. Case Report: Successful treatment of advanced hepatocarcinoma with the PD-1 inhibitor Camrelizumab.

Front Immunol

2023 Jul 27

Ye W, Cai L, Zhang M

154. Response to SARS-CoV-2 initial series and additional dose vaccine in pediatric patients with predominantly antibody deficiency.

Front Immunol

2023 Jul 27

Tandon M, DiGiacomo DV, Zhou B

155. NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Front Immunol

2023 Jul 27

Verma M, Verma D, Sripada AS

156. Phorbol-12-myristate-13-acetate is a potent enhancer of B cells with a granzyme B(+) regulatory phenotype.

Front Immunol

2023 Jul 27

Veh J, Mangold C, Felsen A

157. Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption.

Front Immunol

2023 Jul 27

Gröning R, Dernstedt A, Ahlm C

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

158. Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS.

Front Immunol

2023 Jul 27

Clénet ML, Keaney J, Gillet G

NOD-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome modulation has emerged as a potential therapeutic approach targeting inflammation amplified by pyroptotic innate immune cell death. In diseases characterized by non-cell autonomous neurodegeneration including amyotrophic lateral sclerosis (ALS), the activation of several inflammasomes has been reported. Since functional redundancy can exist among inflammasome pathways, here we investigate the effects of NLRP3 inhibition on NLRP3, NLR family CARD Domain Containing 4 (NLRC4) and non-canonical pathways to understand whether NLRP3 blockade alone can mitigate pro-inflammatory cytokine release and pyroptotic cell death in contexts where single or multiple inflammasome pathways independent of NLRP3 are activated. In this study we do not limit our insights into inflammasome biology by solely relying on the THP-1 monocytic line under the LPS/nigericin-mediated NLRP3 pathway activation paradigm. We assess therapeutic potential and limitations of NLRP3 inhibition in multi-inflammasome activation contexts utilizing various human cellular systems including cell lines expressing gain of function (GoF) mutations for several inflammasomes, primary human monocytes, macrophages, healthy and Amyotrophic Lateral Sclerosis (ALS) patient induced pluripotent stem cells (iPSC)-derived microglia (iMGL) stimulated for canonical and non-canonical inflammasome pathways. We demonstrate that NLRP3 inhibition can modulate the NLRC4 and non-canonical inflammasome pathways; however, these effects differ between immortalized, human primary innate immune cells, and iMGL. We extend our investigation in more complex systems characterized by activation of multiple inflammasomes such as the SOD1G93A mouse model. Through deep immune phenotyping by single-cell mass cytometry we demonstrate that acute NLRP3 inhibition does not ameliorate spinal cord inflammation in this model. Taken together, our data suggests that NLRP3 inhibition alone may not be sufficient to address dynamic and complex neuroinflammatory pathobiological mechanisms including dysregulation of multiple inflammasome pathways in neurodegenerative disease such as ALS.

159. Causality between inflammatory bowel disease and the cerebral cortex: insights from Mendelian randomization and integrated bioinformatics analysis.

Front Immunol

2023 Jul 27

He S, Peng Y, Chen X

160. Resveratrol induces apoptosis by modulating the reciprocal crosstalk between p53 and Sirt-1 in the CRC tumor microenvironment.

Front Immunol

2023 Jul 27

Brockmueller A, Buhrmann C, Shayan P

161. A contrast-enhanced ultrasound-based nomogram for the prediction of therapeutic efficiency of anti-PD-1 plus anti-VEGF agents in advanced hepatocellular carcinoma patients.

Front Immunol

2023 Jul 27

Sun C, Wang Q, Hou L

162. A chimeric protein-based vaccine elicits a strong IgG antibody response and confers partial protection against Shiga toxin-producing Escherichia coli in mice.

Front Immunol

2023 Jul 27

Montero DA, Garcia-Betancourt R, Vidal RM

163. Unveiling efferocytosis-related signatures through the integration of single-cell analysis and machine learning: a predictive framework for prognosis and immunotherapy response in hepatocellular carcinoma.

Front Immunol

2023 Jul 27

Liu T, Li C, Zhang J

BACKGROUND: Hepatocellular carcinoma (HCC) represents a prominent gastrointestinal malignancy with a grim clinical outlook. In this regard, the discovery of novel early biomarkers holds substantial promise for ameliorating HCC-associated mortality. Efferocytosis, a vital immunological process, assumes a central position in the elimination of apoptotic cells. However, comprehensive investigations exploring the role of efferocytosis-related genes (EFRGs) in HCC are sparse, and their regulatory influence on HCC immunotherapy and targeted drug interventions remain poorly understood. METHODS: RNA sequencing data and clinical characteristics of HCC patients were acquired from the TCGA database. To identify prognostically significant genes in HCC, we performed the limma package and conducted univariate Cox regression analysis. Subsequently, machine learning algorithms were employed to identify hub genes. To assess the immunological landscape of different HCC subtypes, we employed the CIBERSORT algorithm. Furthermore, single-cell RNA sequencing (scRNA-seq) was utilized to investigate the expression levels of ERFGs in immune cells and to explore intercellular communication within HCC tissues. The migratory capacity of HCC cells was evaluated using CCK-8 assays, while drug sensitivity prediction reliability was determined through wound-healing assays. RESULTS: We have successfully identified a set of nine genes, termed EFRGs, that hold significant potential for the establishment of a hepatocellular carcinoma-specific prognostic model. Furthermore, leveraging the individual risk scores derived from this model, we were able to stratify patients into two distinct risk groups, unveiling notable disparities in terms of immune infiltration patterns and response to immunotherapy. Notably, the model's capacity to accurately predict drug responses was substantiated through comprehensive experimental investigations, encompassing wound-healing assay, and CCK8 experiments conducted on the HepG2 and Huh7 cell lines. CONCLUSIONS: We constructed an EFRGs model that serves as valuable tools for prognostic assessment and decision-making support in the context of immunotherapy and chemotherapy.

164. Combining network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification to examine the efficacy and immunoregulation mechanism of FHB granules on vitiligo.

Front Immunol

2023 Jul 27

Li X, Miao F, Xin R

BACKGROUND: Fufang Honghua Buji (FHB) granules, have proven efficacy against vitiligo in long-term clinical practice. However, its major active chemical components and molecular mechanisms of action remain unknown. The purpose of this study was to confirm the molecular mechanism of FHB's therapeutic effect on vitiligo utilizing network pharmacology, molecular docking, and molecular dynamics simulation prediction, as well as experimental verification. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP) and HERB databases were used to obtain the chemical composition and action targets of FHB. Online Mendelian Inheritance in Man (OMIM), DrugBank, DisGeNET, GeneCards, and Therapeutic Target Database (TTD) databases were applied to screen for vitiligo-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed through the Matascape database. Molecular docking and dynamics simulation methods were for the analysis of the binding sites and binding energies between the FHB's active components and the targets. Finally, a vitiligo mouse model was created, and the therapeutic effect and molecular mechanism of action of FHB were validated using enzyme linked immunosorbent assay (ELISA), western blot (WB), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, hematoxylin-eosin staining (HE) and blood biochemical assays were conducted to assess the biosafety of FHB. RESULT: The screening of chemical composition and targets suggested that 94 genetic targets of FHB were associated with vitiligo. The bioinformatics analysis suggested that luteolin, quercetin, and wogonin may be major active components, and nuclear factor-kappa B p65 subunit (RELA), signal transducer, and activator of transcription (STAT) 3 and RAC-alpha serine/threonine-protein kinase (AKT) 1 may be potential targets of FHB-vitiligo therapy. Molecular docking and dynamics simulation further demonstrated that luteolin, quercetin, and wogonin all bound best to STAT3. Through experimental verification, FHB has been demonstrated to alleviate the pathogenic characteristics of vitiligo mice, suppress the JAK-STAT signaling pathway, reduce inflammation, and increase melanogenesis. The in vivo safety evaluation experiments also demonstrated the non-toxicity of FHB. CONCLUSIONS: FHB exerts anti-inflammatory and melanogenesis-promoting effects via the effect of multi-component on multi-target, among which the JAK-STAT pathway is a validated FHB-vitiligo target, providing new ideas and clues for the development of vitiligo therapy.

165. Orally administrated Lactobacillus gasseri TM13 and Lactobacillus crispatus LG55 can restore the vaginal health of patients recovering from bacterial vaginosis.

Front Immunol

2023 Jul 27

Qi F, Fan S, Fang C

Bacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with live Lactobacillus may benefit the recovery of BV, however, the outcomes vary in people from different regions. Herein, we aim to evaluate the effectiveness of oral Chinese-origin Lactobacillus with adjuvant metronidazole (MET) on treating Chinese BV patients. In total, 67 Chinese women with BV were enrolled in this parallel controlled trial and randomly assigned to two study groups: a control group treated with MET vaginal suppositories for 7 days and a probiotic group treated with oral Lactobacillus gasseri TM13 and Lactobacillus crispatus LG55 as an adjuvant to MET for 30 days. By comparing the participants with Nugent Scores ≥ 7 and < 7 on days 14, 30, and 90, we found that oral administration of probiotics did not improve BV cure rates (72.73% and 84.00% at day 14, 57.14% and 60.00% at day 30, 32.14% and 48.39% at day 90 for probiotic and control group respectively). However, the probiotics were effective in restoring vaginal health after cure by showing higher proportion of participants with Nugent Scores < 4 in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90). The relative abundance of the probiotic strains was significantly increased in the intestinal microbiome of the probiotic group compared to the control group at day 14, but no significance was detected after 30 and 90 days. Also, the probiotics were not detected in vaginal microbiome, suggesting that L. gasseri TM13 and L. crispatus LG55 mainly acted through the intestine. A higher abundance of Prevotella timonensis at baseline was significantly associated with long-term cure failure of BV and greatly contributed to the enrichment of the lipid IVA synthesis pathway, which could aggravate inflammation response. To sum up, L. gasseri TM13 and L. crispatus LG55 can restore the vaginal health of patients recovering from BV, and individualized intervention mode should be developed to restore the vaginal health of patients recovering from BV. CLINICAL TRIAL REGISTRATION: https://classic.clinicaltrials.gov/ct2/show/, identifier NCT04771728.

166. A novel stratification framework based on anoikis-related genes for predicting the prognosis in patients with osteosarcoma.

Front Immunol

2023 Jul 27

Zhang X, Wen Z, Wang Q

BACKGROUND: Anoikis resistance is a prerequisite for the successful development of osteosarcoma (OS) metastases, whether the expression of anoikis-related genes (ARGs) correlates with OS prognosis remains unclear. This study aimed to investigate the feasibility of using ARGs as prognostic tools for the risk stratification of OS. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provided transcriptome information relevant to OS. The GeneCards database was used to identify ARGs. Differentially expressed ARGs (DEARGs) were identified by overlapping ARGs with common differentially expressed genes (DEGs) between OS and normal samples from the GSE16088, GSE19276, and GSE99671 datasets. Anoikis-related clusters of patients were obtained by consistent clustering, and gene set variation analysis (GSVA) of the different clusters was completed. Next, a risk model was created using Cox regression analyses. Risk scores and clinical features were assessed for independent prognostic values, and a nomogram model was constructed. Subsequently, a functional enrichment analysis of the high- and low-risk groups was performed. In addition, the immunological characteristics of OS samples were compared between the high- and low-risk groups, and their sensitivity to therapeutic agents was explored. RESULTS: Seven DEARGs between OS and normal samples were obtained by intersecting 501 ARGs with 68 common DEGs. BNIP3 and CXCL12 were significantly differentially expressed between both clusters (P<0.05) and were identified as prognosis-related genes. The risk model showed that the risk score and tumor metastasis were independent prognostic factors of patients with OS. A nomogram combining risk score and tumor metastasis effectively predicted the prognosis. In addition, patients in the high-risk group had low immune scores and high tumor purity. The levels of immune cell infiltration, expression of human leukocyte antigen (HLA) genes, immune response gene sets, and immune checkpoints were lower in the high-risk group than those in the low-risk group. The low-risk group was sensitive to the immune checkpoint PD-1 inhibitor, and the high-risk group exhibited lower inhibitory concentration values by 50% for 24 drugs, including AG.014699, AMG.706, and AZD6482. CONCLUSION: The prognostic stratification framework of patients with OS based on ARGs, such as BNIP3 and CXCL12, may lead to more efficient clinical management.

167. Dupilumab effectively and rapidly treats bullous pemphigoid by inhibiting the activities of multiple cell types.

Front Immunol

2023 Jul 27

Yan T, Xie Y, Liu Y

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune skin-blistering disease. Systemic corticosteroids remain the first line treatment for moderate-to-severe BP with the potential for severe adverse events. Dupilumab has emerged as an alternative option for BP patients. OBJECTIVE: We evaluated the efficiency and safety of dupilumab on BP treatment and explored a mode of drug action in depth. METHODS AND RESULTS: A multicenter retrospective cohort included 20 BP patients who received dupilumab with or without systemic corticosteroid in dupilumab group, and 20 matched BP patients who received corticosteroid alone in conventional group. Serum samples were collected from 20 patients (10 from dupilumab group and 10 from conventional group) at baseline and week 4. Compared to systemic corticosteroid alone, dupilumab with or without systemic corticosteroid was similarly efficacious in clinical remission at week4 (complete remission plus partial remission: 100%) and week24 (complete remission plus partial remission:100%), but allowing significant decreases in the cumulative doses of corticosteroids with reducing the incidence of adverse events. However, dupilumab did not decrease BP180 antibody despite an obvious clinical improvement. Comparative plasma proteomic analysis performed before and after treatment in 3 BP patients from dupilumab group revealed that drug use was associated with 30 differentially expressed proteins, including 26 down-regulated and 4 up-regulated proteins. The former consisted of immune related proteins involved in T/B cell interactions (inducible T-cell co-stimulator ligand, ICOSL) and in the activation of eosinophils (PRG2), mast cells (S100A12), and complement (CR2). TARC and ICOSL levels correlated with BP severity in patients who received either dupilumab or conventional treatment. CONCLUSION: Dupilumab has similar efficacy in treating BP as conventional drugs, by inhibiting the activities of many types of immune cells and complement, and regulating the interactions between T and B cells.

168. IL-12/15/18-induced cell death and mitochondrial dynamics of human NK cells.

Front Immunol

2023 Jul 27

Terrén I, Sandá V, Amarilla-Irusta A

169. Tumor microenvironment responsive metal nanoparticles in cancer immunotherapy.

Front Immunol

2023 Jul 27

Yang R, Chen L, Wang Y

170. scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics.

Front Immunol

2023 Jul 27

Hildebrandt F, Mohammed M, Dziedziech A

171. Fc receptors act as innate immune receptors during infection?

Front Immunol

2023 Jul 26

Laassili C, Ben El Hend F, Benzidane R

172. The impact of SARS-CoV-2 infection and vaccination on inflammatory arthritis: a cohort study.

Front Immunol

2023 Jul 26

Striani G, Hoxha A, Lorenzin M

173. Berberine-containing natural-medicine with boiled peanut-OIT induces sustained peanut-tolerance associated with distinct microbiota signature.

Front Immunol

2023 Jul 26

Srivastava K, Cao M, Fidan O

174. Cellular immune response of SARS-CoV-2 vaccination in kidney transplant recipients: a systematic review and meta-analysis.

Front Immunol

2023 Jul 26

Udomkarnjananun S, Gatechompol S, Leelahavanichkul A

BACKGROUND: Evidence has demonstrated inferior humoral immune responses after SARS-CoV-2 vaccination in kidney transplant recipients compared to the general population. However, data on cellular immune responses in this population have not been established. METHODS: We searched the MEDLINE, Scopus, and Cochrane databases and included studies reporting cellular immune response rates in kidney transplant recipients after receiving SARS-CoV-2 vaccines. Studies that reported factors associated with cellular immune responders or non-responders were also included (PROSPERO: CRD42022375544). RESULTS: From a total of 1,494 articles searched, 53 articles were included in the meta-analysis. In all, 21 studies assessed cellular immune response by interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISPOT), 22 studies used interferon-γ release assay (IGRA), and 10 studies used flow cytometric analysis. The pooled response rate after two doses (standard regimen) and three doses of vaccination was 47.5% (95%CI 38.4-56.7%) and 69.1% (95%CI 56.3-80.6%) from IFN-γ ELISPOT, 25.8% (95%CI 19.7-32.4%) and 14.7% (95%CI 8.5-22.2%) from IGRA, and 73.7% (95%CI 55.2-88.8%) and 86.5% (95%CI 75.3-94.9%) from flow cytometry, respectively. Recipients with seroconversion were associated with a higher chance of having cellular immune response (OR 2.58; 95%CI 1.89-3.54). Cellular immune response in kidney transplant recipients was lower than in dialysis patients (OR 0.24; 95%CI 0.16-0.34) and the general population (OR 0.10; 95%CI 0.07-0.14). Age and immunosuppressants containing tacrolimus or corticosteroid were associated with inferior cellular immune response. CONCLUSION: Cellular immune response after SARS-CoV-2 vaccination in kidney transplant recipients was lower than in dialysis patients and the general population. Age, tacrolimus, and corticosteroid were associated with poor response. Cellular immune response should also be prioritized in vaccination studies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42022375544.

175. Integrative multi-omics analyses unravel the immunological implication and prognostic significance of CXCL12 in breast cancer.

Front Immunol

2023 Jul 26

Gao ZJ, Fang Z, Yuan JP

BACKGROUND: CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in breast cancer, and explore novel CXCL12-related biomarkers through integrative multi-omics analyses to build a powerful prognostic model for breast cancer patients. METHODS: Immunohistochemistry analysis of the tissue microarray was performed to evaluate the correlation between CXCL12 expression levels and breast cancer patient outcomes. Combined single-nucleus and spatial transcriptomics data was used to uncover the expression distribution of CXCL12 in breast cancer microenvironment. CXCL12-related genes were identified by WGCNA analysis. Univariate Cox and LASSO regression analyses were then conducted to screen prognostic genes from above CXCL12-related genes, followed by the construction of the CXCL12-related prognostic signature, identification of risk groups, and external validation of the prognostic signature. Analyses of biological function, mutation landscape, immune checkpoint genes and immune cells, were performed to further reveal the differences between high/low-risk groups. Paired single-cell RNA-seq and bulk RNA-seq were analyzed to further disclose the association between the risk score and the complex tumor immune microenvironment. To screen potential therapeutic agents for breast cancer patients, analyses of gene-drug correlation and sensitivity to immunotherapy were conducted. RESULTS: High expression of CXCL12 was linked with a prolonged survival in breast cancer. A total of 402 genes were identified by WGCNA analysis and 11 genes, covering VAT1L, TMEM92, SDC1, RORB, PCSK9, NRN1, NACAD, JPH3, GJA1, BMP8B and ADAMTS2, were screened as the candidate prognostic genes. Next, the prognostic signature was built and validated using these genes to predict the outcomes of breast cancers. The high-risk group patients exhibited significantly inferior prognoses. The combination of the risk score and tumor mutational burden (TMB) had remarkably improved performance in predicting patient outcomes. Besides, high-risk group patients showed higher infiltration of M2-like macrophages. Finally, several potential anticancer drugs were identified. The high-risk group patients were more sensitive to immunotherapy but resistant to docetaxel. CONCLUSIONS: CXCL12 has important immunological implication and prognostic significance in breast cancer. The CXCL12-related prognostic model could well predict the prognosis and treatment response of breast cancers.

176. High expression of IL6 and decrease in immune cells in COVID-19 patients combined with myocardial injury.

Front Immunol

2023 Jul 26

Chen T, Chen H, Chen P

PURPOSE: Myocardial injury, as a serious complication of coronavirus disease-2019 (COVID-19), increases the occurrence of adverse outcomes. Identification of key regulatory molecules of myocardial injury may help formulate corresponding treatment strategies and improve the prognosis of COVID-19 patients. METHODS: Gene Set Enrichment Analysis (GSEA) was conducted to identify co-regulatory pathways. Differentially expressed genes (DEGs) in GSE150392 and GSE169241 were screened and an intersection analysis with key genes of the co-regulatory pathway was conducted. A protein-protein interaction (PPI) network was constructed to screen for key regulatory genes. Preliminarily screened genes were verified using other datasets to identify genes with consistent expression. Based on the hierarchical cluster, we divided the patients from GSE177477 into high- and low-risk groups and compared the proportion of immune cells. A total of 267 COVID-19 patients from the Zhejiang Provincial Hospital of Chinese Medicine from December 26, 2022, to January 11, 2023, were enrolled to verify the bioinformatics results. Univariate and multivariate analyses were performed to analyze the risk factors for myocardial injury. According to high-sensitivity troponin (hsTnI) levels, patients with COVID-19 were divided into high- and low-sensitivity groups, and interleukin 6 (IL6) expression and lymphocyte subsets were compared. Patients were also divided into high and low groups according to the IL6 expression, and hsTnI levels were compared. RESULTS: Interleukin signaling pathway and GPCR ligand binding were shown to be co-regulatory pathways in myocardial injury associated with COVID-19. According to the hierarchical cluster analysis of seven genes (IL6, NFKBIA, CSF1, CXCL1, IL1R1, SOCS3, and CASP1), patients with myocardial injury could be distinguished from those without myocardial injury. Age, IL6 levels, and hospital stay may be factors influencing myocardial injury caused by COVID-19. Compared with COVID-19 patients without myocardial injury, the levels of IL6 in patients with myocardial injury increased, while the number of CD4+ T cells, CD8+ T cells, B cells, and NK cells decreased (P<0.05). The hsTnI levels in COVID-19 patients with high IL6 levels were higher than those in patients with low IL6 (P<0.05). CONCLUSIONS: The COVID-19 patients with myocardial injury had elevated IL6 expression and decreased lymphocyte counts. IL6 may participate in myocardial injury through the interleukin signaling pathway.

177. RSV replication modifies the XBP1s binding complex on the IRF1 upstream enhancer to potentiate the mucosal anti-viral response.

Front Immunol

2023 Jul 26

Qiao D, Xu X, Zhang Y

INTRODUCTION: The unfolded protein response (UPR) has emerged as an important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. Earlier we found that RSV replication predominantly activates the evolutionarily conserved Inositol Requiring Enzyme 1α (IRE1α)-X-Box Binding Protein 1 spliced (XBP1s) arm of the Unfolded Protein Response (UPR) producing inflammation, metabolic adaptation and cellular plasticity, yet the mechanisms how the UPR potentiates inflammation are not well understood. METHODS: To understand this process better, we examined the genomic response integrating RNA-seq and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analyses. These data were integrated with an RNA-seq analysis conducted on RSV-infected small airway cells ± an IRE1α RNAse inhibitor. RESULTS: We identified RSV induced expression changes in ~3.2K genes; of these, 279 required IRE1α and were enriched in IL-10/cytokine signaling pathways. From this data set, we identify those genes directly under XBP1s control by CUT&RUN. Although XBP1s binds to ~4.2 K high-confidence genomic binding sites, surprisingly only a small subset of IL10/cytokine signaling genes are directly bound. We further apply CUT&RUN to find that RSV infection enhances XBP1s loading on 786 genomic sites enriched in AP1/Fra-1, RELA and SP1 binding sites. These control a subset of cytokine regulatory factor genes including IFN response factor 1 (IRF1), CSF2, NFKB1A and DUSP10. Focusing on the downstream role of IRF1, selective knockdown (KD) and overexpression experiments demonstrate IRF1 induction controls type I and -III interferon (IFN) and IFN-stimulated gene (ISG) expression, demonstrating that ISG are indirectly regulated by XBP1 through IRF1 transactivation. Examining the mechanism of IRF1 activation, we observe that XBP1s directly binds a 5' enhancer sequence whose XBP1s loading is increased by RSV. The functional requirement for the enhancer is demonstrated by targeting a dCas9-KRAB silencer, reducing IRF1 activation. Chromatin immunoprecipitation shows that XBP1 is required, but not sufficient, for RSV-induced recruitment of activated phospho-Ser2 Pol II to the enhancer. DISCUSSION: We conclude that XBP1s is a direct activator of a core subset of IFN and cytokine regulatory genes in response to RSV. Of these IRF1 is upstream of the type III IFN and ISG response. We find that RSV modulates the XBP1s binding complex on the IRF1 5' enhancer whose activation is required for IRF1 expression. These findings provide novel insight into how the IRE1α-XBP1s pathway potentiates airway mucosal anti-viral responses.

178. Multi-phasic gene profiling using candidate gene approach predict the capacity of specific antibody production and maintenance following COVID-19 vaccination in Japanese population.

Front Immunol

2023 Jul 26

Takemoto Y, Tanimine N, Yoshinaka H

BACKGROUND: Vaccination against severe acute respiratory syndrome coronavirus type 2 is highly effective in preventing infection and reducing the severity of coronavirus disease (COVID-19). However, acquired humoral immunity wanes within six months. Focusing on the different tempo of acquisition and attenuation of specific antibody titers in individuals, we investigated the impact of genetic polymorphisms on antibody production after COVID-19 vaccination. METHODS: In total 236 healthcare workers from a Japanese municipal hospital, who received two doses of the vaccine were recruited. We employed a candidate gene approach to identify the target genetic polymorphisms affecting antibody production after vaccination. DNA samples from the study populations were genotyped for 33 polymorphisms in 15 distinct candidate genes encoding proteins involved in antigen-presenting cell activation, T cell activation, T-B interaction, and B cell survival. We measured total anti-SARS-Cov2 spike IgG antibody titers and analyzed the association with genetic polymorphisms at several time points after vaccination using an unbiased statistical method, and stepwise logistic regression following multivariate regression. RESULTS: Significant associations were observed between seven SNPs in NLRP3, OAS1, IL12B, CTLA4, and IL4, and antibody titers at 3 weeks after the first vaccination as an initial response. Six SNPs in NLRP3, TNF, OAS1, IL12B, and CTLA4 were associated with high responders with serum antibody titer > 4000 BAU/ml as boosting effect at 3 weeks after the second vaccination. Analysis of long-term maintenance showed the significance of the three SNPs in IL12B, IL7R, and MIF for the maintenance of antibody titers and that in BAFF for attenuation of neutralizing antibodies. Finally, we proposed a predictive model composed of gene profiles to identify the individuals with rapid antibody attenuation by receiver operating characteristic (ROC) analysis (area under the curve (AUC)= 0.76, sensitivity = 82.5%, specificity=67.8%). CONCLUSIONS: The candidate gene approach successfully showed shifting responsible gene profiles and initial and boosting effect mainly related to the priming phase into antibody maintenance including B cell survival, which traces the phase of immune reactions. These gene profiles provide valuable information for further investigation of humoral immunity against COVID-19 and for building a strategy for personalized vaccine schedules.

179. Visualizing temporal dynamics and research trends of macrophage-related diabetes studies between 2000 and 2022: a bibliometric analysis.

Front Immunol

2023 Jul 26

Wang S, Zhang L, Jin Z

180. Prognostic and immunomodulatory roles of schizophrenia-associated genes HTR2A, COMT, and PRODH in pan-cancer analysis and glioma survival prediction model.

Front Immunol

2023 Jul 26

Shen J, Wang Q, Lu F

BACKGROUND: The shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZ-related genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG). METHODS AND RESULTS: SCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma. CONCLUSION: SCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis.

181. The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity.

Front Immunol

2023 Jul 26

Burke GW 3rd, Mitrofanova A, Fontanella A

182. Targeting Th17 cells: a promising strategy to treat oral mucosal inflammatory diseases.

Front Immunol

2023 Jul 26

Wang Y, Xue N, Wang Z

183. Transcriptomic profile of TNF(high) MAIT cells is linked to B cell response following SARS-CoV-2 vaccination.

Front Immunol

2023 Jul 26

Marzano P, Balin S, Terzoli S

INTRODUCTION: Higher frequencies of mucosal-associated invariant T (MAIT) cells were associated with an increased adaptive response to mRNA BNT162b2 SARS-CoV-2 vaccine, however, the mechanistic insights into this relationship are unknown. In the present study, we hypothesized that the TNF response of MAIT cells supports B cell activation following SARS-CoV-2 immunization. METHODS: To investigate the effects of repeated SARS-CoV-2 vaccinations on the peripheral blood mononuclear cells (PBMCs), we performed a longitudinal single cell (sc)RNA-seq and scTCR-seq analysis of SARS-CoV-2 vaccinated healthy adults with two doses of the Pfizer-BioNTech BNT162b2 mRNA vaccine. Collection of PBMCs was performed 1 day before, 3 and 17 days after prime vaccination, and 3 days and 3 months following vaccine boost. Based on scRNA/TCR-seq data related to regulatory signals induced by the vaccine, we used computational approaches for the functional pathway enrichment analysis (Reactome), dynamics of the effector cell-polarization (RNA Velocity and CellRank), and cell-cell communication (NicheNet). RESULTS: We identified MAIT cells as an important source of TNF across circulating lymphocytes in response to repeated SARS-CoV-2 BNT162b2 vaccination. The TNFhigh signature of MAIT cells was induced by the second administration of the vaccine. Notably, the increased TNF expression was associated with MAIT cell proliferation and efficient anti-SARS-CoV-2 antibody production. Finally, by decoding the ligand-receptor interactions and incorporating intracellular signaling, we predicted TNFhigh MAIT cell interplay with different B cell subsets. In specific, predicted TNF-mediated activation was selectively directed to conventional switched memory B cells, which are deputed to high-affinity long-term memory. DISCUSSION: Overall, our results indicate that SARS-CoV-2 BNT162b2 vaccination influences MAIT cell frequencies and their transcriptional effector profile with the potential to promote B cell activation. This research also provides a blueprint for the promising use of MAIT cells as cellular adjuvants in mRNA-based vaccines.

184. Immunomodulatory potential of mesenchymal stromal cell-derived extracellular vesicles in chondrocyte inflammation.

Front Immunol

2023 Jul 26

Ossendorff R, Grad S, Tertel T

INTRODUCTION: Osteoarthritis (OA) affects a large percentage of the population worldwide. Current surgical and nonsurgical concepts for treating OA only result in symptom-modifying effects. However, there is no disease-modifying therapy available. Extracellular vesicles released by mesenchymal stem/stromal cells (MSC-EV) are promising agents to positively influence joint homeostasis in the osteoarthritic surroundings. This pilot study aimed to investigate the effect of characterized MSC-EVs on chondrogenesis in a 3D chondrocyte inflammation model with the pro-inflammatory cytokine TNFα. METHODS: Bovine articular chondrocytes were expanded and transferred into pellet culture at passage 3. TNFα, human MSC-EV preparations (MSC-EV batches 41.5-EVi1 and 84-EVi), EVs from human platelet lysate (hPL4-EV), or the combination of TNFα and EVs were supplemented. To assess the effect of MSC-EVs in the chondrocyte inflammation model after 14 days, DNA, glycosaminoglycan (GAG), total collagen, IL-6, and NO release were quantified, and gene expression of anabolic (COL-II, aggrecan, COMP, and PRG-4), catabolic (MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5), dedifferentiation (COL-I), hypertrophy (COL-X, VEGF), and inflammatory (IL-8) markers were analyzed; histological evaluation was performed using safranin O/Fast Green staining and immunohistochemistry of COL I and II. For statistical evaluation, nonparametric tests were chosen with a significance level of p < 0.05. RESULTS: TNFα supplementation resulted in catabolic stimulation with increased levels of NO and IL-6, upregulation of catabolic gene expression, and downregulation of anabolic markers. These findings were supported by a decrease in matrix differentiation (COL-II). Supplementation of EVs resulted in an upregulation of the chondrogenic marker PRG-4. All MSC-EV preparations significantly increased GAG retention per pellet. In contrast, catabolic markers and IL-8 expression were upregulated by 41.5-EVi1. Regarding protein levels, IL-6 and NO release were increased by 41.5-EVi1. Histologic and immunohistochemical evaluations indicated a higher differentiation potential of chondrocytes treated with 84-EVi. DISCUSSION: MSC-EVs can positively influence chondrocyte matrix production in pro-inflammatory surroundings, but can also stimulate inflammation. In this study MSC-EV 41.5-EVi1 supplementation increased chondrocyte inflammation, whereas MSC-84-EVi supplementation resulted a higher chondrogenic potential of chondrocytes in 3D pellet culture. In summary, the selected MSC-EVs exhibited promising chondrogenic effects indicating their significant potential for the treatment of OA; however, the functional heterogeneity in MSC-EV preparations has to be solved.

185. Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.

Front Immunol

2023 Jul 26

Vakrakou AG, Karachaliou E, Chroni E

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

186. IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models.

Front Immunol

2023 Jul 26

Shi H, Li A, Dai Z

Claudin 18.2 (CLDN18.2)-targeting chimeric antigen receptor (CAR)-modified T cells are one of the few cell therapies currently producing an impressive therapeutic effect in treating solid tumors; however, their long-term therapeutic efficacy is not satisfactory with a short duration of response. Transgenic expression of interleukin (IL)-15 has been reported to promote T-cell expansion, survival, and function and enhance the antitumor activity of engineered T cells in vitro and in vivo. Therefore, this study aimed to explore whether IL-15 modification would increase the antitumor activity of CLDN18.2-targeting CAR-modified T (CAR-T) cells in immunocompetent murine tumor models. CLDN18.2-specific CAR-T cells with (H9 CAR-IL15) or without transgenic IL-15 expression (H9 CAR) were generated by retroviral transduction of mouse splenic T cells. In vitro, compared with H9 CAR T cells, H9 CAR-IL15 T cells exhibited better expansion and viability in the absence of antigen stimulation, with a less differentiated and T-cell exhausted phenotype; although IL-15 modification did not affect the production of effector cytokines and cytotoxic activity in the short-term killing assay, it moderately improved the in vitro recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. In vivo, H9 CAR T cells showed no antitumor activity against CLDN18.2-expressing pancreatic tumors in immunocompetent mice without lymphodepleting pretreatment; however, H9 CAR-IL15 T cells produced significant tumor-suppressive effects. Furthermore, H9 CAR-IL15 T cells exhibited greater in vivo expansion and tumor infiltration when combined with lymphodepleting preconditioning, resulting in superior antitumor activity in two murine tumor models and a survival advantage in one tumor model. We further demonstrated that recurrent tumors following H9 CAR-IL15 T-cell therapy downregulated CLDN18.2 expression, suggesting immune escape through the selection of antigen-negative cells under persistent CAR-T-cell immune pressure. In conclusion, our findings provide preclinical evidence supporting the clinical evaluation of IL-15-expressing CLDN18.2 CAR-T cells in patients with CLDN18.2-positive tumors.

187. What are NLRP3-ASC specks? an experimental progress of 22 years of inflammasome research.

Front Immunol

2023 Jul 26

Nagar A, Bharadwaj R, Shaikh MOF

188. C-reactive protein: a target for therapy to reduce inflammation.

Front Immunol

2023 Jul 26

Rizo-Téllez SA, Sekheri M, Filep JG.

189. Specific attributes of the V(L) domain influence both the structure and structural variability of CDR-H3 through steric effects.

Front Immunol

2023 Jul 26

Guloglu B, Deane CM.

190. T-lymphocytes from focused ultrasound ablation subsequently mediate cellular antitumor immunity after adoptive cell transfer immunotherapy.

Front Immunol

2023 Jul 26

Ran LF, Xie XP, Xia JZ

191. Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.

Front Immunol

2023 Jul 26

Tao H, Zhong X, Zeng A

192. Microglial crosstalk with astrocytes and immune cells in amyotrophic lateral sclerosis.

Front Immunol

2023 Jul 26

Calafatti M, Cocozza G, Limatola C

193. Salvianolic acid B ameliorates neuroinflammation and neuronal injury via blocking NLRP3 inflammasome and promoting SIRT1 in experimental subarachnoid hemorrhage.

Front Immunol

2023 Jul 26

Xia D, Yuan J, Wu D

194. Case Report: Life-threatening pancytopenia with tislelizumab followed by cerebral infarction in a patient with lung adenocarcinoma.

Front Immunol

2023 Jul 25

Gu HY, Zhao JW, Wang YS

195. Identification of the novel FOXP3-dependent T(reg) cell transcription factor MEOX1 by high-dimensional analysis of human CD4(+) T cells.

Front Immunol

2023 Jul 25

Baßler K, Schmidleithner L, Shakiba MH

196. Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets.

Front Immunol

2023 Jul 25

Li J, Wang Y, Deng H

197. Molecular signature associated with cladribine treatment in patients with multiple sclerosis.

Front Immunol

2023 Jul 25

Fissolo N, Calvo-Barreiro L, Eixarch H

INTRODUCTION: Little is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment response biomarkers to cladribine in patients with MS. METHODS: Gene, protein and microRNA (miRNA) expression profiles were determined by microarrays (genes, miRNAs) and mass spectrometry (proteins) in peripheral blood mononuclear cells (PBMCs) from MS patients after in vitro treatment with cladribine in its active and inactive forms. Two bioinformatics approaches to integrate the three obtained datasets were applied: (i) a multiomics discriminant analysis (DIABLO - Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies); and (ii) a multi-stage integration of features selected in differential expression analysis on each dataset and then merged. Selected molecules from the in vitro study were quantified by qPCR ex vivo in PBMCs from MS patients receiving cladribine. RESULTS: PBMCs treated in vitro with cladribine were characterized by a major downregulation of gene, protein, and miRNA expression compared with the untreated cells. An intermediate pattern between the cladribine-treated and untreated conditions was observed in PBMCs treated with cladribine in its inactive form. The differential expression analysis of each dataset led to the identification of four genes and their encoded proteins, and twenty-two miRNAs regulating their expression, that were associated with cladribine treatment. Two of these genes (PPIF and NHLRC2), and three miRNAs (miR-21-5p, miR-30b-5p, and miR-30e-5p) were validated ex vivo in MS patients treated with cladribine. DISCUSSION: By using a combination of omics data and bioinformatics approaches we were able to identify a multiomics molecular profile induced by cladribine in vitro in PBMCs. We also identified a number of biomarkers that were validated ex vivo in PBMCs from patients with MS treated with cladribine that have the potential to become treatment response biomarkers to this drug.

198. Immunogenicity and reactogenicity of inactivated SARS-CoV-2 vaccines in healthy adults.

Front Immunol

2023 Jul 25

Wu Y, Huang P, Xu M

199. A luminescence-based method to assess antigen presentation and antigen-specific T cell responses for in vitro screening of immunomodulatory checkpoints and therapeutics.

Front Immunol

2023 Jul 25

Álvarez Freile J, Qi Y, Jacob L

200. Clonal composition and differentiation stage of human CD30(+) B cells in reactive lymph nodes.

Front Immunol

2023 Jul 25

Küppers R, Budeus B, Hartmann S

201. Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis.

Front Immunol

2023 Jul 25

Farley AM, Chengrui A, Palmer S

202. Role of epithelial sodium channel-related inflammation in human diseases.

Front Immunol

2023 Jul 25

Chen Y, Yu X, Yan Z

203. Unraveling tumor specific neoantigen immunogenicity prediction: a comprehensive analysis.

Front Immunol

2023 Jul 25

Nibeyro G, Baronetto V, Folco JI

204. Cell type-specific roles of NLRP3, inflammasome-dependent and -independent, in host defense, sterile necroinflammation, tissue repair, and fibrosis.

Front Immunol

2023 Jul 25

Honda TSB, Ku J, Anders HJ.

205. The anti-PD-1 era of cervical cancer: achievement, opportunity, and challenge.

Front Immunol

2023 Jul 25

Li C, Cang W, Gu Y

206. T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis.

Front Immunol

2023 Jul 25

Schultz AB, Kugler DG, Nivelo L

207. Cysticercus pisiformis-derived novel-miR1 targets TLR2 to inhibit the immune response in rabbits.

Front Immunol

2023 Jul 25

Chen G, Pu G, Wang L

208. Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM.

Front Immunol

2023 Jul 25

Wong S, Hamidi H, Costa LJ

209. Identification of prior dengue-naïve Dengvaxia recipients with an increased risk for symptomatic dengue during fever surveillance in the Philippines.

Front Immunol

2023 Jul 24

Dai YC, Sy AK, Jiz M

INTRODUCTION: Dengue virus (DENV) is the leading cause of mosquito-borne viral diseases in humans. Dengvaxia, the first licensed dengue vaccine, is recommended for DENV-seropositive individuals aged 9-45 years. In the Philippines, Dengvaxia was administered to more than 830,000 children without prior serological testing in 2016-2017. Subsequently, it was revealed that DENV-seronegative children who received Dengvaxia developed severe disease following breakthrough DENV infection. As a result, thousands of children participating in the mass vaccination campaign were at higher risk of severe dengue disease. It is vital that an assay that identifies baseline DENV-naïve Dengvaxia recipients be developed and validated. This would permit more frequent and extensive assessments and timely treatment of breakthrough DENV infections. METHODS: We evaluated the performance of a candidate assay, the DENV1-4 nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay (ELISA), developed by the University of Hawaii (UH), using well-documented serum/plasma samples including those >20 years post-DENV infection, and tested samples from 199 study participants including 100 Dengvaxia recipients from the fever surveillance programs in the Philippines. RESULTS: The sensitivity and specificity of the assay were 96.6% and 99.4%, respectively, which are higher than those reported for pre-vaccination screening. A significantly higher rate of symptomatic breakthrough DENV infection was found among children that were DENV-naïve (10/23) than among those that were DENV-immune (7/53) when vaccinated with Dengvaxia (p=0.004, Fisher's exact test), demonstrating the feasibility of the assay and algorithms in clinical practice. CONCLUSION: The UH DENV1-4 NS1 IgG ELISA can determine baseline DENV serostatus among Dengvaxia recipients not only during non-acute dengue but also during breakthrough DENV infection, and has implications for assessing the long-term safety and effectiveness of Dengvaxia in the post-licensure period.

210. The predictive values of monocyte-lymphocyte ratio in postoperative acute kidney injury and prognosis of patients with Stanford type A aortic dissection.

Front Immunol

2023 Jul 24

Chen Y, Dong K, Fang C

OBJECTIVES: Postoperative acute kidney injury (pAKI) is a serious complication of Stanford type A aortic dissection (TAAD) surgery, which is significantly associated with the inflammatory response. This study aimed to explore the relationship between blood count-derived inflammatory markers (BCDIMs) and pAKI and to construct a predictive model for pAKI. METHODS: Patients who underwent TAAD surgery were obtained from our center and the Medical Information Mart for Intensive Care (MIMIC)-IV database. The differences in preoperative BCDIMs and clinical outcomes of patients with and without pAKI were analyzed. Logistic regression was used to construct predictive models based on preoperative BCDIMs or white cell counts (WCCs). The performance of the BCDIMs and WCCs models was evaluated and compared using the receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), Hosmer-Lemeshow test, calibration plot, net reclassification index (NRI), integrated discrimination improvement index (IDI), and decision curve analysis (DCA). The Kaplan-Meier curves were applied to compare the survival rate between different groups. RESULTS: The overall incidence of pAKI in patients who underwent TAAD surgery from our center was 48.63% (124/255). The presence of pAKI was associated with longer ventilation time, higher incidence of cerebral complications and postoperative hepatic dysfunction, and higher in-hospital mortality. The results of the logistic regression indicated that the monocyte-lymphocyte ratio (MLR) was an independent risk factor for pAKI. The BCDIMs model had good discriminating ability, predictive ability, and clinical utility. In addition, the performance of the BCDIMs model was significantly better than that of the WCCs model. Analysis of data from the MIMIC-IV database validated that MLR was an independent risk factor for pAKI and had predictive value for pAKI. Finally, data from the MIMIC-IV database demonstrated that patients with a high MLR had a significantly poor 28-day survival rate when compared to patients with a low MLR. CONCLUSION: Our study suggested that the MLR is an independent risk factor for pAKI. A predictive model based on BCDIMs had good discriminating ability, predictive ability, and clinical utility. Moreover, the performance of the BCDIMs model was significantly better than that of the WCCs model. Finally, a high MLR was significantly associated with poor short-term survival of patients who underwent TAAD surgery.

211. Machine-learning algorithm-based prediction of a diagnostic model based on oxidative stress-related genes involved in immune infiltration in diabetic nephropathy patients.

Front Immunol

2023 Jul 24

Zhu HM, Liu N, Sun DX

Diabetic nephropathy (DN) is the most prevalent microvascular consequence of diabetes and has recently risen to the position of the world's second biggest cause of end-stage renal diseases. Growing studies suggest that oxidative stress (OS) responses are connected to the advancement of DN. This study aimed to developed a novel diagnostic model based on OS-related genes. The differentially expressed oxidative stress-related genes (DE-OSRGs) experiments required two human gene expression datasets, which were given by the GEO database (GSE30528 and GSE96804, respectively). The potential diagnostic genes were identified using the SVM-RFE assays and the LASSO regression model. CIBERSORT was used to determine the compositional patterns of the 22 different kinds of immune cell fraction seen in DN. These estimates were based on the combined cohorts. DN serum samples and normal samples were both subjected to RT-PCR in order to investigate the degree to which certain genes were expressed. In this study, we were able to locate 774 DE-OSRGs in DN. The three marker genes (DUSP1, PRDX6 and S100A8) were discovered via machine learning on two different machines. The high diagnostic value was validated by ROC tests, which focused on distinguishing DN samples from normal samples. The results of the CIBERSORT study suggested that DUSP1, PRDX6, and S100A8 may be associated to the alterations that occur in the immunological microenvironment of DN patients. Besides, the results of RT-PCR indicated that the expression of DUSP1, PRDX6, and S100A8 was much lower in DN serum samples compared normal serum samples. The diagnostic value of the proposed model was likewise verified in our cohort, with an area under the curve of 9.946. Overall, DUSP1, PRDX6, and S100A8 were identified to be the three diagnostic characteristic genes of DN. It's possible that combining these genes will be effective in diagnosing DN and determining the extent of immune cell infiltration.

212. Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth.

Front Immunol

2023 Jul 24

Jeong S, Cho WK, Jo Y

BACKGROUND: Microenvironmental factors, including microbe-induced inflammation and immune-checkpoint proteins that modulate immune cells have been associated with both cervical insufficiency and preterm delivery. These factors are incompletely understood. This study aimed to explore and compare interactions among microbiome and inflammatory factors, such as cytokines and immune-checkpoint proteins, in patients with cervical insufficiency and preterm birth. In particular, factors related to predicting preterm birth were identified and the performance of the combination of these factors was evaluated. METHODS: A total of 220 swab samples from 110 pregnant women, prospectively recruited at the High-Risk Maternal Neonatal Intensive Care Center, were collected between February 2020 and March 2021. This study included 63 patients with cervical insufficiency receiving cerclage and 47 control participants. Endo- and exocervical swabs and fluids were collected simultaneously. Shotgun metagenomic sequencing for the microbiome and the measurement of 34 immune-checkpoint proteins and inflammatory cytokines were performed. RESULTS: First, we demonstrated that immune-checkpoint proteins, the key immune-regulatory molecules, could be measured in endocervical and exocervical samples. Secondly, we identified significantly different microenvironments in cervical insufficiency and preterm birth, with precise cervical locations, to provide information about practically useful cervical locations in clinical settings. Finally, the presence of Moraxella osloensis (odds ratio = 14.785; P = 0.037) and chemokine CC motif ligand 2 levels higher than 73 pg/mL (odds ratio = 40.049; P = 0.005) in endocervical samples were associated with preterm birth. Combining M. osloensis and chemokine CC motif ligand 2 yielded excellent performance for predicting preterm birth (area under the receiver operating characteristic curve = 0.846, 95% confidence interval = 0.733-0.925). CONCLUSION: Multiple relationships between microbiomes, immune-checkpoint proteins, and inflammatory cytokines in the cervical microenvironment were identified. We focus on these factors to aid in the comprehensive understanding and therapeutic modulation of local microbial and immunologic compositions for the management of cervical insufficiency and preterm birth.

213. Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

Front Immunol

2023 Jul 24

Feng C, Zhang L, Chang X

214. Strategies for overcoming bottlenecks in allogeneic CAR-T cell therapy.

Front Immunol

2023 Jul 24

Lv Z, Luo F, Chu Y.

215. Inhibition of NK1.1 signaling attenuates pressure overload-induced heart failure, and consequent pulmonary inflammation and remodeling.

Front Immunol

2023 Jul 24

He X, Xu R, Pan L

216. Risk factors for multiple sclerosis in the context of Epstein-Barr virus infection.

Front Immunol

2023 Jul 24

Hedström AK.

217. GPR182 is a broadly scavenging atypical chemokine receptor influencing T-independent immunity.

Front Immunol

2023 Jul 24

Melgrati S, Gerken OJ, Artinger M

218. Immunoprecipitation methods impact the peptide repertoire in immunopeptidomics.

Front Immunol

2023 Jul 21

Wacker M, Bauer J, Wessling L

219. A comprehensive analysis of biomarkers associated with synovitis and chondrocyte apoptosis in osteoarthritis.

Front Immunol

2023 Jul 21

Yang L, Yu X, Liu M

INTRODUCTION: Osteoarthritis (OA) is a chronic disease with high morbidity and disability rates whose molecular mechanism remains unclear. This study sought to identify OA markers associated with synovitis and cartilage apoptosis by bioinformatics analysis. METHODS: A total of five gene-expression profiles were selected from the Gene Expression Omnibus database. We combined the GEO with the GeneCards database and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses; then, the least absolute shrinkage and selection operator (LASSO) algorithm was used to identify the characteristic genes, and a predictive risk score was established. We used the uniform manifold approximation and projection (UMAP) method to identify subtypes of OA patients, while the CytoHubba algorithm and GOSemSim R package were used to screen out hub genes. Next, an immunological assessment was performed using single-sample gene set enrichment analysis and CIBERSORTx. RESULTS: A total of 56OA-related differential genes were selected, and 10 characteristic genes were identified by the LASSO algorithm. OA samples were classified into cluster 1 and cluster 2 subtypes byUMAP, and the clustering results showed that the characteristic genes were significantly different between these groups. MYOC, CYP4B1, P2RY14, ADIPOQ, PLIN1, MFAP5, and LYVE1 were highly expressed in cluster 2, and ANKHLRC15, CEMIP, GPR88, CSN1S1, TAC1, and SPP1 were highly expressed in cluster 1. Protein-protein interaction network analysis showed that MMP9, COL1A, and IGF1 were high nodes, and the differential genes affected the IL-17 pathway and tumor necrosis factor pathway. The GOSemSim R package showed that ADIPOQ, COL1A, and SPP1 are closely related to the function of 31 hub genes. In addition, it was determined that mmp9 and Fos interact with multiple transcription factors, and the ssGSEA and CIBERSORTx algorithms revealed significant differences in immune infiltration between the two OA subtypes. Finally, a qPCR experiment was performed to explore the important genes in rat cartilage and synovium tissues; the qPCR results showed that COL1A and IL-17A were both highly expressed in synovitis tissues and cartilage tissues of OA rats, which is consistent with the predicted results. DISCUSSION: In the future, common therapeutic targets might be found forsimultaneous remissions of both phenotypes of OA.

220. Targeting reactive oxygen species and fat acid oxidation for the modulation of tumor-associated macrophages: a narrative review.

Front Immunol

2023 Jul 21

Teng Y, Xu L, Li W

221. Glutaminolysis and peripheral CD4(+) T cell differentiation: from mechanism to intervention strategy.

Front Immunol

2023 Jul 21

Liu T, Ren S, Sun C

222. Prognostic nutritional index as a prognostic biomarker for gastrointestinal cancer patients treated with immune checkpoint inhibitors.

Front Immunol

2023 Jul 21

Zhang L, Ma W, Qiu Z

223. Di(2-ethylhexyl) phthalate mediates IL-33 production via aryl hydrocarbon receptor and is associated with childhood allergy development.

Front Immunol

2023 Jul 21

Tsai ML, Hsu SH, Wang LT

224. The effect of calcitriol on the development and implantation capacity of embryos from hyper-stimulated mice.

Front Immunol

2023 Jul 21

Bognár Z, Csabai-Tanics TJ, Görgey É

225. Intratumoral NKp46(+) natural killer cells are spatially distanced from T and MHC-I(+) cells with prognostic implications in soft tissue sarcoma.

Front Immunol

2023 Jul 21

Cruz SM, Sholevar CJ, Judge SJ

226. Adenosine pathway regulates inflammation during Plasmodium vivax infection.

Front Immunol

2023 Jul 21

Diniz SQ, Figueiredo MM, Costa PAC

227. Application of spatial transcriptomics analysis using the Visium system for the mouse nasal cavity after intranasal vaccination.

Front Immunol

2023 Jul 21

Toyama S, Honda T, Iwabuchi S

Intranasal vaccines that elicit mucosal immunity are deemed effective against respiratory tract infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their ability to induce humoral immunity characterized by immunoglobulin A (IgA) and IgG production is low. It has been reported that vaccination with a mixture of a viscous base carboxyvinyl polymer (CVP) and viral antigens induced robust systemic and mucosal immune responses. In this study, we analyzed the behavior of immunocompetent cells in the nasal cavity over time by spatial transcriptome profiling induced immediately after antigen vaccination using CVP. We established a method for performing spatial transcriptomics using the Visium system in the mouse nasal cavity and analyzed gene expression profiles within the nasal cavity after intranasal vaccination. Glycoprotein 2 (Gp2)-, SRY-box transcription factor 8 (Sox8)-, or Spi-B transcription factor (Spib)-expressing cells were increased in the nasal passage (NP) region at 3-6 hr after SARS-CoV-2 spike protein and CVP (S-CVP) vaccination. The results suggested that microfold (M) cells are activated within a short period of time (3-6 hr). Subsequent cluster analysis of cells in the nasal cavity showed an increase in Cluster 9 at 3-6 hr after intranasal vaccination with the S-CVP. We found that Il6 in Cluster 9 had the highest log2 fold values within the NP at 3-6 hr. A search for gene expression patterns similar to that of Il6 revealed that the log2 fold values of Edn2, Ccl20, and Hk2 also increased in the nasal cavity after 3-6 hr. The results showed that the early response of immune cells occurred immediately after intranasal vaccination. In this study, we identified changes in gene expression that contribute to the activation of M cells and immunocompetent cells after intranasal vaccination of mice with antigen-CVP using a time-series analysis of spatial transcriptomics data. The results facilitated the identification of the cell types that are activated during the initial induction of nasal mucosal immunity.

228. Retained avidity despite reduced cross-binding and cross-neutralizing antibody levels to Omicron after SARS-COV-2 wild-type infection or mRNA double vaccination.

Front Immunol

2023 Jul 21

Harthaller T, Falkensammer B, Bante D

229. Low T-cell reactivity to TDP-43 peptides in ALS.

Front Immunol

2023 Jul 21

Ramachandran S, Grozdanov V, Leins B

230. Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRβ complex in hepatocellular carcinoma.

Front Immunol

2023 Jul 21

Yang J, Guo Z, Song M

231. Safety and efficacy of transarterial chemoembolization combined with tyrosine kinase inhibitors and camrelizumab in the treatment of patients with advanced unresectable hepatocellular carcinoma.

Front Immunol

2023 Jul 21

Li J, Kong M, Yu G

232. Building better barriers: how nutrition and undernutrition impact pediatric intestinal health.

Front Immunol

2023 Jul 21

Andres SF, Zhang Y, Kuhn M

233. Rai14 is a novel interactor of Invariant chain that regulates macropinocytosis.

Front Immunol

2023 Jul 21

Lobos Patorniti N, Zulkefli KL, McAdam ME

234. Modeling the tumor microenvironment of anaplastic thyroid cancer: an orthotopic tumor model in C57BL/6 mice.

Front Immunol

2023 Jul 21

Xu Z, Shin HS, Kim YH

INTRODUCTION: Securing a well-established mouse model is important in identifying and validating new therapeutic targets for immuno-oncology. The C57BL/6 mouse is one of the most fully characterised immune system of any animal and provides powerful platform for immuno-oncology discovery. An orthotopic tumor model has been established using TBP3743 (murine anaplastic thyroid cancer [ATC]) cells in B6129SF1 hybrid mice, this model has limited data on tumor immunology than C57BL/6 inbred mice. This study aimed to establish a novel orthotopic ATC model in C57BL/6 mice and characterize the tumor microenvironment focusing immunity in the model. METHODS: Adapted TBP3743 cells were generated via in vivo serial passaging in C57BL/6 mice. Subsequently, the following orthotopic tumor models were established via intrathyroidal injection: B6129SF1 mice injected with original TBP3743 cells (original/129), B6129SF1 mice injected with adapted cells (adapted/129), and C57BL/6 mice injected with adapted cells (adapted/B6). RESULTS: The adapted TBP3743 cells de-differentiated but exhibited cell morphology, viability, and migration/invasion potential comparable with those of original cells in vitro. The adapted/129 contained a higher Ki-67+ cell fraction than the original/129. RNA sequencing data of orthotopic tumors revealed enhanced oncogenic properties in the adapted/129 compared with those in the original/129. In contrast, the orthotopic tumors grown in the adapted/B6 were smaller, with a lower Ki-67+ cell fraction than those in the adapted/129. However, the oncogenic properties of the tumors within the adapted/B6 and adapted/129 were similar. Immune-related pathways were enriched in the adapted/B6 compared with those in the adapted/129. Flow cytometric analysis of the orthotopic tumors revealed higher cytotoxic CD8+ T cell and monocytic-myeloid-derived suppressor cell fractions in the adapted/B6 compared with the adapted/129. The estimated CD8+ and CD4+ cell fractions in the adapted/B6 were similar to those in human ATCs but negligible in the original/B6. CONCLUSION: A novel orthotopic tumor model of ATC was established in C57BL/6 mice. Compared with the original B6129SF1 murine model, the novel model exhibited more aggressive tumor cell behaviours and strong immune responses. We expect that this novel model contributes to the understanding tumor microenvironment and provides the platform for drug development.

235. B lymphocytes transdifferentiate into immunosuppressive erythroblast-like cells.

Front Immunol

2023 Jul 21

Yang Z, Wang Z, Wu L

236. HDAC6 inhibition: a significant potential regulator and therapeutic option to translate into clinical practice in renal transplantation.

Front Immunol

2023 Jul 21

Zhang QQ, Zhang WJ, Chang S.

237. Evaluation of humoral immune response in relation to COVID-19 severity over 1 year post-infection: critical cases higher humoral immune response than mild cases.

Front Immunol

2023 Jul 21

Bang MS, Kim CM, Cho NH

238. Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment.

Front Immunol

2023 Jul 21

Chen L, Wang Y, Hu Q

239. Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols.

Front Immunol

2023 Jul 21

Jin Q, Liu T, Qiao Y

240. Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment.

Front Immunol

2023 Jul 20

Vanselow S, Wahn V, Schuetz C.

241. sc-ImmuCC: hierarchical annotation for immune cell types in single-cell RNA-seq.

Front Immunol

2023 Jul 20

Jiang Y, Chen Z, Han N

242. Inhibition of MC38 colon cancer growth by multicomponent chemoimmunotherapy with anti-IL-10R antibodies, HES-MTX nanoconjugate, depends on application of IL-12, IL-15 or IL-18 secreting dendritic cell vaccines.

Front Immunol

2023 Jul 20

Węgierek-Ciura K, Mierzejewska J, Szczygieł A

BACKGROUND: The tumor microenvironment (TME) provides a conducive environment for the growth and survival of tumors. Negative factors present in TME, such as IL-10, may limit the effectiveness of cellular vaccines based on dendritic cells, therefore, it is important to control its effect. The influence of IL-10 on immune cells can be abolished e.g., by using antibodies against the receptor for this cytokine - anti-IL-10R. Furthermore, the anticancer activity of cellular vaccines can be enhanced by modifying them to produce proinflammatory cytokines, such as IL-12, IL-15 or IL-18. Additionally, an immunomodulatory dose of methotrexate and hydroxyethyl starch (HES-MTX) nanoconjugate may stimulate effector immune cells and eliminate regulatory T cells, which should enhance the antitumor action of immunotherapy based on DC vaccines. The main aim of our study was to determine whether the HES-MTX administered before immunotherapy with anti-IL-10R antibodies would change the effect of vaccines based on dendritic cells overproducing IL-12, IL-15, or IL-18. METHODS: The activity of modified DCs was checked in two therapeutic protocols - immunotherapy with the addition of anti-IL10R antibodies and chemoimmunotherapy with HES-MTX and anti-IL10R antibodies. The inhibition of tumor growth and the effectiveness of the therapy in inducing a specific antitumor response were determined by analyzing lymphoid and myeloid cell populations in tumor nodules, and the activity of restimulated splenocytes. RESULTS AND CONCLUSIONS: Using the HES-MTX nanoconjugate before immunotherapy based on multiple administrations of anti-IL-10R antibodies and cellular vaccines capable of overproducing proinflammatory cytokines IL-12, IL-15 or IL-18 created optimal conditions for the effective action of these vaccines in murine colon carcinoma MC38 model. The applied chemoimmunotherapy caused the highest inhibition of tumor growth in the group receiving DC/IL-15/IL-15Rα/TAg + DC/IL-18/TAg at the level of 72.4%. The use of cellular vaccines resulted in cytotoxic activity increase in both immuno- or chemoimmunotherapy. However, the greatest potential was observed both in tumor tissue and splenocytes obtained from mice receiving two- or three-component vaccines in the course of combined application. Thus, the designed treatment schedule may be promising in anticancer therapy.

243. Intranasal immunization with a Bucl8-based vaccine ameliorates bacterial burden and pathological inflammation, and promotes an IgG2a/b dominant response in an outbred mouse model of Burkholderia infection.

Front Immunol

2023 Jul 20

Grund M, Choi SJ, Powell L

Burkholderia pseudomallei is a gram-negative bacterium that is the etiological agent of the tropical disease melioidosis. Currently, there is no licensed vaccine for melioidosis, but numerous candidates are being tested for protective efficacy and characterization of the elicited immune response. Our lab has previously reported the immunogenicity of a Bucl8-protein-based peptide antigen, designated L1-CRM197 (Cross-reacting material 197). When given subcutaneously, this vaccine formulation promoted a strong Th2 (IgG1) antibody response, however immunization did not protect from death. In this study, we hypothesized that an intranasally administered L1-CRM197 vaccine would induce protective mucosal immunity. To evaluate vaccine efficacy, we developed a surrogate Burkholderia infection model that employs outbred CD-1 mice which imitates the immunogenetic diversity of humans. Mice were immunized with either L1-CRM197 adjuvanted with fluorinated cyclic diguanosine monophosphate (FCDG) or with FCDG-only control. These mice were then challenged intranasally with an infectious dose of a luminescent strain of B. thailandensis E264 two weeks post-immunization, and correlates of protection were assessed in euthanized mice on days 1, 2, 3, and 7 post-infection. Overall, intranasal vaccination, compared to subcutaneous administration, induced a stronger Th1 (IgG2a/2b) to Th2 (IgG1) antibody response and promoted anti-L1 nasal, pulmonary, and systemic IgA. Additionally, sera IgG from L1-CRM197-vaccinated mice recognized whole-cell B. thailandensis and B. pseudomallei, a select agent exempt strain Bp82. Vaccination ameliorated disease indicators, including luminescent signal and bacterial cell counts, weight and temperature loss, and organ weight, which negatively correlated with IgG2a antibody levels and mucosa-stimulating cytokines IL-13 and IL-9. L1-CRM197-vaccinated mice also had earlier resolution of inflammatory and tissue-damaging cytokines compared to the FCDG-only controls. These results suggest a balanced humoral and cell-mediated response, along with mucosa-based immunity are beneficial for protection. Future efforts should further assess mucosal cellular and humoral mechanisms of protection and test such protection, using aerosolized B. pseudomallei select agent strain(s).

244. SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling.

Front Immunol

2023 Jul 20

López-Ayllón BD, de Lucas-Rius A, Mendoza-García L

245. Suppressive myeloid cells in SARS-CoV-2 and Mycobacterium tuberculosis co-infection.

Front Immunol

2023 Jul 20

Shaw JA, Malherbe ST, Walzl G

246. Anti-interleukin 4 receptor α antibody for the treatment of Chinese bullous pemphigoid patients with diverse comorbidities and a 1-year follow-up: a monocentric real-world study.

Front Immunol

2023 Jul 20

Wang SH, Shan Y, Li SZ

247. Potential therapeutic targets of macrophages in inhibiting immune damage and fibrotic processes in musculoskeletal diseases.

Front Immunol

2023 Jul 20

Zhu J, Fan J, Xia Y

248. Disturbed lipid profile in common variable immunodeficiency - a pathogenic loop of inflammation and metabolic disturbances.

Front Immunol

2023 Jul 20

Jorgensen SF, Macpherson ME, Skarpengland T

249. Development of a novel immune infiltration-related diagnostic model for Alzheimer's disease using bioinformatic strategies.

Front Immunol

2023 Jul 20

Zhuang X, Zhang G, Bao M

BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex and multi-factorial. Increasing evidence has shown the important role of immune infiltration in AD. Thus the current study was designed to identify immune infiltration-related genes and to explore their diagnostic value in AD. METHODS: The expression data of AD patients were downloaded from the GEO database. The limma R package identified differentially expressed genes (DEGs) between AD and controls. The CIBERSORT algorithm identified differentially infiltrated immune cells (DIICs) between AD and controls. DIIC-correlated DEGs were obtained by Pearson correlation analysis. WGCNA was employed to identify DIIC-related modules. Next, LASSO, RFE, and RF machine learning methods were applied to screen robust DIIC-related gene signatures in AD, followed by the construction and validation of a diagnostic nomogram. Detection of the expression of related genes in the peripheral blood of Alzheimer's disease and healthy volunteers by RT-PCR. In addition, the CTD database predicted chemicals targeting DIIC-related gene signatures in the treatment of AD. RESULTS: NK cells, M0 macrophages, activated myeloid dendritic cells, resting mast cells, CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, and M2 macrophages were differentially infiltrated between AD and controls. Pearson analysis identified a total of 277 DIIC-correlated DEGs between AD and controls. Thereafter, 177 DIIC-related genes were further obtained by WGCNA analysis. By LASSO, RFE and RF algorithms, CMTM2, DDIT4, LDHB, NDUFA1, NDUFB2, NDUFS5, RPL17, RPL21, RPL26 and NDUFAF2 were identified as robust gene signature in AD. The results of RT-PCR detection of peripheral blood samples from Alzheimer's disease and healthy volunteers showed that the expression trend of ten genes screened was consistent with the detection results; among them, the expression levels of CMTM2, DDIT4, LDHB, NDUFS5, and RPL21 are significantly different among groups. Thus, a diagnostic nomogram based on a DIIC-related signature was constructed and validated. Moreover, candidate chemicals targeting those biomarkers in the treatment of AD, such as 4-hydroxy-2-nonenal, rosiglitazone, and resveratrol, were identified in the CTD database. CONCLUSION: For the first time, we identified 10 immune infiltration-related biomarkers in AD, which may be helpful for the diagnosis of AD and provide guidance in the treatment of AD.

250. SARS-CoV-2 infection risk is higher in vaccinated patients with inflammatory autoimmune diseases or liver transplantation treated with mycophenolate due to an impaired antiviral immune response: results of the extended follow up of the RIVALSA prospective cohort.

Front Immunol

2023 Jul 20

Rizzi M, Tonello S, Brinno C

251. Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model.

Front Immunol

2023 Jul 20

Assil S, Buters TP, Hameeteman PW

252. Comprehensive analysis and immune landscape of chemokines- and chemokine receptors-based signature in hepatocellular carcinoma.

Front Immunol

2023 Jul 20

Zhang Z, Mao M, Wang F

BACKGROUND: Despite encouraging results from immunotherapy combined with targeted therapy for hepatocellular carcinoma (HCC), the prognosis remains poor. Chemokines and their receptors are an essential component in the development of HCC, but their significance in HCC have not yet been fully elucidated. We aimed to establish chemokine-related prognostic signature and investigate the association between the genes and tumor immune microenvironment (TIME). METHODS: 342 HCC patients have screened from the TCGA cohort. A prognostic signature was developed using least absolute shrinkage and selection operator regression and Cox proportional risk regression analysis. External validation was performed using the LIHC-JP cohort deployed from the ICGC database. Single-cell RNA sequencing (scRNA-seq) data from the GEO database. Two nomograms were developed to estimate the outcome of HCC patients. RT-qPCR was used to validate the differences in the expression of genes contained in the signature. RESULTS: The prognostic signature containing two chemokines-(CCL14, CCL20) and one chemokine receptor-(CCR3) was successfully established. The HCC patients were stratified into high- and low-risk groups according to their median risk scores. We found that patients in the low-risk group had better outcomes than those in the high-risk group. The results of univariate and multivariate Cox regression analyses suggested that this prognostic signature could be considered an independent risk factor for the outcome of HCC patients. We discovered significant differences in the infiltration of various immune cell subtypes, tumor mutation burden, biological pathways, the expression of immune activation or suppression genes, and the sensitivity of different groups to chemotherapy agents and small molecule-targeted drugs in the high- and low-risk groups. Subsequently, single-cell analysis results showed that the higher expression of CCL20 was associated with HCC metastasis. The RT-qPCR results demonstrated remarkable discrepancies in the expression of CCL14, CCL20, and CCR3 between HCC and its paired adjacent non-tumor tissues. CONCLUSION: In this study, a novel prognostic biomarker explored in depth the association between the prognostic model and TIME was developed and verified. These results may be applied in the future to improve the efficacy of immunotherapy or targeted therapy for HCC.

253. Exome sequencing to explore the possibility of predicting genetic susceptibility to the joint occurrence of polycystic ovary syndrome and Hashimoto's thyroiditis.

Front Immunol

2023 Jul 20

Zeber-Lubecka N, Suchta K, Kulecka M

254. NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines.

Front Immunol

2023 Jul 20

Mueller-Enz M, Woopen C, Katoul Al Rahbani G

IMPORTANCE: Immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies. OBJECTIVE: This study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination. DESIGN SETTING AND PARTICIPANTS: We conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S). INTERVENTIONS: Intramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up. MAIN OUTCOMES AND MEASURES: The development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated. RESULTS: For the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination. CONCLUSIONS: Vaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.

255. A novel 3D spheroid model of rheumatoid arthritis synovial tissue incorporating fibroblasts, endothelial cells, and macrophages.

Front Immunol

2023 Jul 20

Philippon EML, van Rooijen LJE, Khodadust F

OBJECTIVE: Rheumatoid Arthritis (RA) is a progressive and systemic autoimmune disorder associated with chronic and destructive joint inflammation. The hallmarks of joint synovial inflammation are cellular proliferation, extensive neoangiogenesis and infiltration of immune cells, including macrophages. In vitro approaches simulating RA synovial tissue are crucial in preclinical and translational research to evaluate novel diagnostic and/or therapeutic markers. Two-dimensional (2D) settings present very limited in vivo physiological proximity as they cannot recapitulate cell-cell and cell-matrix interactions occurring in the three-dimensional (3D) tissue compartment. Here, we present the engineering of a spheroid-based model of RA synovial tissue which mimics 3D interactions between cells and pro-inflammatory mediators present in the inflamed synovium. METHODS: Spheroids were generated by culturing RA fibroblast-like-synoviocytes (RAFLS), human umbilical vein endothelial cells (ECs) and monocyte-derived macrophages in a collagen-based 3D scaffold. The spheroids were cultured in the presence or absence of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (bFGF) or RA synovial fluid (SF). Spheroid expansion and cell migration were quantified for all conditions using confocal microscopy and digital image analysis. RESULTS: A novel approach using machine learning was developed to quantify spheroid outgrowth and used to reexamine the existing spheroid-based model of RA synovial angiogenesis consisting of ECs and RAFLS. A 2-fold increase in the spheroid outgrowth ratio was demonstrated upon VEGF/bFGF stimulation (p<0.05). The addition of macrophages within the spheroid structure (3.75x104 RAFLS, 7.5x104 ECs and 3.0x104 macrophages) resulted in good incorporation of the new cell type. The addition of VEGF/bFGF significantly induced spheroid outgrowth (p<0.05) in the new system. SF stimulation enhanced containment of macrophages within the spheroids. CONCLUSION: We present a novel spheroid based model consisting of RAFLS, ECs and macrophages that reflects the RA synovial tissue microenvironment. This model may be used to dissect the role of specific cell types in inflammatory responses in RA, to study specific signaling pathways involved in the disease pathogenesis and examine the effects of novel diagnostic (molecular imaging) and therapeutic compounds, including small molecule inhibitors and biologics.

256. The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes.

Front Immunol

2023 Jul 20

Horitani S, Ueda Y, Kamioka Y

257. Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy.

Front Immunol

2023 Jul 20

Damei I, Trickovic T, Mami-Chouaib F

258. Divergent adaptive immune responses define two types of long COVID.

Front Immunol

2023 Jul 20

Kervevan J, Staropoli I, Slama D

BACKGROUND: The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination. METHODS: Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29). RESULTS: The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups. Multiplexed antibody analyses to 30 different viral antigens showed that LC- patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC- patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC- group. CONCLUSIONS: These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

259. Targeted degradation of MERTK and other TAM receptor paralogs by heterobifunctional targeted protein degraders.

Front Immunol

2023 Jul 20

Gadiyar V, Patel G, Chen J

260. Selenomethionine against titanium particle-induced osteolysis by regulating the ROS-dependent NLRP3 inflammasome activation via the β-catenin signaling pathway.

Front Immunol

2023 Jul 20

Yu R, Yuan Y, Liu Z

261. Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma.

Front Immunol

2023 Jul 20

Ju F, Wang D, Huang L

262. Alterations of natural killer cells activatory molecules phenotype and function in mothers of ASD children: a pilot study.

Front Immunol

2023 Jul 20

Saresella M, Marventano I, Piancone F

263. Clodronate is not protective in lethal viral encephalitis despite substantially reducing inflammatory monocyte infiltration in the CNS.

Front Immunol

2023 Jul 20

Spiteri AG, van Vreden C, Ashhurst TM

264. Reframing the link between metabolism and NLRP3 inflammasome: therapeutic opportunities.

Front Immunol

2023 Jul 20

Ortega MA, De Leon-Oliva D, García-Montero C

265. EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells.

Front Immunol

2023 Jul 20

Melo V, Nelemans LC, Vlaming M

266. Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis.

Front Immunol

2023 Jul 19

Li R, Guo Q, Zhao J

BACKGROUND: Accumulating evidence has suggested that gut microbiota dysbiosis is commonly observed in asthmatics. However, it remains unclear whether dysbiosis is a cause or consequence of asthma. We aimed to examine the genetic causal relationships of gut microbiota with asthma and its three phenotypes, including adult-onset asthma, childhood-onset asthma, and moderate-severe asthma. METHODS: To elucidate the causality of gut microbiota with asthma, we applied two sample Mendelian randomization (MR) based on the largest publicly available genome-wide association study (GWAS) summary statistics. Inverse variance weighting meta-analysis (IVW) was used to obtain the main estimates; and Weighted median, MR-Egger, Robust Adjusted Profile Score (MR-RAPS), Maximum likelihood method (ML), and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied in sensitivity analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. RESULTS: In the absence of heterogeneity and horizontal pleiotropy, the IVW method revealed that genetically predicted Barnesiella and RuminococcaceaeUCG014 were positively correlated with the risk of asthma, while the association between genetically predicted CandidatusSoleaferrea and asthma was negative. And for the three phenotypes of asthma, genetically predicted Akkermansia reduced the risk of adult-onset asthma, Collinsella and RuminococcaceaeUCG014 increased the risk of childhood-onset asthma, and FamilyXIIIAD3011group, Eisenbergiella, and Ruminiclostridium6 were correlated with the risk of moderate-severe asthma (all P<0.05). The reverse MR analysis didn't find evidence supporting the reverse causality from asthma and its three phenotypes to the gut microbiota genus. CONCLUSION: This study suggested that microbial genera were causally associated with asthma as well as its three phenotypes. The findings deepened our understanding of the role of gut microbiota in the pathology of asthma, which emphasizes the potential of opening up a new vista for the prevention and diagnosis of asthma.

267. Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells.

Front Immunol

2023 Jul 19

Yi Q, Yang J, Wu Y

268. An optimized cultivation method for future in vivo application of γδ T cells.

Front Immunol

2023 Jul 19

Bold A, Gross H, Holzmann E

269. Distribution and clinical significance of anti-carbamylation protein antibodies in rheumatological diseases among the Chinese Han population.

Front Immunol

2023 Jul 19

Dong R, Sun Y, Xu W

OBJECTIVE: Several studies have demonstrated that anti-carbamylation protein antibodies (Anti-CarPA) are persistent in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), primary Sjögren's syndrome (pSS), and interstitial lung disease associated with RA (RA-ILD). However, the relationship between anti-CarPA and other rheumatic diseases (RDs) and non-RA-ILD is not known till now. This study sought to examine the presence of anti-CarPA in Chinese Han patients with RDs and its clinical significance. METHODS: The study included 90 healthy controls (HCs) and 300 patients with RDs, including RA, SLE, polymyositis/dermatomyositis (PM/DM), pSS, SSC, spondyloarthritis (SpA), anti-neutrophil cytoplasmic autoantibodies associated with vasculitis (AAV), undifferentiated connective tissue disease (UCTD), and Behcet's disease (BD). Antibodies against carbamylated human serum albumin were detected using commercial enzyme-linked immunosorbent assay kits. Correlations between clinical and laboratory parameters were analyzed. RESULT: Serum levels of anti-CarPA in RA (34.43 ± 33.34 ng/ml), SLE (21.12 ± 22.23 ng/ml), pSS (16.32 ± 13.54 ng/ml), PM/DM (30.85 ± 17.34 ng/ml), SSC (23.53 ± 10.70 ng/ml), and UCTD (28.35 ± 21.91 ng/ml) were higher than those of anti-CarPA in the HCs (7.30 ± 5.05 ng/ml). The concentration of serum anti-CarPA was higher in patients with rheumatic disease-related interstitial lung disease (RD-ILD), especially RA-ILD, PM/DM-ILD, and pSS-ILD. Patients with RD-ILD who tested positive for anti-CarPA were more likely to have a more severe radiographic classification (grades II, p = 0.045; grades III, p = 0.003). Binary logistic regression analysis suggested that anti-CarPA had an association with ILD in RA (p = 0.033), PM/DM (p = 0.039), and pSS (p = 0.048). Based on receiver operating characteristics (ROC) analysis, anti-CarPA cutoffs best discriminated ILD in RA (>32.59 ng/ml, p = 0.050), PM/DM (>23.46 ng/ml, p = 0.038), and pSS (>37.08 ng/ml, p = 0.040). Moreover, serum levels of anti-CarPA were correlated with antibodies against transcription intermediary factor 1 complex (anti-TIF1) (R = -0.28, p = 0.044), antibodies against glycyl-transfer ribonucleic acid synthetase (anti-EJ) (R = 0.30, p = 0.031), and antibodies against melanoma differentiation-associated gene 5 (anti-MDA5) (R = 0.35, p = 0.011). CONCLUSION: Serum anti-CarPA could be detected in patients with RA, PM/DM, pSS, SSC, and UCTD among the Chinese Han population. And it may also assist in identifying ILD in patients with RA, PM/DM, and pSS, which emphasized attention to the lung involvement in anti-CarPA-positive patients.

270. Microenvironmental and cell intrinsic factors governing human cDC2 differentiation and monocyte reprogramming.

Front Immunol

2023 Jul 19

Lang M, Krump C, Meshcheryakova A

271. ChemR23 activation reprograms macrophages toward a less inflammatory phenotype and dampens carcinoma progression.

Front Immunol

2023 Jul 19

Lavy M, Gauttier V, Dumont A

INTRODUCTION: Tumor Associated Macrophages (TAM) are a major component of the tumor environment and their accumulation often correlates with poor prognosis by contributing to local inflammation, inhibition of anti-tumor immune response and resistance to anticancer treatments. In this study, we thus investigated the anti-cancer therapeutic interest to target ChemR23, a receptor of the resolution of inflammation expressed by macrophages, using an agonist monoclonal antibody, αChemR23. METHODS: Human GM-CSF, M-CSF and Tumor Associated Macrophage (TAM)-like macrophages were obtained by incubation of monocytes from healthy donors with GM-CSF, M-CSF or tumor cell supernatants (Breast cancer (BC) or malignant pleural mesothelioma (MPM) cells). The effects of αChemR23 on macrophages were studied at the transcriptomic, protein and functional level. Datasets from The Cancer Genome Atlas (TCGA) were used to study CMKLR1 expression, coding for ChemR23, in BC and MPM tumors. In vivo, αChemR23 was evaluated on overall survival, metastasis development and transcriptomic modification of the metastatic niche using a model of resected triple negative breast cancer. RESULTS: We show that ChemR23 is expressed at higher levels in M-CSF and tumor cell supernatant differentiated macrophages (TAM-like) than in GM-CSF-differentiated macrophages. ChemR23 activation triggered by αChemR23 deeply modulates M-CSF and TAM-like macrophages including profile of cell surface markers, cytokine secretion, gene mRNA expression and immune functions. The expression of ChemR23 coding gene (CMKLR1) strongly correlates to TAM markers in human BC tumors and MPM and its histological detection in these tumors mainly corresponds to TAM expression. In vivo, treatment with αChemR23 agonist increased mouse survival and decreased metastasis occurrence in a model of triple-negative BC in correlation with modulation of TAM phenotype in the metastatic niche. CONCLUSION: These results open an attractive opportunity to target TAM and the resolution of inflammation pathways through ChemR23 to circumvent TAM pro-tumoral effects.

272. Plasmodium curtails autoimmune nephritis via lasting bone marrow alterations, independent of hemozoin accumulation.

Front Immunol

2023 Jul 19

Amo L, Kole HK, Scott B

The host response against infection with Plasmodium commonly raises self-reactivity as a side effect, and antibody deposition in kidney has been cited as a possible cause of kidney injury during severe malaria. In contrast, animal models show that infection with the parasite confers long-term protection from lethal lupus nephritis initiated by autoantibody deposition in kidney. We have limited knowledge of the factors that make parasite infection more likely to induce kidney damage in humans, or the mechanisms underlying protection from autoimmune nephritis in animal models. Our experiments with the autoimmune-prone FcγR2B[KO] mice have shown that a prior infection with P. yoelii 17XNL protects from end-stage nephritis for a year, even when overall autoreactivity and systemic inflammation are maintained at high levels. In this report we evaluate post-infection alterations, such as hemozoin accumulation and compensatory changes in immune cells, and their potential role in the kidney-specific protective effect by Plasmodium. We ruled out the role of pigment accumulation with the use of a hemozoin-restricted P. berghei ANKA parasite, which induced a self-resolved infection that protected from autoimmune nephritis with the same mechanism as parasitic infections that accumulated normal levels of hemozoin. In contrast, adoptive transfer experiments revealed that bone marrow cells were altered by the infection and could transmit the kidney protective effect to a new host. While changes in the frequency of bone marrow cell populations after infection were variable and unique to a particular parasite strain, we detected a sustained bias in cytokine/chemokine expression that suggested lower fibrotic potential and higher Th1 bias likely affecting multiple cell populations. Sustained changes in bone marrow cell activation profile could have repercussions in immune responses long after the infection was cleared.

273. Surface plasmon resonance and microscale thermophoresis approaches for determining the affinity of perforin for calcium ions.

Front Immunol

2023 Jul 19

Naneh O, Kozorog M, Merzel F

274. Unveiling the key genes, environmental toxins, and drug exposures in modulating the severity of ulcerative colitis: a comprehensive analysis.

Front Immunol

2023 Jul 19

Wang Y, Zhuang H, Jiang XH

BACKGROUND: As yet, the genetic abnormalities involved in the exacerbation of Ulcerative colitis (UC) have not been adequately explored based on bioinformatic methods. MATERIALS AND METHODS: The gene microarray data and clinical information were downloaded from Gene Expression Omnibus (GEO) repository. The scale-free gene co-expression networks were constructed by R package "WGCNA". Gene enrichment analysis was performed via Metascape database. Differential expression analysis was performed using "Limma" R package. The "randomForest" packages in R was used to construct the random forest model. Unsupervised clustering analysis performed by "ConsensusClusterPlus"R package was utilized to identify different subtypes of UC patients. Heat map was established using the R package "pheatmap". Diagnostic parameter capability was evaluated by ROC curve. The"XSum"packages in R was used to screen out small-molecule drugs for the exacerbation of UC based on cMap database. Molecular docking was performed with Schrodinger molecular docking software. RESULTS: Via WGCNA, a total 77 high Mayo score-associated genes specific in UC were identified. Subsequently, the 9 gene signatures of the exacerbation of UC was screened out by random forest algorithm and Limma analysis, including BGN,CHST15,CYYR1,GPR137B,GPR4,ITGA5,LILRB1,SLFN11 and ST3GAL2. The ROC curve suggested good predictive performance of the signatures for exacerbation of UC in both the training set and the validation set. We generated a novel genotyping scheme based on the 9 signatures. The percentage of patients achieved remission after 4 weeks intravenous corticosteroids (CS-IV) treatment was higher in cluster C1 than that in cluster C2 (54% vs. 27%, Chi-square test, p=0.02). Energy metabolism-associated signaling pathways were significantly up-regulated in cluster C1, including the oxidative phosphorylation, pentose and glucuronate interconversions and citrate cycle TCA cycle pathways. The cluster C2 had a significant higher level of CD4+ T cells. The"XSum"algorithm revealed that Exisulind has a therapeutic potential for UC. Exisulind showed a good binding affinity for GPR4, ST3GAL2 and LILRB1 protein with the docking glide scores of -7.400 kcal/mol, -7.191 kcal/mol and -6.721 kcal/mol, respectively.We also provided a comprehensive review of the environmental toxins and drug exposures that potentially impact the progression of UC. CONCLUSION: Using WGCNA and random forest algorithm, we identified 9 gene signatures of the exacerbation of UC. A novel genotyping scheme was constructed to predict the severity of UC and screen UC patients suitable for CS-IV treatment. Subsequently, we identified a small molecule drug (Exisulind) with potential therapeutic effects for UC. Thus, our study provided new ideas and materials for the personalized clinical treatment plans for patients with UC.

275. The abscopal effect of immune-radiation therapy in recurrent and metastatic cervical cancer: a narrative review.

Front Immunol

2023 Jul 19

Ollivier L, Moreau Bachelard C, Renaud E

276. Characterization of the humoral and cellular immunity induced by a recombinant BCG vaccine for the respiratory syncytial virus in healthy adults.

Front Immunol

2023 Jul 18

Pacheco GA, Andrade CA, Gálvez NMS

277. A comparison of the binding sites of antibodies and single-domain antibodies.

Front Immunol

2023 Jul 18

Gordon GL, Capel HL, Guloglu B

278. MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

Front Immunol

2023 Jul 18

Medina JP, Bermejo-Álvarez I, Pérez-Baos S

OBJECTIVE: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. METHODS: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. RESULTS: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-β, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1β and TNF. CONCLUSION: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

279. Understanding NK cell biology for harnessing NK cell therapies: targeting cancer and beyond.

Front Immunol

2023 Jul 18

Shin E, Bak SH, Park T

280. The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.

Front Immunol

2023 Jul 18

Ye J, Hu X, Wang Z

281. CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases.

Front Immunol

2023 Jul 18

Petruk N, Siddiqui A, Tadayon S

INTRODUCTION: Bisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known. METHODS: We used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody. RESULTS: Sh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups. DISCUSSION: Taken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor.

282. Gut microbiota: a newly identified environmental factor in systemic lupus erythematosus.

Front Immunol

2023 Jul 18

Yao K, Xie Y, Wang J

283. Multivalent vaccines demonstrate immunogenicity and protect against Coxiella burnetii aerosol challenge.

Front Immunol

2023 Jul 18

Jan S, Fratzke AP, Felgner J

Vaccines are among the most cost-effective public health measures for controlling infectious diseases. Coxiella burnetii is the etiological agent of Q fever, a disease with a wide clinical spectrum that ranges from mild symptoms, such as fever and fatigue, to more severe disease, such as pneumonia and endocarditis. The formalin-inactivated whole-cell vaccine Q-VAX® contains hundreds of antigens and confers lifelong protection in humans, but prior sensitization from infection or vaccination can result in deleterious reactogenic responses to vaccination. Consequently, there is great interest in developing non-reactogenic alternatives based on adjuvanted recombinant proteins. In this study, we aimed to develop a multivalent vaccine that conferred protection with reduced reactogenicity. We hypothesized that a multivalent vaccine consisting of multiple antigens would be more immunogenic and protective than a monovalent vaccine owing to the large number of potential protective antigens in the C. burnetii proteome. To address this, we identified immunogenic T and B cell antigens, and selected proteins were purified to evaluate with a combination adjuvant (IVAX-1), with or without C. burnetii lipopolysaccharide (LPS) in immunogenicity studies in vivo in mice and in a Hartley guinea pig intratracheal aerosol challenge model using C. burnetii strain NMI RSA 493. The data showed that multivalent vaccines are more immunogenic than monovalent vaccines and more closely emulate the protection achieved by Q-VAX. Although six antigens were the most immunogenic, we also discovered that multiplexing beyond four antigens introduces detectable reactogenicity, indicating that there is an upper limit to the number of antigens that can be safely included in a multivalent Q-fever vaccine. C. burnetii LPS also demonstrates efficacy as a vaccine antigen in conferring protection in an otherwise monovalent vaccine formulation, suggesting that its addition in multivalent vaccines, as demonstrated by a quadrivalent formulation, would improve protective responses.

284. T cell migration and effector function differences in familial adenomatous polyposis patients with APC gene mutations.

Front Immunol

2023 Jul 18

Cuche C, Mastrogiovanni M, Juzans M

Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond ex vivo to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.

285. Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

Front Immunol

2023 Jul 18

Novak T, Crawford JC, Hahn G

286. Advances in the application of neuroinflammatory molecular imaging in brain malignancies.

Front Immunol

2023 Jul 18

Dong W, Wang N, Qi Z.

287. Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression.

Front Immunol

2023 Jul 18

Rafaeva M, Jensen ARD, Horton ER

288. Association of torque teno virus viremia with liver fibrosis in the first year after liver transplantation.

Front Immunol

2023 Jul 18

Engel B, Görzer I, Campos-Murguia A

289. COVID, complement, and the brain.

Front Immunol

2023 Jul 18

Vlaicu SI, Tatomir A, Cuevas J

290. NF-kB's contribution to B cell fate decisions.

Front Immunol

2023 Jul 18

Guldenpfennig C, Teixeiro E, Daniels M.

291. Interleukin-17-targeted treatment in patients with spondyloarthritis and associated cardiometabolic risk profile.

Front Immunol

2023 Jul 18

Queiro R, Aurrecoechea E, Alonso Castro S

Spondyloarthritis is a group of immune-mediated rheumatic disorders that significantly impact patients' physical function and quality of life. Patients with spondyloarthritis experience a greater prevalence of cardiometabolic disorders, such as obesity, hypertension, dyslipidemia and diabetes mellitus, and these comorbidities are associated with increased spondyloarthritis disease activity and risk of cardiovascular events. This narrative review summarizes the evidence for a physiological link between inflammatory status and cardiometabolic comorbidities in spondyloarthritis, as well as the impact of interleukin (IL)-17 blockade versus other molecular mechanisms in patients with cardiometabolic conditions. The IL-23/IL-17 axis plays a pivotal role in the pathophysiology of spondyloarthritis by promoting inflammation and tissue remodeling at the affected joints and entheses. The importance of the IL-23/IL-17 signaling cascade in underlying sub-clinical inflammation in common cardiometabolic disorders suggests the existence of shared pathways between these processes and spondyloarthritis pathophysiology. Thus, a bidirectional relationship exists between the effects of biologic drugs and patients' cardiometabolic profile, which must be considered during treatment decision making. Biologic therapy may induce changes in patients' cardiometabolic status and cardiometabolic conditions may conversely impact the clinical response to biologic therapy. Available evidence regarding the impact of IL-17 blockade with secukinumab on cardiometabolic parameters suggests this drug does not interfere with traditional cardiovascular risk markers and could be associated with a decreased risk of cardiovascular events. Additionally, the efficacy and retention rates of secukinumab do not appear to be negatively affected by obesity, with some studies reporting a positive impact on clinical outcomes, contrary to that described with other approaches, such as tumor necrosis factor blockade. In this article, we also review evidence for this bidirectional association with other treatments for spondyloarthritis. Current evidence suggests that IL-17-targeted therapy with secukinumab is highly effective in spondyloarthritis patients with cardiometabolic comorbidities and may provide additional cardiometabolic benefits.

292. CRISPR-Cas- induced IRF3 and MAVS knockouts in a salmonid cell line disrupt PRR signaling and affect viral replication.

Front Immunol

2023 Jul 17

van der Wal YA, Nordli H, Akandwanaho A

BACKGROUND: Interferon (IFN) responses are critical in the resolution of viral infections and are actively targeted by many viruses. They also play a role in inducing protective responses after vaccination and have been successfully tested as vaccine adjuvants. IFN responses are well conserved and function very similar in teleosts and mammals. Like in mammals, IFN responses in piscine cells are initiated by intracellular detection of the viral infection by different pattern recognition receptors. Upon the recognition of viral components, IFN responses are rapidly induced to combat the infection. However, many viruses may still replicate and be able to inhibit or circumvent the IFN response by different means. METHODS: By employing CRISPR Cas9 technology, we have disrupted proteins that are central for IFN signaling in the salmonid cell line CHSE-214. We successfully generated KO clones for the mitochondrial antiviral signaling protein MAVS, the transcription factors IRF3 and IRF7-1, as well as a double KO for IRF7-1/3 using an optimized protocol for delivery of CRISPR-Cas ribonucleoproteins through nucleofection. RESULTS: We found that MAVS and IRF3 KOs inhibited IFN and IFN-stimulated gene induction after intracellular poly I:C stimulation as determined through gene expression and promoter activation assays. In contrast, the IRF7-1 KO had no clear effect. This shows that MAVS and IRF3 are essential for initiation of intracellular RNA-induced IFN responses in CHSE-214 cells. To elucidate viral interference with IFN induction pathways, the KOs were infected with Salmon alphavirus 3 (SAV3) and infectious pancreatic necrosis virus (IPNV). SAV3 infection in control and IRF7-1 KO cells yielded similar titers and no cytopathic effect, while IRF3 and MAVS KOs presented with severe cytopathic effect and increased titers 6 days after SAV 3 infection. In contrast, IPNV yields were reduced in IRF3 and MAVS KOs, suggesting a dependency on interactions between viral proteins and pattern recognition receptor signaling components during viral replication. CONCLUSION: Aside from more insight in this signaling in salmonids, our results indicate a possible method to increase viral titers in salmonid cells.

293. Kidney function and cardiovascular diseases: a large-scale observational and Mendelian randomization study.

Front Immunol

2023 Jul 17

Hu C, Li Y, Qian Y

BACKGROUND: Prior observational studies have found an association between kidney function and cardiovascular diseases (CVDs). However, these studies did not investigate causality. Therefore, the aim of this study is to examine the causal relationship between kidney function and CVDs. METHODS: We utilized data from the eICU Collaborative Research Database (eICU-CRD) from the years 2014-2015 to evaluate the observational association between renal failure (RF) and CVDs. To investigate the causal effects of kidney function (estimated glomerular filtration rate [eGFR] and chronic kidney disease [CKD]) and CVDs (including atrial fibrillation [AF], coronary artery disease [CAD], heart failure [HF], any stroke [AS], and any ischemic stroke [AIS]), we conducted a two-sample bidirectional Mendelian randomization (MR) analysis. RESULTS: In the observational analysis, a total of 157,883 patients were included. After adjusting for potential confounding factors, there was no significant association between baseline RF and an increased risk of developing CVDs during hospitalization [adjusted odds ratio (OR): 1.056, 95% confidence interval (CI): 0.993 to 1.123, P = 0.083]. Conversely, baseline CVDs was significantly associated with an increased risk of developing RF during hospitalization (adjusted OR: 1.189, 95% CI: 1.139 to 1.240, P < 0.001). In the MR analysis, genetically predicted AF was associated with an increased risk of CKD (OR: 1.050, 95% CI: 1.016 to 1.085, P = 0.004). HF was correlated with lower eGFR (β: -0.056, 95% CI: -0.090 to -0.022, P = 0.001). A genetic susceptibility for AS and AIS was linked to lower eGFR (β: -0.057, 95% CI: -0.079 to -0.036, P < 0.001; β: -0.029, 95% CI: -0.050 to -0.009, P = 0.005; respectively) and a higher risk of CKD (OR: 1.332, 95% CI: 1.162 to 1.528, P < 0.001; OR: 1.197, 95% CI: 1.023 to 1.400, P = 0.025; respectively). Regarding the reverse direction analysis, there was insufficient evidence to prove the causal effects of kidney function on CVDs. Outcomes remained consistent in sensitivity analyses. CONCLUSION: Our study provides evidence for causal effects of CVDs on kidney function. However, the evidence to support the causal effects of kidney function on CVDs is currently insufficient. Further mechanistic studies are required to determine the causality.

294. HLA class II antigens in Croatian patients with pemphigus vulgaris and their correlation with anti-desmoglein antibodies.

Front Immunol

2023 Jul 17

Lakoš Jukić I, Mokos M, Marinović B.

295. Bacterial outer-membrane vesicles promote Vγ9Vδ2 T cell oncolytic activity.

Front Immunol

2023 Jul 17

Firth J, Sun J, George V

296. Identification of cuproptosis-related molecular subtypes and a novel predictive model of COVID-19 based on machine learning.

Front Immunol

2023 Jul 17

Luo H, Yan J, Zhang D

297. ELK4 exerts opposite roles in cytokine/chemokine production and degranulation in activated mast cells.

Front Immunol

2023 Jul 17

Huang Y, Zhu Z, Li W

298. Plasma PD-L1 as a biomarker in the clinical management of glioblastoma multiforme-a retrospective cohort study.

Front Immunol

2023 Jul 17

Masood AB, Batool S, Bhatti SN

BACKGROUND AND OBJECTIVES: Glioblastoma multiforme (GBM) is the most aggressive, malignant, and therapy-resistant tumor of the brain. Blockade therapy targeting the programmed cell death protein 1 (PD-1)/programmed death ligand (PD-L1) axis is currently under investigation for the clinical management of the GBM. This study has quantified the plasma levels of PD-L1 as a biomarker for the clinical management of GBM. METHODS: A cohort (n = 128) of Pakistani adult glioblastoma patients together with age- and sex-matched healthy controls was used for quantification of pre-surgery levels of plasma PD-L1. PD-L1 protein and mRNA were measured by PD-L1 platinum enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. Receiver operating characteristic (ROC) curve analysis was used to compute area under the curve (AUC) for specificity and sensitivity analyses. The Kaplan-Meier survival analysis was employed to compute overall survival. RESULTS: PD-L1 protein and mRNA were significantly higher in GBM compared to the healthy controls (p < 0.0001). Mean PD-L1 concentration for the GBM was found to be 48.98 ± 2.290 pg/ml compared to 27.63 ± 1.281 pg/ml for controls. Gene expression analysis showed statistically significant upregulation (p < 0.0001) of PD-L1 in blood of GBM compared to healthy controls. Plasma PD-L1 showed an AUC of 0.840 (p < 0.0001; 95% CI = 0.7716 to 0.9090) where a cutoff value higher than 46 pg/ml demonstrated 100% specificity and 57.81% sensitivity. Higher pre-surgery levels of PD-L1 were found to be associated with overall poor survival [p < 0.0001; HR (log-rank) = 0.08; 95% CI = 0.04 to 0.15]. Age, gender, and ethnic background were not found to be associated with plasma PD-L1 levels. CONCLUSION: The study concludes that blood-based measurements of PD-L1 in GBM can be a promising prognostic marker and therapeutic target besides a rapid and relatively non-invasive screening tool for routine clinical management. Future work extending the analysis to larger cohorts through multi-center collaborations involving pre-treatment and post-treatment groups is required to fully explore the usefulness of circulating PD-L1 for effective clinical applications.

299. Immune cell ratio and coagulation markers in assessing prognosis of asthma: a cross-sectional study from Saudi Arabia.

Front Immunol

2023 Jul 17

Aldakheel FM, Alruwaili ZA, Alduraywish SA

300. Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation.

Front Immunol

2023 Jul 17

Cross-Najafi AA, Farag K, Isidan A

301. The immune mechanism of the nasal epithelium in COVID-19-related olfactory dysfunction.

Front Immunol

2023 Jul 17

Chen S, Wang S.

302. A d-peptide-based oral nanotherapeutic modulates the PD-1/PD-L1 interaction for tumor immunotherapy.

Front Immunol

2023 Jul 17

Liu D, Wang J, You W

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors are currently the most commonly utilized agents in clinical practice, which elicit an immunostimulatory response to combat malignancies. However, all these inhibitors are currently administered via injection using antibody-based therapies, while there is a growing need for oral alternatives. METHODS: This study has developed and synthesized exosome-wrapped gold-peptide nanocomplexes with low immunogenicity, which can target PD-L1 and activate antitumor immunity in vivo through oral absorption. The SuperPDL1exo was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and gel silver staining. The transmembrane ability of SuperPDL1exo was evaluated by flow cytometry and immunofluorescence. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay. ELISA experiments were conducted to detect serum and tissue inflammatory factors, as well as serum biochemical indicators. Tissue sections were stained with H&E for the evaluation of the safety of SuperPDL1exo. An MC38 colon cancer model was established in immunocompetent C56BL/6 mice to evaluate the effects of SuperPDL1exo on tumor growth in vivo. Immunohistochemistry (IHC) staining was performed to detect cytotoxicity factors such as perforin and granzymes. RESULTS: First, SuperPDL1 was successfully synthesized, and milk exosome membranes were encapsulated through ultrasound, repeated freeze-thaw cycles, and extrusion, resulting in the synthesis of SuperPDL1exo. Multiple characterization results confirmed the successful synthesis of SuperPDL1exo nanoparticles. Furthermore, our data demonstrated that SuperPDL1exo exhibited excellent colloidal stability and superior cell transmembrane ability. In vitro and in vivo experiments revealed that SuperPDL1exo did not cause damage to multiple systemic organs, demonstrating its good biocompatibility. Finally, in the MC38 colon cancer mouse model, it was discovered that SuperPDL1exo could inhibit the progression of colon cancer, and this tumor-suppressive effect was mediated through the activation of tumor-specific cytotoxic T lymphocyte (CTL)-related immune responses. CONCLUSION: This study has successfully designed and synthesized an oral nanotherapeutic, SuperPDL1exo, which demonstrates small particle size, excellent colloidal stability, transmembrane ability in tumor cells, and biocompatibility. In vivo experiments have shown that it effectively activates T-cell immunity and exerts antitumor effects.

303. Dietary artemisinin boosts intestinal immunity and healthy in fat greenling (Hexagrammos otakii).

Front Immunol

2023 Jul 17

Gu Y, Wang W, Zhan Y

INTRODUCTION: Artemisinin (ART) is very common as a diet additive due to its immunoregulatory activities. Nonetheless, the immunoregulatory mechanism of ART in marine fish remains unknown. This study comprehensively examined the effects and explored the potential mechanism of ART ameliorating intestinal immune disease (IID) in fat greenlings (Hexagrammos otakii). METHODS AND RESULTS: The targets of ART were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Here, eight putative targets of ART were collected and identified with the Uniprot database, and 1419 IID-associated target proteins were filtered through the Drugbank, Genecards, OMIM, and PHARMGKB Databases. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways point out that ART may have immunoprotective effects by regulating cellular responses to stress, hypoxia, inflammation, and vascular endothelial growth factor stimulus through the hypoxia-inducible factor 1 (HIF-1) signaling pathway. The findings of molecular docking indicated that ART contains one active ingredient and three cross-targets, which showed a kind combination with hypoxia-inducible factor 1-alpha (HIF1-a), transcription factor p65 (RELA), and vascular endothelial growth factor A (VEGF-A), respectively. Furthermore, an ART feeding model was established to assess the ART's immunoprotect effect on the intestine of H.otakii in vivo. The D48 group showed smaller intestinal structural changes after being challenged by Edwardsiella tarda. The supplementation of ART to the diet improved total superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and reduced the malondialdehyde (MDA) in intestine of H. otakii. The expression of transcription factor p65, HIF1-α, VEGF-A, cyclin D1, matrix metalloprotease 9 (MMP9), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) was decreased after dietary ART in the intestinal of H. otakii. DISCUSSION: The present results demonstrated that dietary ART improved antioxidants and immunity, optimized the intestinal structure, and increased resistance to E. tarda through the SOD2/nuclear-factor-kappa- B (NFkB)/HIF1-a/VEGF-A pathway in the intestinal tract of H.otakii. This study integrated pharmacological analysis and experimental validation and revealed the mechanism of ART on IID, which provides insight into the improvement of IID in H. otakii.

304. Phenotypic and proteomic analysis of plasma extracellular vesicles highlights them as potential biomarkers of primary Sjögren syndrome.

Front Immunol

2023 Jul 17

Ferrant J, Pontis A, Zimmermann F

305. Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes.

Front Immunol

2023 Jul 17

Torres A, Kang S, Mahony CB

306. Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy.

Front Immunol

2023 Jul 17

Zou X, Guan C, Gao J

307. Combined intranasal and intramuscular parainfluenza 5-, simian adenovirus ChAdOx1- and poxvirus MVA-vectored vaccines induce synergistically HIV-1-specific T cells in the mucosa.

Front Immunol

2023 Jul 17

Beavis AC, Wee EG, Akis Yildirim BM

308. Exosome-based crosstalk in glaucoma pathogenesis: a focus on oxidative stress and neuroinflammation.

Front Immunol

2023 Jul 17

Wang L, Wei X.

309. Application of single-cell RNA sequencing methods to develop B cell targeted treatments for autoimmunity.

Front Immunol

2023 Jul 14

Nicholas CA, Smith MJ.

310. Crosstalk between ferroptosis and chondrocytes in osteoarthritis: a systematic review of in vivo and in vitro studies.

Front Immunol

2023 Jul 14

Cao S, Wei Y, Xu H

311. An immuno-lipidomic signature revealed by metabolomic and machine-learning approaches in labial salivary gland to diagnose primary Sjögren's syndrome.

Front Immunol

2023 Jul 14

Urbanski G, Chabrun F, Delattre E

INTRODUCTION: Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren's syndrome, although earlier recognition of primary Sjögren's syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren's syndrome in labial salivary gland combining metabolomics and machine-learning approaches. METHODS: We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren's syndrome (n=40) and non- primary Sjögren's syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren's syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets. RESULTS: Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren's syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum. CONCLUSION: Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren's syndrome from other causes of sicca symptoms.

Front Immunol

2023 Jul 14

Hao W, Zhang J, Wang Y

OBJECTIVE: The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile. METHODS: We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs. RESULTS: There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups. CONCLUSION: Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.

313. Two case reports and a systematic review of the literature on adult cerebral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody.

Front Immunol

2023 Jul 14

Xu M, Ma C, Dong M

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has gained recognition in recent years as an immune-mediated inflammatory demyelinating disease of the central nervous system. The clinical features and prognosis of MOGAD adult cerebral cortical encephalitis (adult CCE) have not been fully elucidated. This study aims to further characterize the clinical symptoms, magnetic resonance imaging (MRI) findings, and prognosis of CCE with anti-MOG antibody. METHODS: We present two adult cases of CCE with anti-MOG antibody and summarize the clinical symptoms, magnetic resonance imaging (MRI) findings, and prognosis of this phenotype as per a completed systematic review of the literature. RESULTS: We found a total of 39 cases of MOGAD adult CCE (36% females; average age of onset of 29 years). Among them, 85% had seizure, 82% had headache, 64% had cortical symptoms, 64% had fever, 54% had changes of consciousness, and 38% had ocular symptoms. All cases demonstrated cerebral cortical T2 fluid-attenuated inversion recovery (FLAIR) lesions on MRI. Of the 25 patients (with seizure or not) who had EEG reports, 76% of patients showed abnormal EEG. Cerebrospinal fluid (CSF) white blood cell count of 90% of patients and CSF total protein of 67% of patients were elevated. In 16 patients with available CSF cytology data, 11 (69%) had abnormal cytology findings with monocytic predominance. In the 15 cases for which MOG antibody IgG was tested in both serum and CSF, 14 (93%) demonstrated a higher positive MOG IgG titer in serum than CSF. The majority of patients were treated with immunosuppressive therapy (97% corticosteroids, 15% mycophenolate mofetil, 13% IVIg, 5% azathioprine, and 5% other). The majority of patients had a favorable prognosis after treatment, as exemplified by improved clinical symptoms and imaging. Two patients relapsed. CONCLUSIONS: The clinical presentation and prognosis of adult CCE remain less understood in comparison to more common MOGAD phenotypes. It is important to consider MOGAD as an underlying etiology for adult CCE, as early detection and immunotherapy may improve outcomes.

314. Whole-transcriptome analysis reveals virulence-specific pathogen-host interactions at the placenta in bovine neosporosis.

Front Immunol

2023 Jul 14

Horcajo P, Coronado M, Pastor-Fernández I

Research on bovine neosporosis has achieved relevant milestones, but the mechanisms underlying the occurrence of foetal death or protection against foetal death remain unclear. In a recent study, placentas from heifers challenged with the high-virulence isolate Nc-Spain7 exhibited focal necrosis and inflammatory infiltrates as soon as 10 days post-infection (dpi), although parasite detection was minimal. These lesions were more frequent at 20 dpi, coinciding with higher rates of parasite detection and the occurrence of foetal death in some animals. In contrast, such lesions were not observed in placentas from animals infected with the low-virulence isolate Nc-Spain1H, where the parasite was detected only in placenta from one animal at 20 dpi. This work aimed to study which mechanisms are triggered in the placentas (caruncles and cotyledons) of these pregnant heifers at early stages of infection (10 and 20 dpi) through whole-transcriptome analysis. In caruncles, infection with the high-virulence isolate provoked a strong proinflammatory response at 10 dpi. This effect was not observed in heifers infected with the low-virulence isolate, where IL-6/JAK/STAT3 signalling and TNF-alpha signalling via NF-κB pathways were down-regulated. Interestingly, the expression of E2F target genes, related to restraining the inflammatory response, was higher in these animals. At 20 dpi, more pronounced proinflammatory gene signatures were detectable in heifers infected with the high-virulence isolate, being more intense in heifers carrying dead fetuses. However, the low-virulence isolate continued without activating the proinflammatory response. In cotyledons, the response to infection with the high-virulence isolate was similar to that observed in caruncles; however, the low-virulence isolate induced mild proinflammatory signals at 20 dpi. Finally, a deconvolutional analysis of gene signatures from both placentome tissues revealed a markedly higher fraction of activated natural killers, M1 macrophages and CD8+ T cells for the high-virulence isolate. Therefore, our transcriptomic analysis supports the hypothesis that an intense immune response probably triggered by parasite multiplication could be a key contributor to abortion. Further studies are required to determine the parasite effectors that govern the distinct interactions of high- and low-virulence isolates with the host, which could help elucidate the molecular processes underlying the pathogenesis of neosporosis in cattle.

315. Immunoglobulin A levels and its correlation with neutrophil-to-lymphocyte ratio as inflammatory biomarkers for dry eye disease in type 2 diabetes: a retrospective study.

Front Immunol

2023 Jul 14

Alhalwani AY, Abudawood K, Qadizadah ABEA

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and immunoglobulin A (IgA) level are commonly used as biomarkers for inflammation. Patients with type 2 diabetes (T2D) may experience an imbalance of tear film and inflammation, which can result in dry eye disease (DED). This study aimed to assess the levels of IgA and explore its correlation with the NLR as potential inflammatory biomarkers for dry eye disease in patients with T2D. METHODS: A retrospective study was conducted at the cornea clinic and diabetes centre of King Abdulaziz Medical City (Jeddah, Saudi Arabia). The study included patients with DED and the number of available T2D-DED patients determined the sample size. Neutrophil, lymphocyte, IgA and CRP (C-reactive protein) laboratory values were obtained from medical records and correlational analyses were performed. RESULTS: The study included 85 patients with an average age of 54 ± 14.4 years for the DED group (n=32) and 62 ± 13.9 years for the T2D-DED group (n=53). The age difference between the two groups was statistically significant (p 0.0001). The NLR values of the T2D-DED and DED groups were 3.203 ± 0.66 and 2.406 ± 0.46, respectively, with no significant difference (p<0.285). Similarly, there were no significant differences in neutrophil and lymphocyte values between the two groups. The IgA levels showed no significant variation between T2D-DED and DED groups (p<0.364). Spearman's correlation analysis in the DED group showed a significant negative correlation between IgA and lymphocyte (p=0.011; r= - 0.471) values and significant positive correlations between IgA and neutrophil (p=0.014; r=0.309) and NLR (p=0.052; r= - 0.283) values. In the T2D-DED group, a significant correlation was found between IgA and CRP values (p=0.032; r=0.33). CONCLUSION: Although diabetic patients may exhibit higher levels of NLR and IgA that correlate with disease severity, our study did not find significant differences in NLR and IgA values between the two groups. These findings may guide future research and enhance understanding of the disease's underlying mechanisms.

316. Immunomodulatory actions of vitamin D in various immune-related disorders: a comprehensive review.

Front Immunol

2023 Jul 14

Ghaseminejad-Raeini A, Ghaderi A, Sharafi A

317. Effects of dietary Clostridium butyricum on the growth performance, digestion, and intestinal health of spotted sea bass (Lateolabrax maculatus).

Front Immunol

2023 Jul 14

Kong L, Ma J, Zhou S

318. Persistent and transient olfactory deficits in COVID-19 are associated to inflammation and zinc homeostasis.

Front Immunol

2023 Jul 14

Lupi L, Bordin A, Sales G

319. Transcriptional regulation of dendritic cell development and function.

Front Immunol

2023 Jul 14

Zhang S, Audiger C, Chopin M

320. Longitudinal study of humoral immunity against SARS-CoV-2 of health professionals in Brazil: the impact of booster dose and reinfection on antibody dynamics.

Front Immunol

2023 Jul 14

Franco-Luiz APM, Fernandes NMGS, Silva TBS

321. Cytokine response and damages in the lungs of aging Syrian hamsters on a high-fat diet infected with the SARS-CoV-2 virus.

Front Immunol

2023 Jul 14

Fomin G, Tabynov K, Islamov R

322. Development and validation of prognostic risk prediction models for hepatocellular carcinoma patients treated with immune checkpoint inhibitors based on a systematic review and meta-analysis of 47 cohorts.

Front Immunol

2023 Jul 14

Ma D, Liu M, Zhai X

OBJECTIVE: To identify the risk factors associated with prognosis in patients with hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICI) via meta-analysis. And to construct prediction models to aid in the prediction and improvement of prognosis. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library for relevant studies from inception to March 29, 2023. After completing literature screening and data extraction, we performed meta-analysis, sensitivity analysis, and subgroup analysis to identify risk factors associated with OS and PFS. Using the pooled hazard ratio value for each risk factor, we constructed prediction models, which were then validated using datasets from 19 centers in Japan and two centers in China, comprising a total of 204 patients. RESULTS: A total of 47 studies, involving a total of 7649 ICI-treated HCC patients, were included in the meta-analysis. After analyzing 18 risk factors, we identified AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number, vascular invasion and combination therapy as predictors for OS prediction model, while AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number and vascular invasion were selected as predictors for PFS model. To validate the models, we scored two independent cohorts of patients using both prediction models. Our models demonstrated good performance in these cohorts. In addition, in the pooled cohort of 204 patients, Our models also showed good performance with area under the curve (AUC) values of 0.712, 0.753, and 0.822 for the OS prediction model at 1-year, 2-year, and 3-year follow-up points, respectively, and AUC values of 0.575, 0.749 and 0.691 for the PFS prediction model Additionally, the calibration curve, decision curve analysis, and Kaplan-Meier curves in the pooled cohort all supported the validity of both models. CONCLUSION: Based on the meta-analysis, we successfully constructed the OS and PFS prediction models for ICI-treated HCC patients. We also validated the models externally and observed good discrimination and calibration. The model's selected indicators are easily obtainable, making them suitable for further application in clinical practice.

323. From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.

Front Immunol

2023 Jul 14

Khawar MB, Ge F, Afzal A

324. Case Report: Intervention of radiotherapy improves the prognosis of rectal squamous cell carcinoma with high PD-L1 expression and enable patients to obtain NED status.

Front Immunol

2023 Jul 14

Qu F, Xiao L, Xiao Y

325. Circulatory HMGB1 is an early predictive and prognostic biomarker of ARDS and mortality in a swine model of polytrauma.

Front Immunol

2023 Jul 14

Young MD, Cancio TS, Thorpe CR

Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in polytrauma patients. Pharmacological treatments of ARDS are lacking, and ARDS patients rely on supportive care. Accurate diagnosis of ARDS is vital for early intervention and improved outcomes but is presently delayed up to days. The use of biomarkers for early identification of ARDS development is a potential solution. Inflammatory mediators high-mobility group box 1 (HMGB1), syndecan-1 (SDC-1), and C3a have been previously proposed as potential biomarkers. For this study, we analyzed these biomarkers in animals undergoing smoke inhalation and 40% total body surface area burns, followed by intensive care for 72 h post-injury (PI) to determine their association with ARDS and mortality. We found that the levels of inflammatory mediators in serum were affected, as well as the degree of HMGB1 and Toll-like receptor 4 (TLR4) signal activation in the lung. The results showed significantly increased HMGB1 expression levels in animals that developed ARDS compared with those that did not. Receiver operating characteristic (ROC) analysis showed that HMGB1 levels at 6 h PI were significantly associated with ARDS development (AUROC=0.77) and mortality (AUROC=0.82). Logistic regression analysis revealed that levels of HMGB1 ≥24.10 ng/ml are associated with a 13-fold higher incidence of ARDS [OR:13.57 (2.76-104.3)], whereas the levels of HMGB1 ≥31.39 ng/ml are associated with a 12-fold increase in mortality [OR: 12.00 (2.36-93.47)]. In addition, we found that mesenchymal stem cell (MSC) therapeutic treatment led to a significant decrease in systemic HMGB1 elevation but failed to block SDC-1 and C3a increases. Immunohistochemistry analyses showed that smoke inhalation and burn injury induced the expression of HMGB1 and TLR4 and stimulated co-localization of HMGB1 and TLR4 in the lung. Interestingly, MSC treatment reduced the presence of HMGB1, TLR4, and the HMGB1-TLR4 co-localization. These results show that serum HMGB1 is a prognostic biomarker for predicting the incidence of ARDS and mortality in swine with smoke inhalation and burn injury. Therapeutically blocking HMGB1 signal activation might be an effective approach for attenuating ARDS development in combat casualties or civilian patients.

326. Decidual macrophages derived NO downregulates PD-L1 in trophoblasts leading to decreased Treg cells in recurrent miscarriage.

Front Immunol

2023 Jul 14

Zhang Y, Wang H, Qiu P

INTRODUCTION: Placental trophoblasts contribute to regulatory T (Treg) function via the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) pathway during normal pregnancy. Decreased expression of PD-L1 in trophoblasts was closely associated with Treg deficiency in the development of pregnancy failure. Thus, targeting PD-L1 might be a novel therapy to prevent pregnancy loss. However, the mechanisms for modulating the expression of PD-L1 in trophoblasts are an enigma. METHODS: The proportion of decidual Treg cells, and the profile of decidual macrophages (DMs) sampled from women with normal pregnancy (NP) and recurrent miscarriage (RM) were evaluated by flow cytometry. The expression of Yin and Yang 1 protein (YY1) and PD-L1 in human villous were measured by Immunohistochemistry (IHC), qRT-PCR and western blot. The determination of soluble PD-L1 (sPD-L1) in serum from NP and RM, and trophoblast conditioned media (TCM) was performed by the PD-L1 SimpleStep ELISA kit. Knockdown of YY1 was processed in the human trophoblast derived cell lines, HTR-8 and Bewo, with siYY1 transfection. Peripheral naïve CD4+ T cells were isolated from women with NP for the in vitro culture. The percentages of Treg cells differentiated from peripheral naïve CD4+ T cells were measured by flow cytometry. The interaction between YY1 and CD274 was proved by CHIP. The expression of inducible nitric oxide synthase (iNOS) in decidua was evaluated by IHC. The level of NO in serum from women with NP and RM was determined by the Griess reagent system. The effects of NO on YY1 were determined by the in vitro culture of HTR-8 cells with the NO donor, SNAP. The in vivo model comprising twelve pregnant mice and underwent different treatment. The percentages of Treg cells in murine uterus were measured by flow cytometry. Similarly, Western blot and IHC were performed to determine the expression of YY1 and PD-L1 in murine placenta. RESULTS: Decreased expression of YY1 and PD-L1 in trophoblasts and lower proportion of decidual Treg cells were observed in patients with RM. Knockdown of YY1 contributes to a lower expression of YY1 and PD-L1. Soluble PD-L1 in the supernatant from HTR-8 cells was also decreased with siYY1 administration. Lower Treg differentiation was observed in the presence of supernatant from HTR-8 cells treated with siYY1. CHIP analysis revealed that endogenous YY1 directly occupied the promoter region of the CD274 (PD-L1) gene. Accompanied with increased M1 DMs, higher NO was observed in serum sampled from patients with RM. In the presence of Reduced expression of YY1 and PD-L1 was observed in HTR-8 cells with the treatment of SNAP. Furthermore, less Treg differentiation was observed with SNAP treated TCM. Moreover, our in vivo data found that YY1 deficiency was associated with decreased PD-L1, which further resulting in less Treg differentiation and Treg deficiency at the maternal-fetal interface and increased embryo loss. DISCUSSION: Our work found the modulatory capacity of YY1 on PD-L1 in trophoblasts during early pregnancy. Furthermore, reduced YY1 was supposed resulting from higher levels of NO produced from the M1 DMs in RM.

327. Metabolomics acts as a powerful tool for comprehensively evaluating vaccines approved under emergency: a CoronaVac retrospective study.

Front Immunol

2023 Jul 14

Liu X, Xiao C, Guan P

INTRODUCTION: To control the COVID-19 pandemic, great efforts have been made to realize herd immunity by vaccination since 2020. Unfortunately, most of the vaccines against COVID-19 were approved in emergency without a full-cycle and comprehensive evaluation process as recommended to the previous vaccines. Metabolome has a close tie with the phenotype and can sensitively reflect the responses to stimuli, rendering metabolomic analysis have the potential to appraise and monitor vaccine effects authentically. METHODS: In this study, a retrospective study was carried out for 330 Chinese volunteers receiving recommended two-dose CoronaVac, a vaccine approved in emergency in 2020. Venous blood was sampled before and after vaccination at 5 separate time points for all the recipients. Routine clinical laboratory analysis, metabolomic and lipidomic analysis data were collected. RESULTS AND DISCUSSION: It was found that the serum antibody-positive rate of this population was around 81.82%. Most of the laboratory parameters were slightly perturbated within the relevant reference intervals after vaccination. The metabolomic and lipidomic analyses showed that the metabolic shift after inoculation was mainly in the glycolysis, tricarboxylic acid cycle, amino acid metabolism, urea cycle, as well as microbe-related metabolism (bile acid metabolism, tryptophan metabolism and phenylalanine metabolism). Time-course metabolome changes were found in parallel with the progress of immunity establishment and peripheral immune cell counting fluctuation, proving metabolomics analysis was an applicable solution to evaluate immune effects complementary to traditional antibody detection. Taurocholic acid, lysophosphatidylcholine 16:0 sn-1, glutamic acid, and phenylalanine were defined as valuable metabolite markers to indicate the establishment of immunity after vaccination. Integrated with the traditional laboratory analysis, this study provided a feasible metabolomics-based solution to relatively comprehensively evaluate vaccines approved under emergency.

328. Mechanisms and applications of adipose-derived stem cell-extracellular vesicles in the inflammation of wound healing.

Front Immunol

2023 Jul 14

Jia Q, Zhao H, Wang Y

329. Antibody-dependent cellular cytotoxicity-inducing antibodies enhance the natural killer cell anti-cancer response against patient-derived pancreatic cancer organoids.

Front Immunol

2023 Jul 14

Beelen NA, Aberle MR, Bruno V

INTRODUCTION: Pancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination with antibodies inducing antibody-dependent cell-mediated cytotoxicity (ADCC) could be a highly effective new therapeutic option in pancreatic cancer. Accurate predictive preclinical models are needed to develop successful NK cell immunotherapy. Tumor organoids, in vitro 3D organ-like structures that retain important pathophysiological characteristics of the in vivo tumor, may provide such a model. In the current study, we assessed the cytotoxic potential of adoptive NK cells against human pancreatic cancer organoids. We hypothesized that NK cell anti-tumor responses could be enhanced by including ADCC-triggering antibodies. METHODS: We performed cytotoxicity assays with healthy donor-derived IL-2-activated NK cells and pancreatic cancer organoids from four patients. A 3D cytotoxicity assay using live-cell-imaging was developed and enabled real-time assessment of the response. RESULTS: We show that NK cells migrate to and target pancreatic cancer organoids, resulting in an increased organoid death, compared to the no NK cell controls (reaching an average fold change from baseline of 2.1±0.8 vs 1.4±0.6). After 24-hours of co-culture, organoid 2D growth increased. Organoids from 2 out of 4 patients were sensitive to NK cells, while organoids from the other two patients were relatively resistant, indicating patient-specific heterogeneity among organoid cultures. The ADCC-inducing antibodies avelumab (anti-PD-L1) and trastuzumab (anti-HER2) increased NK cell-induced organoid cell death (reaching an average fold change from baseline of 3.5±1.0 and 4.5±1.8, respectively). Moreover, combination therapy with avelumab or trastuzumab resulted in complete disintegration of organoids. Finally, inclusion of ADCC-inducing antibodies was able to overcome resistance in NK-organoid combinations with low or no kill. DISCUSSION: These results support the use of organoids as a relevant and personalized model to study the anti-tumor response of NK cells in vitro and the potential of ADCC-inducing antibodies to enhance NK cell effector function.

330. Transition practice for primary immunodeficiency diseases in Southeast Asia: a regional survey.

Front Immunol

2023 Jul 13

Chan CM, Abdul Latiff AH, Noh LM

331. Cerebrospinal fluid inflammatory biomarkers for disease progression in Alzheimer's disease and multiple sclerosis: a systematic review.

Front Immunol

2023 Jul 13

Temmerman J, Engelborghs S, Bjerke M

Inflammatory processes are involved in the pathophysiology of both Alzheimer's disease (AD) and multiple sclerosis (MS) but their exact contribution to disease progression remains to be deciphered. Biomarkers are needed to define pathophysiological processes of these disorders, who may increasingly co-exist in the elderly generations of the future, due to the rising prevalence in both and ameliorated treatment options with improved life expectancy in MS. The purpose of this review was to provide a systematic overview of inflammatory biomarkers, as measured in the cerebrospinal fluid (CSF), that are associated with clinical disease progression. International peer-reviewed literature was screened using the PubMed and Web of Science databases. Disease progression had to be measured using clinically validated tests representing baseline functional and/or cognitive status, the evolution of such clinical scores over time and/or the transitioning from one disease stage to a more severe stage. The quality of included studies was systematically evaluated using a set of questions for clinical, neurochemical and statistical characteristics of the study. A total of 84 papers were included (twenty-five for AD and 59 for MS). Elevated CSF levels of chitinase-3-like protein 1 (YKL-40) were associated with disease progression in both AD and MS. Osteopontin and monocyte chemoattractant protein-1 were more specifically related to disease progression in AD, whereas the same was true for interleukin-1 beta, tumor necrosis factor alpha, C-X-C motif ligand 13, glial fibrillary acidic protein and IgG oligoclonal bands in MS. We observed a broad heterogeneity of studies with varying cohort characterization, non-disclosure of quality measures for neurochemical analyses and a lack of adequate longitudinal designs. Most of the retrieved biomarkers are related to innate immune system activity, which seems to be an important mediator of clinical disease progression in AD and MS. Overall study quality was limited and we have framed some recommendations for future biomarker research in this field. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42021264741.

332. Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding.

Front Immunol

2023 Jul 13

Hoch J, Burkhard N, Zhang S

INTRODUCTION: Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far. METHODS: SERT-deficient (Sert -/-) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, Sert -/- and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization. RESULTS: After 19 weeks of high-fat diet, Sert -/- and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in Sert -/-. In obese Sert -/- animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese Sert -/- mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, Sert -/- mice fed a control diet did not display adipose tissue inflammation. DISCUSSION: Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.

333. Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.

Front Immunol

2023 Jul 13

Del Pozo-Yauner L, Herrera GA, Perez Carreon JI

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

334. NLRP3: a new therapeutic target in alcoholic liver disease.

Front Immunol

2023 Jul 13

Brahadeeswaran S, Dasgupta T, Manickam V

335. Natural killer cell-related prognostic risk model predicts prognosis and treatment outcomes in triple-negative breast cancer.

Front Immunol

2023 Jul 13

Liu Z, Ding M, Qiu P

BACKGROUND: Natural killer (NK) cells are crucial to the emergence, identification, and prognosis of cancers. The roles of NK cell-related genes in the tumor immune microenvironment (TIME) and immunotherapy treatment are unclear. Triple-negative breast cancer (TNBC) is a highly aggressive malignant tumor. Hence, this study was conducted to develop a reliable risk model related to NK cells and provide a novel system for predicting the prognosis of TNBC. METHODS: NK cell-related genes were collected from previous studies. Based on TCGA and GEO database, univariate and LASSO cox regression analysis were used to establish the NK cell-related gene signature. The patients with TNBC were separated to high-risk and low-risk groups. After that, survival analysis was conducted and the responses to immunotherapies were evaluated on the basis of the signature. Moreover, the drug sensitivity of some traditional chemotherapeutic drugs was assessed by using the "oncoPredict" R package. In addition, the expression levels of the genes involved in the signature were validated by using qRT-PCR in TNBC cell lines. RESULTS: The patients with TNBC were divided into high- and low-risk groups according to the median risk score of the 5-NK cell-related gene signature. The low-risk group was associated with a better clinical outcome. Besides, the differentially expressed genes between the different risk groups were enriched in the biological activities associated with immunity. The tumor immune cells were found to be highly infiltrated in the low-risk groups. In accordance with the TIDE score and immune checkpoint-related gene expression analysis, TNBC patients in the low-risk groups were suggested to have better responses to immunotherapies. Eventually, some classical anti-tumor drugs were shown to be less effective in high-risk groups than in low-risk groups. CONCLUSION: The 5-NK cell-related gene signature exhibit outstanding predictive performance and provide fresh viewpoints for evaluating the success of immunotherapy. It will provide new insights to achieve precision and integrated treatment for TNBC in the future.

336. The protective effect of inactivated Flavobacterium columnare vaccine in grass carp (Ctenopharyngodon idellus).

Front Immunol

2023 Jul 13

Guo W, Han R, Xu W

337. Treatment-free survival after discontinuation of immune checkpoint inhibitors in mNSCLC: a systematic review and meta-analysis.

Front Immunol

2023 Jul 13

Hu Y, Liu S, Wang L

BACKGROUND: Recent research has suggested that patients with metastatic non-small cell lung cancer (mNSCLC) can achieve ongoing response after discontinuation of immune checkpoint inhibitor (ICI), but the best time to discontinue and the factors influencing efficacy remain unknown. METHOD: A systematic search was performed for prospective clinical trials in patients with mNSCLC treated with ICIs published up to July 10, 2022. Eligible studies reported treatment-free survival (TFS) after discontinuation of ICI in partial objective responders. We calculated objective response rate (ORR) and TFS using random-effects models with respective 95% confidence intervals (Cis), and performed subgroup analyses to discuss the specific associations between ORR and TFS and the associated influencing factors. RESULTS: Across the 26 cohorts (3833 patients) included, the weighted mean ORR for all patients was 29.30% (95% CI 24.28% to 34.57%), with ICI plus chemotherapy (48.83%, 95% CI 44.36% to 53.30%) significantly higher than monotherapy (23.40%, 95% CI 18.53% to 28.62%). 395 patients were all patients who were complete or partial responders in the study, 194 discontinued ICI treatment, and nearly 35.5% achieved a durable response. No significant differences in TFS were found between subgroups according to the ICI regimen classification. Four cohorts of patients who completed 35 courses of treatment showed high levels of pooled TFS at 6 (80.18%, 95% CI 53.03% to 97.87%) and 12 months (66.98%, 95% CI 46.90% to 84.47%). Three cohorts of patients discontinued ICI treatment due to treatment-related adverse events (TRAEs) with the TFS rates at 6 (76.98%, 95% CI 65.79% to 86.65%) and 12 months (64.79%, 95% CI 50.20% to 78.19%). CONCLUSION: Patients with mNSCLC were able to achieve ongoing responses after discontinuation of ICI. In conclusion, the results of this meta-analysis indicate that different treatment regimens, different drugs or different treatment durations may have an impact on TFS.

338. Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.

Front Immunol

2023 Jul 13

Pichler R, Diem G, Hackl H

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.

339. Assessing the causal relationship between genetically determined inflammatory biomarkers and low back pain risk: a bidirectional two-sample Mendelian randomization study.

Front Immunol

2023 Jul 13

Li W, Lu Q, Qian J

340. The methylation profile of IL4, IL5, IL10, IFNG and FOXP3 associated with environmental exposures differed between Polish infants with the food allergy and/or atopic dermatitis and without the disease.

Front Immunol

2023 Jul 13

Gorzkiewicz M, Łoś-Rycharska E, Gawryjołek J

OBJECTIVES: Epigenetic dynamics has been indicated to play a role in allergy development. The environmental stimuli have been shown to influence the methylation processes. This study investigated the differences in CpGs methylation rate of immune-attached genes between healthy and allergic infants. The research was aimed at finding evidence for the impact of environmental factors on methylation-based regulation of immunological processes in early childhood. METHODS: The analysis of methylation level of CpGs in the IL4, IL5, IL10, IFNG and FOXP3 genes was performed using high resolution melt real time PCR technology. DNA was isolated from whole blood of Polish healthy and allergic infants, with food allergy and/or atopic dermatitis, aged under six months. RESULTS: The significantly lower methylation level of FOXP3 among allergic infants compared to healthy ones was reported. Additional differences in methylation rates were found, when combining with environmental factors. In different studied groups, negative correlations between age and the IL10 and FOXP3 methylation were detected, and positive - in the case of IL4. Among infants with different allergy symptoms, the decrease in methylation level of IFNG, IL10, IL4 and FOXP3 associated with passive smoke exposure was observed. Complications during pregnancy were linked to different pattern of the IFNG, IL5, IL4 and IL10 methylation depending on allergy status. The IFNG and IL5 methylation rates were higher among exclusively breastfed infants with atopic dermatitis compared to the non-breastfed. A decrease in the IFNG methylation was noted among allergic patients fed exclusively with milk formula. In different study groups, a negative correlation between IFNG, IL5 methylation and maternal BMI or IL5 methylation and weight was noted. Some positive correlations between methylation rate of IL10 and child's weight were found. A higher methylation of IL4 was positively correlated with the number of family members with allergy. CONCLUSION: The FOXP3 methylation in allergic infants was lower than in the healthy ones. The methylation profile of IL4, IL5, IL10, IFNG and FOXP3 associated with environmental exposures differed between the studied groups. The results offer insights into epigenetic regulation of immunological response in early childhood.

341. Immunogenicity of Bacillus Calmette-Guérin in pigs: potential as a translational model of non-specific effects of BCG.

Front Immunol

2023 Jul 13

Jensen KJ, Hansen MS, Skovgaard K

BACKGROUND: Clinical and immunological studies in humans show that the live attenuated Bacillus Calmette-Guérin (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG. METHODS: In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in ex vivo blood and in vitro stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or Actinobacillus pleuropneumoniae. RESULTS: The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific in vitro responses of IFN-γ to antigen-specific re-stimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes RIG-I and CSF1, although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after A. pleuropneumoniae challenge. DISCUSSION: BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals.

342. Secretory pathways and multiple functions of nonstructural protein 1 in flavivirus infection.

Front Immunol

2023 Jul 13

Zhang S, He Y, Wu Z

343. Immune responses in COVID-19 patients during breakthrough infection with SARS-CoV-2 variants Delta, Omicron-BA.1 and Omicron-BA.5.

Front Immunol

2023 Jul 13

Bormann M, Brochhagen L, Alt M

BACKGROUND: Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are increasingly observed in vaccinated individuals. Immune responses towards SARS-CoV-2 variants, particularly Omicron-BA.5, are poorly understood. We investigated the humoral and cellular immune responses of hospitalized COVID-19 patients during Delta and Omicron infection waves. METHODS: The corresponding SARS-CoV-2 variant of the respective patients were identified by whole genome sequencing. Humoral immune responses were analyzed by ELISA and a cell culture-based neutralization assay against SARS-CoV-2 D614G isolate (wildtype), Alpha, Delta (AY.43) and Omicron (BA.1 and BA.5). Cellular immunity was evaluated with an IFN-γ ELISpot assay. RESULTS: On a cellular level, patients showed a minor IFN-γ response after stimulating PBMCs with mutated regions of SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced. Double-vaccinated patients with Delta breakthrough infection showed a significantly increased neutralizing antibody response against Delta compared to double-vaccinated uninfected controls (median complete neutralization titer (NT100) 640 versus 80, p<0.05). Omicron-BA.1 infection increased neutralization titers against BA.1 in double-vaccinated patients (median NT100 of 160 in patients versus 20 in controls, p=0.07) and patients that received booster vaccination (median NT100 of 50 in patients versus 20 in controls, p=0.68). For boosted patients with BA.5 breakthrough infection, we found no enhancing effect on humoral immunity against SARS-CoV-2 variants. CONCLUSION: Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced in SARS-CoV-2 breakthrough infections. Delta and Omicron-BA.1 but not Omicron-BA.5 infections boosted the humoral immunity in double-vaccinated patients and patients with booster vaccination. Despite BA.5 breakthrough infection, those patients may still be vulnerable for reinfections with BA.5 or other newly emerging variants of concern.

344. Early protective effect of a ("pan") coronavirus vaccine (PanCoVac) in Roborovski dwarf hamsters after single-low dose intranasal administration.

Front Immunol

2023 Jul 13

Abdelaziz MO, Raftery MJ, Weihs J

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the danger posed by human coronaviruses. Rapid emergence of immunoevasive variants and waning antiviral immunity decrease the effect of the currently available vaccines, which aim at induction of neutralizing antibodies. In contrast, T cells are marginally affected by antigen evolution although they represent the major mediators of virus control and vaccine protection against virus-induced disease. MATERIALS AND METHODS: We generated a multi-epitope vaccine (PanCoVac) that encodes the conserved T cell epitopes from all structural proteins of coronaviruses. PanCoVac contains elements that facilitate efficient processing and presentation of PanCoVac-encoded T cell epitopes and can be uploaded to any available vaccine platform. For proof of principle, we cloned PanCoVac into a non-integrating lentivirus vector (NILV-PanCoVac). We chose Roborovski dwarf hamsters for a first step in evaluating PanCoVac in vivo. Unlike mice, they are naturally susceptible to SARS-CoV-2 infection. Moreover, Roborovski dwarf hamsters develop COVID-19-like disease after infection with SARS-CoV-2 enabling us to look at pathology and clinical symptoms. RESULTS: Using HLA-A*0201-restricted reporter T cells and U251 cells expressing a tagged version of PanCoVac, we confirmed in vitro that PanCoVac is processed and presented by HLA-A*0201. As mucosal immunity in the respiratory tract is crucial for protection against respiratory viruses such as SARS-CoV-2, we tested the protective effect of single-low dose of NILV-PanCoVac administered via the intranasal (i.n.) route in the Roborovski dwarf hamster model of COVID-19. After infection with ancestral SARS-CoV-2, animals immunized with a single-low dose of NILV-PanCoVac i.n. did not show symptoms and had significantly decreased viral loads in the lung tissue. This protective effect was observed in the early phase (2 days post infection) after challenge and was not dependent on neutralizing antibodies. CONCLUSION: PanCoVac, a multi-epitope vaccine covering conserved T cell epitopes from all structural proteins of coronaviruses, might protect from severe disease caused by SARS-CoV-2 variants and future pathogenic coronaviruses. The use of (HLA-) humanized animal models will allow for further efficacy studies of PanCoVac-based vaccines in vivo.

345. Noninvasive evaluation of neutrophil extracellular traps signature predicts clinical outcomes and immunotherapy response in hepatocellular carcinoma.

Front Immunol

2023 Jul 13

Xin H, Lai Q, Zhou Y

BACKGROUND: Neutrophil extracellular traps (NETs) have been shown to play a pivotal role in promoting metastasis and immune escape in hepatocellular carcinoma (HCC). Therefore, noninvasive tests to detect the formation of NETs in tumors can have significant implications for the treatment and prognoses of patients. Here, we sought to develop and validate a computed tomography (CT)-based radiomics model to predict the gene expression profiles that regulate the formation of NETs in HCC. METHODS: This study included 1133 HCC patients from five retrospective cohorts. Based on the mRNA expression levels of 69 biomarkers correlated with NET formation, a 6-gene score (NETs score, NETS) was constructed in cohort 1 from TCIA database (n=52) and validated in cohort 2 (n=232) from ICGC database and cohort 3 (n=365) from TCGA database. And then based on the radiomics features of CT images, a radiomics signature (RNETS) was developed in cohort 1 to predict NETS status (high- or low-NETS). We further employed two cohorts from Nanfang Hospital (Guangzhou, China) to evaluate the predictive power of RNETS in predicting prognosis in cohort 4 (n=347) and the responses to PD-1 inhibitor of HCC patients in cohort 5 (n=137). RESULTS: For NETS, in cohort 1, the area under the curve (AUC) values predicting 1, 2, and 3-year overall survival (OS) were 0.836, 0.879, and 0.902, respectively. The low-NETS was associated with better survival and higher levels of immune cell infiltration. The RNETS yielded an AUC value of 0.853 in distinguishing between high-NETS or low-NETS and patients with low-RNETS were associated with significantly longer survival time in cohort 1 (P<0.001). Notably, the RNETS was competent in predicting disease-free survival (DFS) and OS in cohort 4 (P<0.001). In cohort 5, the RNETS was found to be an independent risk factor for progression-free survival (PFS) (P<0.001). In addition, the objective response rate of HCC patients treated with PD-1 inhibitor was significantly higher in the low-RNETS group (27.8%) than in the high-RNETS group (10.8%). CONCLUSIONS: This study revealed that RNETS as a radiomics biomarker could effectively predict prognosis and immunotherapy response in HCC patients.

346. Splenic SUMO1 controls systemic inflammation in experimental sepsis.

Front Immunol

2023 Jul 13

Youssef A, Mohammed BK, Prasad A

INTRODUCTION: The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting. METHODS: We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis. RESULTS AND DISCUSSION: Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia. CONCLUSION: These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.

347. Immunodiagnosis - the promise of personalized immunotherapy.

Front Immunol

2023 Jul 13

Wang R, Xiong K, Wang Z

348. Markers of the ageing macrophage: a systematic review and meta-analysis.

Front Immunol

2023 Jul 13

Moss CE, Phipps H, Wilson HL

349. Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype.

Front Immunol

2023 Jul 13

Zhang H, Jiang D, Zhu L

RATIONALE: Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. OBJECTIVES: We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. METHODS: We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. MEASUREMENTS AND RESULTS: An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. CONCLUSION: A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.

350. Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD.

Front Immunol

2023 Jul 13

Raby KL, Michaeloudes C, Tonkin J

The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and remodelling in asthma and COPD. Mechanistic understanding of injury susceptibility and damage response may lead to improved therapies for these diseases.

351. Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta.

Front Immunol

2023 Jul 13

O'Connor RA, Martinez BR, Koppensteiner L

INTRODUCTION: Tumour-reactive T cells producing the B-cell attractant chemokine CXCL13, in solid tumours, promote development of tertiary lymphoid structures (TLS) and are associated with improved prognosis and responsiveness to checkpoint immunotherapy. Cancer associated fibroblasts are the dominant stromal cell type in non-small cell lung cancer (NSCLC) where they co-localise with T cells and can influence T cell activation and exhaustion. We questioned whether CAF directly promote CXCL13-production during T cell activation. METHODS: We characterised surface markers, cytokine production and transcription factor expression in CXCL13-producing T cells in NSCLC tumours and paired non-cancerous lung samples using flow cytometry. We then assessed the influence of human NSCLC-derived primary CAF lines on T cells from healthy donors and NSCLC patients during activation in vitro measuring CXCL13 production and expression of cell-surface markers and transcription factors by flow cytometry. RESULTS: CAFs significantly increased the production of CXCL13 by both CD4+ and CD8+ T cells. CAF-induced CXCL13-producing cells lacked expression of CXCR5 and BCL6 and displayed a T peripheral helper cell phenotype. Furthermore, we demonstrate CXCL13 production by T cells is induced by TGF-β and limited by IL-2. CAF provide TGF-β during T cell activation and reduce availability of IL-2 both directly (by reducing the capacity for IL-2 production) and indirectly, by expanding a population of activated Treg. Inhibition of TGF-β signalling prevented both CAF-driven upregulation of CXCL13 and Treg expansion. DISCUSSION: Promoting CXCL13 production represents a newly described immune-regulatory function of CAF with the potential to shape the immune infiltrate of the tumour microenvironment both by altering the effector-function of tumour infiltrating T-cells and their capacity to attract B cells and promote TLS formation.

352. Research hotspots and trends on neuromyelitis optica spectrum disorders: insights from bibliometric analysis.

Front Immunol

2023 Jul 13

Chen X, Xiao J, Zhou LQ

353. Gut lumen-leaked microbial DNA causes myocardial inflammation and impairs cardiac contractility in ageing mouse heart.

Front Immunol

2023 Jul 13

Gao H, Wang K, Suarez JA

354. Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention.

Front Immunol

2023 Jul 13

Zhang Q, Pan J, Xiong D

355. Comparing clinical and imaging features of patients with MOG antibody-positivity and with and without oligoclonal bands.

Front Immunol

2023 Jul 13

Tomizawa Y, Hoshino Y, Kamo R

356. Recombinant BCG expressing the LTAK63 adjuvant increased memory T cells and induced long-lasting protection against Mycobacterium tuberculosis challenge in mice.

Front Immunol

2023 Jul 13

Marques-Neto LM, Trentini MM, Kanno AI

357. Largely preserved functionality after the combined loss of NKG2D, NCR1 and CD16 demonstrates the remarkable plasticity of NK cell responsiveness.

Front Immunol

2023 Jul 13

Imširović V, Lenartić M, Wensveen FM

358. Endogenous erythropoietin has immunoregulatory functions that limit the expression of autoimmune kidney disease in mice.

Front Immunol

2023 Jul 13

Bin S, Cantarelli C, Horwitz JK

359. On the feasibility of using TCR sequencing to follow a vaccination response - lessons learned.

Front Immunol

2023 Jul 13

de Greef PC, Lanfermeijer J, Hendriks M

360. In vitro differentiated human CD4(+) T cells produce hepatocyte growth factor.

Front Immunol

2023 Jul 13

Ford SL, Buus TB, Nastasi C

361. Cytokine profile characterization of naïve patients with psoriasis and psoriatic arthritis: implications for a pathogenic disease continuum.

Front Immunol

2023 Jul 13

Ruscitti P, Esposito M, Di Cola I

BACKGROUND: The idea of psoriatic disease continuum has been progressively prompted based on the advances of the knowledge about the pathogenic steps underpinning the occurrence of psoriasis (PSO) and psoriatic arthritis (PSA). To evaluate biomolecules (inflammatory cytokines, inflammatory chemokines, cell adhesion and cellular mediators) in naïve patients with PSO, PSA with PSO, and PSA sine PSO. To stratify the results considering the presence of psoriatic nail involvement, extensive skin disease and obesity evaluating all involved patients. METHODS: By multiplex technology, 20 serum biomolecules were assessed with the inclusion of pro-inflammatory cytokines (GM-CSF, IFN-γ, IL-1α, IL-1β, IL-6, IL-8, IL-12p70, IL-17A, IL-23, TNF), anti-inflammatory cytokines (IFN-α, IL-4, IL-10, IL-13), inflammatory chemokines (IP-10, MCP-1, MIP-1α, MIP-1β), cell adhesion and cellular mediators (ICAM-1, E-selectin, P-selectin). The assessment of possible statistical differences between the means of the three groups was performed by One-Way ANOVA. In addition, by non-parametric T-tests, we stratified the results according to selected clinical characteristics (psoriatic nail involvement, PASI ≥ 10, BMI ≥ 30). RESULTS: In 80 assessed naïve patients, patients with PSO showed significant increases of E-selectin (p=0.021) and IL-8 (0.041) than other groups. In patients with PSA with PSO, significant higher levels of ICAM-1 were observed (p=0.009) than other groups. We did not observe further differences comparing pro-inflammatory and anti-inflammatory cytokines, inflammatory chemokines, and cell adhesion and cellular mediators in patients with PSO, PSA with PSO, and PSA sine PSO. Patients with psoriatic onychopathy showed significant increased levels of ICAM-1 (p=0.010) and IP-10 (0.030) than others. In patients with PASI ≥ 10, significantly enhanced values of IL-8 (p=0.004), TNF (p=0.013), E-selectin (p=0.004), MIP-1α (p=0.003), and MIP-1β (p=0.039). In patients with BMI ≥ 30, significantly higher levels of E-selectin were pointed out (p=0.035) than others. CONCLUSION: Our findings may suggest that a similar cytokine profile may characterize naïve patients with PSO, PSA with PSO, and PSA sine PSO, reinforcing the concept of psoriatic disease continuum. However, some differences may be also shown, underlying possible pathogenic differences and leading to the clinical heterogeneity of these patients.

362. Case Report: Genetic and immune microenvironmental characteristics of a rectal cancer patient with MSS/PD-L1-negative recurrent hepatopulmonary metastasis who achieved complete remission after treatment with PD-1 inhibitor.

Front Immunol

2023 Jul 13

Song Y, Long J, Su X

363. End-binding protein 1 regulates the metabolic fate of CD4(+) T lymphoblasts and Jurkat T cells and the organization of the mitochondrial network.

Front Immunol

2023 Jul 13

Gómez-Morón Á, Requena S, Pertusa C

364. Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy.

Front Immunol

2023 Jul 13

Li T, Wang X, Niu M

365. Immunologic and nonimmunologic sclerodermal skin conditions - review.

Front Immunol

2023 Jul 12

Bobeica C, Niculet E, Craescu M

366. Optimizing animal models of autoimmune encephalitis using active immunization.

Front Immunol

2023 Jul 12

Linnoila J, Jalali Motlagh N, Jachimiec G

BACKGROUND AND OBJECTIVES: Encephalitis is a devastating neurologic disorder with high morbidity and mortality. Autoimmune causes are roughly as common as infectious ones. N-methyl-D-aspartic acid receptor (NMDAR) encephalitis (NMDARE), characterized by serum and/or spinal fluid NMDAR antibodies, is the most common form of autoimmune encephalitis (AE). A translational rodent NMDARE model would allow for pathophysiologic studies of AE, leading to advances in the diagnosis and treatment of this debilitating neuropsychiatric disorder. The main objective of this work was to identify optimal active immunization conditions for NMDARE in mice. METHODS: Female C57BL/6J mice aged 8 weeks old were injected subcutaneously with an emulsion of complete Freund's adjuvant, killed and dessicated Mycobacterium tuberculosis, and a 30 amino acid peptide flanking the NMDAR GluN1 subunit N368/G369 residue targeted by NMDARE patients' antibodies. Three different induction methods were examined using subcutaneous injection of the peptide emulsion mixture into mice in 1) the ventral surface, 2) the dorsal surface, or 3) the dorsal surface with reimmunization at 4 and 8 weeks (boosted). Mice were bled biweekly and sacrificed at 2, 4, 6, 8, and 14 weeks. Serum and CSF NMDAR antibody titer, mouse behavior, hippocampal cell surface and postsynaptic NMDAR cluster density, and brain immune cell entry and cytokine content were examined. RESULTS: All immunized mice produced serum and CSF NMDAR antibodies, which peaked at 6 weeks in the serum and at 6 (ventral and dorsal boosted) or 8 weeks (dorsal unboosted) post-immunization in the CSF, and demonstrated decreased hippocampal NMDAR cluster density by 6 weeks post-immunization. In contrast to dorsally-immunized mice, ventrally-induced mice displayed a translationally-relevant phenotype including memory deficits and depressive behavior, changes in cerebral cytokines, and entry of T-cells into the brain at the 4-week timepoint. A similar phenotype of memory dysfunction and anxiety was seen in dorsally-immunized mice only when they were serially boosted, which also resulted in higher antibody titers. DISCUSSION: Our study revealed induction method-dependent differences in active immunization mouse models of NMDARE disease. A novel ventrally-induced NMDARE model demonstrated characteristics of AE earlier compared to dorsally-induced animals and is likely suitable for most short-term studies. However, boosting and improving the durability of the immune response might be preferred in prolonged longitudinal studies.

367. Erratum: Breakthrough infections with the omicron and delta variants of SARS-CoV-2 result in similar re-activation of vaccine-induced immunity.

Front Immunol

2023 Jul 12

Frontiers Production Office.

368. Serum DKK-1 level in ankylosing spondylitis: insights from meta-analysis and Mendelian randomization.

Front Immunol

2023 Jul 12

Fang X, Chen C, Wang ZX

369. Evidence for a causal relationship between psoriasis and cutaneous melanoma: a bidirectional two-sample Mendelian randomized study.

Front Immunol

2023 Jul 12

Zhao N, Guo P, Tang M

370. Successful pregnancies in post-kidney transplant couples: four case reports.

Front Immunol

2023 Jul 12

Huang H, Liu X, Lin X

371. Maternal vaccination: shaping the neonatal response to pertussis.

Front Immunol

2023 Jul 12

Callender M, Harvill ET.

372. Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.

Front Immunol

2023 Jul 12

Parida S, Siddharth S, Gatla HR

INTRODUCTION: Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer. METHODS: We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays. RESULTS: ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice. DISCUSSION: In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

373. Research trends and hotspots of neuropathic pain in neurodegenerative diseases: a bibliometric analysis.

Front Immunol

2023 Jul 12

Fu Y, Gong C, Zhu C

374. Implication of metabolism in the polarization of tumor-associated-macrophages: the mass spectrometry-based point of view.

Front Immunol

2023 Jul 12

De Simone G, Soldani C, Morabito A

375. Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

Front Immunol

2023 Jul 12

Lotti R, Hundt JE, Ludwig RJ

376. Development of a radiomics nomogram to predict the treatment resistance of Chinese MPO-AAV patients with lung involvement: a two-center study.

Front Immunol

2023 Jul 12

Chen J, Meng T, Xu J

BACKGROUND: Previous studies from our group and other investigators have shown that lung involvement is one of the independent predictors for treatment resistance in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). However, it is unclear which image features of lung involvement can predict the therapeutic response in MPO-AAV patients, which is vital in decision-making for these patients. Our aim was to develop and validate a radiomics nomogram to predict treatment resistance of Chinese MPO-AAV patients based on low-dose multiple slices computed tomography (MSCT) of the involved lung with cohorts from two centers. METHODS: A total of 151 MPO-AAV patients with lung involvement (MPO-AAV-LI) from two centers were enrolled. Two different models (Model 1: radiomics signature; Model 2: radiomics nomogram) were built based on the clinical and MSCT data to predict the treatment resistance of MPO-AAV with lung involvement in training and test cohorts. The performance of the models was assessed using the area under the curve (AUC). The better model was further validated. A nomogram was constructed and evaluated by DCA and calibration curves, which further tested in all enrolled data and compared with the other model. RESULTS: Model 2 had a higher predicting ability than Model 1 both in training (AUC: 0.948 vs. 0.824; p = 0.039) and test cohorts (AUC: 0.913 vs. 0.898; p = 0.043). As a better model, Model 2 obtained an excellent predictive performance (AUC: 0.929; 95% CI: 0.827-1.000) in the validation cohort. The DCA curve demonstrated that Model 2 was clinically feasible. The calibration curves of Model 2 closely aligned with the true treatment resistance rate in the training (p = 0.28) and test sets (p = 0.70). In addition, the predictive performance of Model 2 (AUC: 0.929; 95% CI: 0.875-0.964) was superior to Model 1 (AUC: 0.862; 95% CI: 0.796-0.913) and serum creatinine (AUC: 0.867; 95% CI: 0.802-0.917) in all patients (all p< 0.05). CONCLUSION: The radiomics nomogram (Model 2) is a useful, non-invasive tool for predicting the treatment resistance of MPO-AAV patients with lung involvement, which might aid in individualizing treatment decisions.

377. Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review.

Front Immunol

2023 Jul 12

Szymański K, Kowalewski C, Pietrzyk E

378. HPV16 E6/E7 -based mRNA vaccine is therapeutic in mice bearing aggressive HPV-positive lesions.

Front Immunol

2023 Jul 12

Zhou K, Yuzhakov O, Behloul N

379. Case Report: Resolution of Lichen Planus Pemphigoides as an unexpected outcome of SARS-CoV-2 infection.

Front Immunol

2023 Jul 12

Ruffo di Calabria V, Verdelli A, Quintarelli L

380. Single-cell RNA sequencing reveals tumor immune microenvironment in human hypopharygeal squamous cell carcinoma and lymphatic metastasis.

Front Immunol

2023 Jul 12

Li C, Guan R, Li W

BACKGROUND: Human hypopharygeal squamous cell carcinoma (HSCC) is a common head and neck cancer with a poor prognosis in advanced stages. The occurrence and development of tumor is the result of mutual influence and co-evolution between tumor cells and tumor microenvironment (TME). Tumor immune microenvironment (TIME) refers to the immune microenvironment surrounding tumor cells. Studying TIME in HSCC could provide new targets and therapeutic strategies for HSCC. METHODS: We performed single-cell RNA sequencing (scRNA-seq) and analysis of hypopharyngeal carcinoma, paracancerous, and lymphoid tissues from five HSCC patients. Subdivide of B cells, T cells, macrophages cells, and monocytes and their distribution in three kinds of tissues as well as marker genes were analyzed. Different genes of IGHG1 plasma cells and SPP1+ macrophages between HSCC tissues, adjacent normal tissues and lymphatic tissues were analyzed. Additionally, we studied proliferating lymphocytes, T cells exhaustion, and T cell receptor (TCR) repertoire in three kinds of tissues. RESULTS: Transcriptome profiles of 132,869 single cells were obtained and grouped into seven cell clusters, including epithelial cells, lymphocytes, mononuclear phagocytics system (MPs), fibroblasts, endothelial cells (ECs), plasmacytoid dendritic cells (pDCs), and mast cells. Tumor metastasis occurred in three lymphoid tissues. Four distinct populations were identified from lymphocytes, including B cells, plasma cells, T cells and proliferating lymphocytes. We found IGHA1 and IGHG1 specific plasma cells significantly overexpressed in HSCC tissues compared with normal hypopharygeal tissues and lymphatic tissues. Five distinct populations from MPs were identified, including macrophages, monocytes, mature dendritic cells (DCs), Type 1 conventional dendritic cells (cDC1) and Type 2 conventional dendritic cells (cDC2). SPP1+ macrophages were significantly overexpressed in HSCC tissues and lymphatic tissues compared with normal hypopharygeal tissues, which are thought to be M2-type macrophages. Exhaustion of CD8+ Teff cells occurred in HSCC tissues. At last, we verified that IgA and IgG1 protein expression levels were significantly up-regulated in HSCC tissues compared to adjacent normal tissues. CONCLUSION: Overall, this study revealed TIME in HSCC and lymphatic metastasis, and provided potential therapeutic targets for HSCC.

381. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs.

Front Immunol

2023 Jul 12

Vincenti F, Angeletti A, Ghiggeri GM.

382. Identification of aging-related biomarkers and immune infiltration characteristics in osteoarthritis based on bioinformatics analysis and machine learning.

Front Immunol

2023 Jul 12

Zhou J, Huang J, Li Z

BACKGROUND: Osteoarthritis (OA) is a degenerative disease closely related to aging. Nevertheless, the role and mechanisms of aging in osteoarthritis remain unclear. This study aims to identify potential aging-related biomarkers in OA and to explore the role and mechanisms of aging-related genes and the immune microenvironment in OA synovial tissue. METHODS: Normal and OA synovial gene expression profile microarrays were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) from the Human Aging Genomic Resources database (HAGR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), and Gene set variation analysis (GSVA) enrichment analysis were used to uncover the underlying mechanisms. To identify Hub ARDEGs with highly correlated OA features (Hub OA-ARDEGs), Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning methods were used. Furthermore, we created diagnostic nomograms and receiver operating characteristic curves (ROC) to assess Hub OA-ARDEGs' ability to diagnose OA and predict which miRNAs and TFs they might act on. The Single sample gene set enrichment analysis (ssGSEA) algorithm was applied to look at the immune infiltration characteristics of OA and their relationship with Hub OA-ARDEGs. RESULTS: We discovered 87 ARDEGs in normal and OA synovium samples. According to functional enrichment, ARDEGs are primarily associated with inflammatory regulation, cellular stress response, cell cycle regulation, and transcriptional regulation. Hub OA-ARDEGs with excellent OA diagnostic ability were identified as MCL1, SIK1, JUND, NFKBIA, and JUN. Wilcox test showed that Hub OA-ARDEGs were all significantly downregulated in OA and were validated in the validation set and by qRT-PCR. Using the ssGSEA algorithm, we discovered that 15 types of immune cell infiltration and six types of immune cell activation were significantly increased in OA synovial samples and well correlated with Hub OA-ARDEGs. CONCLUSION: Synovial aging may promote the progression of OA by inducing immune inflammation. MCL1, SIK1, JUND, NFKBIA, and JUN can be used as novel diagnostic biomolecular markers and potential therapeutic targets for OA.

383. Integrating scRNA and bulk-RNA sequencing develops a cell senescence signature for analyzing tumor heterogeneity in clear cell renal cell carcinoma.

Front Immunol

2023 Jul 12

Gong Q, Jiang Y, Xiong J

INTRODUCTION: Cellular senescence (CS) plays a critical role in cancer development, including clear cell renal cell carcinoma (ccRCC). Traditional RNA sequencing cannot detect precise molecular composition changes within tumors. This study aimed to analyze cellular senescence's biochemical characteristics in ccRCC using single RNA sequencing (ScRNA-seq) and traditional RNA sequencing (Bulk RNA-seq). METHODS: Researchers analyzed the biochemical characteristics of cellular senescence in ccRCC using ScRNA-seq and Bulk RNA-seq. They combined these approaches to identify differences between malignant and non-malignant phenotypes in ccRCC across three senescence-related pathways. Genes from these pathways were used to identify molecular subtypes associated with senescence, and a new risk model was constructed. The function of the gene DUSP1 in ccRCC was validated through biological experiments. RESULTS: The combined analysis of ScRNA-seq and Bulk RNA-seq revealed significant differences between malignant and non-malignant phenotypes in ccRCC across three senescence-related pathways. Researchers identified genes from these pathways to identify molecular subtypes associated with senescence, constructing a new risk model. Different subgroups showed significant differences in prognosis level, clinical stage and grade, immune infiltration, immunotherapy, and drug sensitivity. DISCUSSION: Senescence signature markers are practical biomarkers and predictors of molecular typing in ccRCC. Differences in prognosis level, clinical stage and grade, immune infiltration, immunotherapy, and drug sensitivity between different subgroups indicate that this approach could provide valuable insights into senescence-related treatment options and prognostic assessment for patients with ccRCC. The function of the gene DUSP1 in ccRCC was validated through biological experiments, confirming its feasibility as a novel biomarker for ccRCC. These findings suggest that targeted therapies based on senescence-related mechanisms could be an effective treatment option for ccRCC.

384. Mini-review: microbiota have potential to prevent PEDV infection by improved intestinal barrier.

Front Immunol

2023 Jul 12

Yang S, Liu G, Savelkoul HFJ

385. IGF2BP family of RNA-binding proteins regulate innate and adaptive immune responses in cancer cells and tumor microenvironment.

Front Immunol

2023 Jul 12

Elcheva IA, Gowda CP, Bogush D

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3) are a family of RNA-binding proteins that play an essential role in the development and disease by regulating mRNA stability and translation of critical regulators of cell division and metabolism. Genetic and chemical inhibition of these proteins slows down cancer cell proliferation, decreases invasiveness, and prolongs life span in a variety of animal models. The role of RNA-binding proteins in the induction of tissues' immunogenicity is increasingly recognized, but, the impact of the IGF2BPs family of proteins on the induction of innate and adaptive immune responses in cancer is not fully understood. Here we report that downregulation of IGF2BP1, 2, and 3 expression facilitates the expression of interferon beta-stimulated genes. IGF2BP1 has a greater effect on interferon beta and gamma signaling compared to IGF2BP2 and IGF2BP3 paralogs. We demonstrate that knockdown or knockout of IGF2BP1, 2, and 3 significantly potentiates inhibition of cell growth induced by IFNβ and IFNγ. Mouse melanoma cells with Igf2bp knockouts demonstrate increased expression of MHC I (H-2) and induce intracellular Ifn-γ expression in syngeneic T-lymphocytes in vitro. Increased immunogenicity, associated with Igf2bp1 inhibition, "inflames" mouse melanoma tumors microenvironment in SM1/C57BL/6 and SW1/C3H mouse models measured by a two-fold increase of NK cells and tumor-associated myeloid cells. Finally, we demonstrate that the efficiency of anti-PD1 immunotherapy in the mouse melanoma model is significantly more efficient in tumors that lack Igf2bp1 expression. Our retrospective data analysis of immunotherapies in human melanoma patients indicates that high levels of IGF2BP1 and IGF2BP3 are associated with resistance to immunotherapies and poor prognosis. In summary, our study provides evidence of the role of IGF2BP proteins in regulating tumor immunogenicity and establishes those RBPs as immunotherapeutic targets in cancer.

386. Immune surveillance and humoral immune responses in kidney transplantation - A look back at T follicular helper cells.

Front Immunol

2023 Jul 12

Subburayalu J.

387. Post-translational modifications and immune responses in liver cancer.

Front Immunol

2023 Jul 11

Wang YW, Zuo JC, Chen C

388. Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity.

Front Immunol

2023 Jul 11

Zaitseva O, Hoffmann A, Löst M

Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.

389. Development of conjugated secondary antibodies for wildlife disease surveillance.

Front Immunol

2023 Jul 11

Ochai SO, Crafford JE, Kamath PL

390. Whole-body bioluminescence imaging of T-cell response in PDAC models.

Front Immunol

2023 Jul 11

McMorrow R, Zambito G, Nigg A

391. T memory stem cell characteristics in autoimmune diseases and their promising therapeutic values.

Front Immunol

2023 Jul 11

Fazeli P, Kalani M, Hosseini M.

392. Consequences of HIV infection in the bone marrow niche.

Front Immunol

2023 Jul 11

Herd CL, Mellet J, Mashingaidze T

393. Mitochondria-related genes and metabolic profiles of innate and adaptive immune cells in primary Sjögren's syndrome.

Front Immunol

2023 Jul 11

Luo D, Li L, Wu Y

BACKGROUND: Primary Sjogren's syndrome (pSS) is a prototypical systemic autoimmune disease characterised by lymphocyte infiltration and immune-complex deposition in multiple organs. The specific distribution of immune cell populations and their relationship with mitochondria remain unknown. METHODS: Histological analysis was performed to assess the specific distribution of innate and adaptive immune cell populations in labial salivary gland (LSG) samples from 30 patients with pSS and 13 patients with non-pSS. The ultrastructural morphometric features of mitochondria within immune cells were observed under the transmission electron microscope (TEM). RNA sequencing was performed on LSG samples from 40 patients with pSS and 7 non-pSS patients. The Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE, and CIBERSORT algorithms and Pearson correlation coefficients were used to examine the relationship between mitochondria-related genes and immune infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify the mitochondria-specific genes and the related pathways based on the immune cell types. RESULTS: HE staining revealed a massive infiltration of plasma cells with abundant immunoglobulin protein distributed around phenotypically normal-appearing acinar and ductal tissues of patients with pSS. Immunohistochemical analyses revealed that innate immune cells (macrophages, eosinophils and NK cells) were distributed throughout the glandular tissue. Dominant adaptive immune cell infiltration composed of B cells, CD4+T cells and CD8+ T cells or ectopic lymphoid follicle-like structures were observed in the LSGs of patients with pSS. TEM validated the swelling of mitochondria with disorganised cristae in some lymphocytes that had invaded the glandular tissue. Subsequently, bioinformatic analysis revealed that innate and adaptive immune cells were associated with different mitochondrial metabolism pathways. Mitochondrial electron transport and respiratory chain complexes in the glandular microenvironment were positively correlated with innate immune cells, whereas amino acid and nucleic acid metabolism were negatively correlated with adaptive immune cells. In addition, mitochondrial biogenesis and mitochondrial apoptosis in the glandular microenvironment were closely associated with adaptive immune cells. CONCLUSION: Innate and adaptive immune cells have distinct distribution profiles in the salivary gland tissues of patients with pSS and are associated with different mitochondrial metabolic pathways, which may contribute to disease progression.

394. Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression.

Front Immunol

2023 Jul 11

Li Q, Yang Z, Wang K

INTRODUCTION: Chronic spinal compression is a common complication of spinal cord injury (SCI), which can lead to spinal stenosis or herniated discs. The ensuing neuropathic pain is often associated with the activation of microglia. In this investigation, our objective was to explore whether modifying the levels of chemokine (C-C motif) ligand 2 (Ccl2) in microglia could alleviate neuropathic pain resulting from chronic spinal compression. METHODS: We used a public database to look for major altered gene associated in a SCI model established in rats. We then employed adeno-associated virus (AAV) vectors, expressing siRNA for the identified significantly altered gene under a microglia-specific TMEM119 promoter. We also tested the impact of this treatment in microglia in vivo on the severity of chronic spinal compression and associated pain using a ttw mouse model for progressive spinal compression. RESULTS: We identified chemokine (C-C motif) ligand 2 (Ccl2) as the primary gene altered in microglia within a rat SCI model, utilizing a public database. Microglial Ccl2 levels were then found to be significantly elevated in disc specimens from SCI patients diagnosed with chronic spinal compression and strongly correlated with the Thompson classification of the degeneration level and pain score. Depletion of Ccl2 in microglia-specific TMEM119 promoter were developed to transfect mouse microglia in vitro, resulting in a proinflammatory to anti-inflammatory phenotypic adaption. In vivo depletion of Ccl2 in microglia mitigated the severity of chronic spinal compression and related pain in ttw mice, likely due to significant changes in pain-associated cytokines and factors. CONCLUSION: Disc microglia expressing high levels of Ccl2 may contribute to chronic spinal compression and SCI-associated pain. Therapeutically targeting Ccl2 in microglia could offer a potential avenue for treating chronic spinal compression and SCI-associated pain.

395. Association between laboratory markers and Covid-19 disease severity and outcome: a retrospective cohort study in Saudi Arabia.

Front Immunol

2023 Jul 11

Alamoudi AA, Eldakhakhny S, Banjar H

396. The roles of inflammasomes in cancer.

Front Immunol

2023 Jul 11

Deng Z, Lu L, Li B

397. Identification of S100A8 as a common diagnostic biomarkers and exploring potential pathogenesis for osteoarthritis and metabolic syndrome.

Front Immunol

2023 Jul 11

Huang X, Liu J, Huang W.

BACKGROUND: Osteoarthritis (OA) is the most frequent musculoskeletal disease and the major contributor to disability worldwide. Metabolic syndrome (MetS) has been recognized as being associated with the pathogenesis of osteoarthritis. However, the exact mechanisms and links between the two are not clear. METHODS: We downloaded clinical information data and gene expression profiles for OA and MetS from the database of Gene Expression Omnibus (GEO), and immune related gene (IRG) from the database of Immunology Database and Analysis Portal (IMMPORT). After screening OA-DEG and MetS-DEG, we identified the common immune hub gene by screening the overlapping genes between OA-DEG, MetS-DEG and IRG. Then we conducted single-gene analysis of S100A8, assessed the correlation of S100A8 with immune cell infiltration, and verified the diagnostic value of S100A8 in OA and MetS database respectively. RESULTS: 323 OA-DEGs,101 MetS-DEGs and an immune-related hub gene, S100A8, were identified. In single gene analysis of S100A8 in OA samples, GSEA suggested that immune-related biological processes were more significantly enriched. The results of immune cell infiltration analysis showed that the enrichment fraction of M2 macrophages was significantly higher in the high S100A8-expressing group, and the level of S100A8 expression was positively correlated with M2 macrophage infiltration. The results of the dataset validation showed that S100A8 expression levels were significantly upregulated in the OA group and performed well in the diagnosis of OA. In single gene analysis of S100A8 in MetS samples, immune cell infiltration analysis showed that monocyte infiltration was higher in the S100A8 high expression samples and that there was a positive correlation between the two. Dataset validation showed that S100A8 is of high value for the diagnosis of MetS. In the validation of the dataset for the four metabolism-related diseases (obesity, diabetes, hypertension and hyperlipidaemia), S100A8 was expressed at higher levels in the disease group and also had a higher diagnostic value for the four metabolism-related diseases. CONCLUSION: S100A8 is a common hub gene and diagnostic biomarker for OA and MetS, and the immune regulation involved in S100A8 may play a central role in the pathogenesis of OA and MetS.

398. The recombinase activating genes: architects of immune diversity during lymphocyte development.

Front Immunol

2023 Jul 11

Braams M, Pike-Overzet K, Staal FJT.

399. Short-term outcomes of robot-assisted versus video-assisted thoracoscopic surgery for non-small cell lung cancer patients with neoadjuvant immunochemotherapy: a single-center retrospective study.

Front Immunol

2023 Jul 11

Pan H, Zou N, Tian Y

BACKGROUND: Neoadjuvant immunochemotherapy has been increasingly applied to treat non-small cell lung cancer (NSCLC). However, the comparison between robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in the feasibility and oncological efficacy following neoadjuvant immunochemotherapy is scarce. This study aims to assess the superiorities of RATS over (VATS) concerning short-term outcomes in treating NSCLC patients with neoadjuvant immunochemotherapy. METHODS: NSCLC patients receiving RATS or VATS lobectomy following neoadjuvant immunochemotherapy at Shanghai Chest Hospital from 2019 to 2022 were retrospectively identified. Baseline clinical characteristics, perioperative outcomes, and survival profiles were analyzed. RESULTS: Forty-six NSCLC patients with neoadjuvant immunochemotherapy were included and divided into the RATS (n=15) and VATS (n=31) groups. The baseline clinical characteristics and induction-related adverse events were comparable between the two groups (all p>0.050). The 30-day mortality in the RATS and VATS groups were 0% and 3.23%, respectively (p=1.000). Patients undergoing RATS were associated with reduced surgical-related intensive unit care (ICU) stay than those receiving VATS (0.0 [0.0-0.0] vs. 0.0 [0.0-1.0] days, p=0.026). Moreover, RATS assessed more N1 LNs (6.27 ± 1.94 vs 4.90 ± 1.92, p=0.042) and LN stations (3.07 ± 1.03 vs 2.52 ± 0.57, p=0.038) compared with VATS. By comparison, no difference was found in surgical outcomes, pathological results, and postoperative complications between the RATS and VATS groups (all p>0.050). Finally, RATS and VATS achieved comparable one-year recurrence-free survival (82.96% vs. 85.23%, p=0.821) and the timing of central nervous system, LN, and bone recurrences (all p>0.050). CONCLUSION: RATS is safe and feasible for NSCLC patients with neoadjuvant immunochemotherapy, reducing surgical-related ICU stay, assessing increased N1 LNs and stations, and achieving similar survival profiles to VATS.

400. E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies.

Front Immunol

2023 Jul 11

Wang M, Zhang Z, Li Z

401. Microenvironmental regulation of T-cells in pulmonary hypertension.

Front Immunol

2023 Jul 11

Plecitá-Hlavatá L, Brázdová A, Křivonosková M

INTRODUCTION: In pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH. METHODS: We used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs). RESULTS: Single-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism. CONCLUSION: This study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH.

402. Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma.

Front Immunol

2023 Jul 11

Secondino S, Pedrazzoli P, Basso S

403. Mast cells in colorectal cancer tumour progression, angiogenesis, and lymphangiogenesis.

Front Immunol

2023 Jul 11

Liu X, Li X, Wei H

404. Identification of immune infiltration and cuproptosis-related molecular clusters in tuberculosis.

Front Immunol

2023 Jul 11

Li S, Long Q, Nong L

BACKGROUND: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection. Cuproptosis is a novel cell death mechanism correlated with various diseases. This study sought to elucidate the role of cuproptosis-related genes (CRGs) in TB. METHODS: Based on the GSE83456 dataset, we analyzed the expression profiles of CRGs and immune cell infiltration in TB. Based on CRGs, the molecular clusters and related immune cell infiltration were explored using 92 TB samples. The Weighted Gene Co-expression Network Analysis (WGCNA) algorithm was utilized to identify the co-expression modules and cluster-specific differentially expressed genes. Subsequently, the optimal machine learning model was determined by comparing the performance of the random forest (RF), support vector machine (SVM), generalized linear model (GLM), and eXtreme Gradient Boosting (XGB). The predictive performance of the machine learning model was assessed by generating calibration curves and decision curve analysis and validated in an external dataset. RESULTS: 11 CRGs were identified as differentially expressed cuproptosis genes. Significant differences in immune cells were observed in TB patients. Two cuproptosis-related molecular clusters expressed genes were identified. Distinct clusters were identified based on the differential expression of CRGs and immune cells. Besides, significant differences in biological functions and pathway activities were observed between the two clusters. A nomogram was generated to facilitate clinical implementation. Next, calibration curves were generated, and decision curve analysis was conducted to validate the accuracy of our model in predicting TB subtypes. XGB machine learning model yielded the best performance in distinguishing TB patients with different clusters. The top five genes from the XGB model were selected as predictor genes. The XGB model exhibited satisfactory performance during validation in an external dataset. Further analysis revealed that these five model-related genes were significantly associated with latent and active TB. CONCLUSION: Our study provided hitherto undocumented evidence of the relationship between cuproptosis and TB and established an optimal machine learning model to evaluate the TB subtypes and latent and active TB patients.

405. Transfusion-dependent non-severe aplastic anemia: characteristics and outcomes in the clinic.

Front Immunol

2023 Jul 11

Zhang Y, He Y, Wang S

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic anemia (SAA). Little is known about the clinical and laboratory characteristics, and disease prognosis and outcomes in TD-NSAA patients. The clinical and laboratory data of 124 consecutive TD-NSAA patients in the Chinese Eastern Collaboration Group of Anemia from December 2013 and January 2017 were analyzed retrospectively. In 124 TD-NSAA patients, the median age was 32 years (range: 3-80) and the median disease course was 38 months (range: 3-363). Common complications were iron overload (53/101, 52.5%), liver and kidney dysfunction (42/124, 33.9%), diabetes mellitus/impaired glucose tolerance (24/124, 19.4%), and severe infection (29 cases, 23.4%). 58% of patients (57/124) developed severe aplastic anemia with a median progression time of 24 months (range: 3-216). Patients with absolute neutrophil count (ANC) <0.5×109/L, severe infection, or iron overload had a higher probability of progression to SAA (P=0.022, P=0.025, P=0.001). Patients receiving antithymocyte globulin (ATG) plus Cyclosporin A (CsA) had a higher overall response rate compared to those receiving CsA alone (56.7% vs 19.3%, P < 0.001). The addition of ATG was the favorable factor for efficacy (P=0.003). Fourteen patients developed secondary clonal hematologic disease: eleven patients with paroxysmal nocturnal hemoglobinuria, two patients with myelodysplastic syndromes, and one patient with acute myeloid leukemia, respectively. Ten patients (8.1%) died with a median follow-up of 12 months (range: 3- 36 months). Patients with TD-NSAA usually have a prolonged course of disease, and are prone to be complicated with important organ damage and disease progression to SAA. Intensive immunosuppressive therapy based on ATG might be an appropriate approach for TD-NSAA. Clinical trial registration: http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

406. The role of CD8+ T cells in endometriosis: a systematic review.

Front Immunol

2023 Jul 11

Kisovar A, Becker CM, Granne I

BACKGROUND: Endometriosis is a chronic disease affecting 6-10% of women of reproductive age. It is an important cause of infertility and chronic pelvic pain with poorly understood aetiology. CD8+ T (CD8 T) cells were shown to be linked to infertility and chronic pain and play a significant role in lesion clearance in other pathologies, yet their function in endometriosis is unknown. We systematically evaluated the literature on the CD8 T in peripheral blood and endometriosis-associated tissues to determine the current understanding of their pathophysiological and clinical relevance in the disease and associated conditions (e.g. infertility and pelvic pain). METHODS: Four databases were searched (MEDLINE, EMBASE, Web of Science, CINAHL), from database inception until September 2022, for papers written in the English language with database-specific relevant terms/free-text terms from two categories: CD8 T cells and endometriosis. We included peer-reviewed papers investigating CD8 T cells in peripheral blood and endometriosis-associated tissues of patients with surgically confirmed endometriosis between menarche and menopause, and animal models with oestrous cycles. Studies enrolling participants with other gynaecological pathologies (except uterine fibroids and tubal factor infertility used as controls), cancer, immune diseases, or taking immune or hormonal therapy were excluded. RESULTS: 28 published case-control studies and gene set analyses investigating CD8 T cells in endometriosis were included. Data consistently indicate that CD8 T cells are enriched in endometriotic lesions in comparison to eutopic endometrium, with no differences in peripheral blood CD8 T populations between patients and healthy controls. Evidence on CD8 T cells in peritoneal fluid and eutopic endometrium is conflicting. CD8 T cell cytotoxicity was increased in the menstrual effluent of patients, and genomic analyses have shown a clear trend of enriched CD8 T effector memory cells in the eutopic endometrium of patients. CONCLUSION: Literature on CD8 T cells in endometriosis-associated tissues is inconsistent. Increased CD8 T levels are found in endometriotic lesions, however, their activation potential is understudied in all relevant tissues. Future research should focus on identifying clinically relevant phenotypes to support the development of non-invasive diagnostic and treatment strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier CRD42021233304.

407. Bringing function to the forefront of cell therapy: how do we demonstrate potency?

Front Immunol

2023 Jul 11

Lowdell MW, Weil B.

408. Current understanding of CTLA-4: from mechanism to autoimmune diseases.

Front Immunol

2023 Jul 11

Hossen MM, Ma Y, Yin Z

409. The association between the CD4/CD8 ratio and surgical site infection risk among HIV-positive adults: insights from a China hospital.

Front Immunol

2023 Jul 11

Liu B, Li K, Li S

PURPOSE: It is well known that the CD4/CD8 ratio is a special immune-inflammation marker. We aimed to explore the relationship between the CD4/CD8 ratio and the risk of surgical site infections (SSI) among human immunodeficiency virus (HIV)-positive adults undergoing orthopedic surgery. METHODS: We collected and analyzed data from 216 HIV-positive patients diagnosed with fractures at the department of orthopedics, Beijing Ditan Hospital between 2011 and 2019. The demographic, surgical, and hematological data for all patients were collected in this retrospective cohort study. We explored the risk factors for SSI using univariate and multivariate logistic regression analysis. Then, the clinical correlation between the CD4 count, CD4/CD8 ratio, and SSI was studied using multivariate logistic regression models after adjusting for potential confounders. Furthermore, the association between the CD4/CD8 ratio and SSI was evaluated on a continuous scale with restricted cubic spline (RCS) curves based on logistic regression models. RESULTS: A total of 23 (10.65%) patients developed SSI during the perioperative period. Patients with hepatopathy (OR=6.10, 95%CI=1.46-28.9), HIV viral load (OR=8.68, 95%CI=1.42-70.2; OR=19.4, 95%CI=3.09-179), operation time (OR=7.84, 95%CI=1.35-77.9), and CD4 count (OR=0.05, 95%CI=0.01-0.23) were risk factors for SSI (P-value < 0.05). Our study demonstrated that a linear relationship between CD4 count and surgical site infection risk. In other words, patients with lower CD4 counts had a higher risk of developing SSI. Furthermore, the relationship between CD4/CD8 ratio and SSI risk was non-linear, inverse 'S' shaped. The risk of SSI increased substantially when the ratio was below 0.913; above 0.913, the risk of SSI was almost unchanged. And there is a 'threshold-saturation' effect between them. CONCLUSION: Our research shows the CD4/CD8 ratio could be a useful predictor and immune-inflammation marker of the risk of SSI in HIV-positive fracture patients. These results, from a Chinese hospital, support the beneficial role of immune reconstitution in HIV-positive patients prior to orthopedic surgery.

410. Five-year follow-up of a phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

Front Immunol

2023 Jul 11

Schaier M, Morath C, Wang L

411. A highly sensitive nanobody-based immunoassay detecting SARS-CoV-2 nucleocapsid protein using all-recombinant reagents.

Front Immunol

2023 Jul 11

Segovia-de Los Santos P, Padula-Roca C, Simon X

412. Curcumin derived from medicinal homologous foods: its main signals in immunoregulation of oxidative stress, inflammation, and apoptosis.

Front Immunol

2023 Jul 11

Hu P, Li K, Peng XX

413. Pre-transplant immune profile defined by principal component analysis predicts acute rejection after kidney transplantation.

Front Immunol

2023 Jul 11

Gaiffe E, Colladant M, Desmaret M

414. Extended cleavage specificities of human granzymes A and K, two closely related enzymes with conserved but still poorly defined functions in T and NK cell-mediated immunity.

Front Immunol

2023 Jul 11

Aybay E, Ryu J, Fu Z

Granzymes A and K are two highly homologous serine proteases expressed by mammalian cytotoxic T cells (CTL) and natural killer cells (NK). Granzyme A is the most abundant of the different granzymes (gzms) expressed by these two cell types. Gzms A and K are found in all jawed vertebrates and are the most well conserved of all hematopoietic serine proteases. Their potential functions have been studied extensively for many years, however, without clear conclusions. Gzm A was for many years thought to serve as a key component in the defense against viral infection by the induction of apoptosis in virus-infected cells, similar to gzm B. However, later studies have questioned this role and instead indicated that gzm A may act as a potent inducer of inflammatory cytokines and chemokines. Gzms A and K form clearly separate branches in a phylogenetic tree indicating separate functions. Transcriptional analyses presented here demonstrate the presence of gzm A and K transcripts in both CD4+ and CD8+ T cells. To enable screening for their primary biological targets we have made a detailed analysis of their extended cleavage specificities. Phage display analysis of the cleavage specificity of the recombinant enzymes showed that both gzms A and K are strict tryptases with high selectivity for Arg over Lys in the P1 position. The major differences in the specificities of these two enzymes are located N-terminally of the cleavage site, where gzm A prefers small amino acids such as Gly in the P3 position and shows a relatively relaxed selectivity in the P2 position. In contrast, gzm K prefers large amino acids such as Phe, Tyr, and Trp in both the P2 and P3 positions and does not tolerate negatively charged residues in the P2 position. This major distinction in extended specificities is likely reflected also in preferred in vivo targets of these two enzymes. This information can now be utilized for high-precision screening of primary targets for gzms A and K in search of their highly conserved but still poorly defined functions in vertebrate immunity.

415. Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report.

Front Immunol

2023 Jul 10

Sagawa T, Sato Y, Nagashima H

416. The prevalence of IgG antibodies against milk and milk antigens in patients with multiple sclerosis.

Front Immunol

2023 Jul 10

Chunder R, Heider T, Kuerten S.

417. Are the integrin binding motifs within SARS CoV-2 spike protein and MHC class II alleles playing the key role in COVID-19?

Front Immunol

2023 Jul 10

Gerencer M, McGuffin LJ.

418. Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis.

Front Immunol

2023 Jul 10

Peng L, Chen L, Wan J

419. Identification and characterization of codon usage pattern and influencing factors in HFRS-causing hantaviruses.

Front Immunol

2023 Jul 10

Noor F, Ashfaq UA, Bakar A

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral zoonosis carried and transmitted by infected rodents through urine, droppings, or saliva. The etiology of HFRS is complex due to the involvement of viral factors and host immune and genetic factors which hinder the development of potential therapeutic solutions for HFRS. Hantaan virus (HTNV), Dobrava-Belgrade virus (DOBV), Seoul virus (SEOV), and Puumala virus (PUUV) are predominantly found in hantaviral species that cause HFRS in patients. Despite ongoing prevention and control efforts, HFRS remains a serious economic burden worldwide. Furthermore, recent studies reported that the hantavirus nucleocapsid protein is a multi-functional protein and plays a major role in the replication cycle of the hantavirus. However, the precise mechanism of the nucleoproteins in viral pathogenesis is not completely understood. In the framework of the current study, various in silico approaches were employed to identify the factors influencing the codon usage pattern of hantaviral nucleoproteins. Based on the relative synonymous codon usage (RSCU) values, a comparative analysis was performed between HFRS-causing hantavirus and their hosts, suggesting that HTNV, DOBV, SEOV, and PUUV, were inclined to evolve their codon usage patterns that were comparable to those of their hosts. The results indicated that most of the overrepresented codons had AU-endings, which revealed that mutational pressure is the major force shaping codon usage patterns. However, the influence of natural selection and geographical factors cannot be ignored on viral codon usage bias. Further analysis also demonstrated that HFRS causing hantaviruses adapted host-specific codon usage patterns to sustain successful replication and transmission chains within hosts. To our knowledge, no study to date reported the factors influencing the codon usage pattern within hantaviral nucleoproteins. Thus, the proposed computational scheme can help in understanding the underlying mechanism of codon usage patterns in HFRS-causing hantaviruses which lend a helping hand in designing effective anti-HFRS treatments in future. This study, although comprehensive, relies on in silico methods and thus necessitates experimental validation for more solid outcomes. Beyond the identified factors influencing viral behavior, there could be other yet undiscovered influences. These potential factors should be targets for further research to improve HFRS therapeutic strategies.

420. Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma.

Front Immunol

2023 Jul 10

Zhang W, Zhao Y, He Q

421. STING signaling in inflammaging: a new target against musculoskeletal diseases.

Front Immunol

2023 Jul 10

Song C, Hu Z, Xu D

Stimulator of Interferon Gene (STING) is a critical signaling linker protein that plays a crucial role in the intrinsic immune response, particularly in the cytoplasmic DNA-mediated immune response in both pathogens and hosts. It is also involved in various signaling processes in vivo. The musculoskeletal system provides humans with morphology, support, stability, and movement. However, its aging can result in various diseases and negatively impact people's lives. While many studies have reported that cellular aging is a leading cause of musculoskeletal disorders, it also offers insight into potential treatments. Under pathological conditions, senescent osteoblasts, chondrocytes, myeloid cells, and muscle fibers exhibit persistent senescence-associated secretory phenotype (SASP), metabolic disturbances, and cell cycle arrest, which are closely linked to abnormal STING activation. The accumulation of cytoplasmic DNA due to chromatin escape from the nucleus following DNA damage or telomere shortening activates the cGAS-STING signaling pathway. Moreover, STING activation is also linked to mitochondrial dysfunction, epigenetic modifications, and impaired cytoplasmic DNA degradation. STING activation upregulates SASP and autophagy directly and indirectly promotes cell cycle arrest. Thus, STING may be involved in the onset and development of various age-related musculoskeletal disorders and represents a potential therapeutic target. In recent years, many STING modulators have been developed and used in the study of musculoskeletal disorders. Therefore, this paper summarizes the effects of STING signaling on the musculoskeletal system at the molecular level and current understanding of the mechanisms of endogenous active ligand production and accumulation. We also discuss the relationship between some age-related musculoskeletal disorders and STING, as well as the current status of STING modulator development.

422. Influence of technical and maternal-infant factors on the measurement and expression of extracellular miRNA in human milk.

Front Immunol

2023 Jul 10

Holzhausen EA, Kupsco A, Chalifour BN

423. Arecoline aggravates acute ulcerative colitis in mice by affecting intestinal microbiota and serum metabolites.

Front Immunol

2023 Jul 10

Zhao H, Ding T, Chen Y

424. Plasma cells are not restricted to the CD27+ phenotype: characterization of CD27-CD43+ antibody-secreting cells.

Front Immunol

2023 Jul 10

Covens K, Verbinnen B, de Jong BG

425. Integrated bioinformatic analysis and experimental validation for exploring the key molecular of brain inflammaging.

Front Immunol

2023 Jul 10

Du Z, Wang Y, Yang L

426. Analysis of platelet and monocyte-to-lymphocyte ratio and diabetes mellitus with benign prostatic enlargement.

Front Immunol

2023 Jul 10

Chen G, Feng L.

427. Immune escape and resistance to immunotherapy in mismatch repair deficient tumors.

Front Immunol

2023 Jul 10

Mestrallet G, Brown M, Bozkus CC

428. Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis.

Front Immunol

2023 Jul 10

He X, Zhang J, Gong M

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and gradual joint degeneration, resulting in function disability. Recently, ferroptosis, a novel form of regulated cell death that involves iron-dependent lipid peroxidation, has been implicated in the pathogenesis of RA. However, the underlying molecular mechanisms and key genes involved in ferroptosis in RA remain largely unknown. METHODS: The GSE134420 and GSE77298 datasets were downloaded and DEGs were identified using R software. The DEGs were then mapped to the dataset of 619 ferroptosis-related genes obtained from the GeneCards database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to investigate the possible biological functions. Protein-protein interaction (PPI) networks were constructed to identify the hub genes. The relationship between hub genes and immune infiltration was estimated using the CIBERSORT algorithms. Gene Set Enrichment Analysis (GSEA) was used to explore the underlying signaling pathways of hub genes. Genome-wide association studies (GWAS) analysis was performed to confirm the pathogenic regions of the hub genes. RcisTarget and Gene-motif ranking databases were used to identify transcription factors (TFs) associated with the hub genes. The miRcode databases were utilized to construct the microRNA (miRNA)-messenger RNA (mRNA) network. Single-cell analysis was utilized to cluster cells and display the expression of hub genes in cell clusters. Finally, the expression and potential mechanism of hub genes were investigated in human and experimental samples. RESULTS: Three hub genes PTGS2, ENO1, and GRN highly associated with ferroptosis were identified. Four pathogenic genes HLA-B, MIF, PSTPIP, TLR1 were identified that were significantly and positively correlated with the expression levels of hub genes. The results of the GSEA showed that the hub genes were significantly enriched in pathways related to immunity, lysosome, phagocytosis and infection. ENO1 and PTGS2 were enriched in the TF-binding motif of cisbp_M5493. The hub genes were validated in experimental and patient samples and highly level of ENO1 expression was found to inhibit ACO1, which reduces ferroptosis in proliferating fibroblast-like synoviocytes (FLS). CONCLUSION: PTGS2, ENO1 and GRN were identified and validated as potential ferroptosis-related biomarkers. Our work first revealed that ENO1 is highly expressed in RA synovium and that ferroptosis may be regulated by the ENO1-ACO1 axis, advancing the understanding of the underlying ferroptosis-related mechanisms of synovial proliferation and providing potential diagnostic and therapeutic targets for RA.

429. Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone.

Front Immunol

2023 Jul 10

Kametani Y, Ito R, Ohshima S

430. Glucocorticoid dysfunction in children with severe malaria.

Front Immunol

2023 Jul 10

Vandermosten L, Prenen F, Fogang B

431. Janus kinase inhibitors in autoimmune bullous diseases.

Front Immunol

2023 Jul 10

Huang D, Zhang Y, Kong L

432. Long-term efficacy and safety of different corticosteroid courses plus mycophenolate mofetil for autoimmune encephalitis with neuronal surface antibodies without tumor.

Front Immunol

2023 Jul 10

Li D, Huang T, Zhang F

OBJECTIVE: To compare the efficacy and safety of different-course corticosteroids plus mycophenolate mofetil (MMF) as maintenance therapy in autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) without tumor and explore the optimal course of corticosteroids. METHODS: Fifty-five patients with definite AE without tumor were enrolled consecutively between June 2015 and November 2020 and retrospectively divided three groups according to the course of treatment with corticosteroid, i.e., a group of patients with a course of 3-6 months (Group 3-6mo), 6-12 months (Group 6-12mo), and >12 months (Group >12mo). Demographic data, clinical manifestation and ancillary tests results were recorded. The dosage and courses of corticosteroid treatment, the recovery of neurological function, the occurrence of adverse effects, and relapses were followed up. RESULTS: A total of 55 patients were included in the final analysis. The numbers of patients in Group 3-6 mo, Group 6-12 mo, and Group >12 mo was 14, 17, and 24, respectively. A significantly higher proportion of patients in Group >12 mo showed a decreased level of consciousness at the onset (12, 50%) than in Group 3-6 mo and Group 6-12 mo (2,14.3%; 3, 17.6%) (p = 0.033). The incidence of MRI abnormalities was significantly higher in Group 6-12 mo and Group >12 mo (10, 58.8%; 16, 66.7%) than in Group 3-6 mo (3, 21.4%) (P=0.023). Ordinal regression analysis indicated that decreased level of consciousness was associated with the course of corticosteroid (OR=3.838, 95% CI: 1.103-13.323, P=0.035). No significant difference was observed between the three groups regarding the cumulative dose of corticosteroids administered during the first three months of long-term treatment (P>0.05). Additionally, no significant difference in the cumulative dosage of corticosteroids was found between patients in Group 6-12 months and Group >12 months during the first 6 months after beginning long-term treatment. The mRS scores of the three groups were not statistically significant before and after first-line treatment or at the last follow-up. Bonferroni multiple comparison test indicated that the mRS scores of patients in Group 6-12 months and Group >12 months were not statistically significant at 3 months and 12 months after the start of long-term treatment. During the follow-up, 50 (90.9%) patients achieved satisfactory neurological function (mRS score ≤2). Five patients (9.1%) experienced a first relapse and 2 of them were overlapped with both anti-NMDA receptor and glial antibodies. The incidence of adverse effects was significantly higher in Group >12 mo (17, 70.8%) than in Group 3-6 mo (3, 21.4%) and Group 6-12 mo (5, 29.4%) (P=0.003). CONCLUSIONS: The beneficial effects of oral corticosteroid treatment may do not persist beyond 12 months and may even contribute to an increased incidence of adverse effects. In order to optimize the effectiveness and safety of treatment, we recommend a corticosteroid course of 3-12 months. Patients with reduced levels of consciousness may be more inclined to choose longer courses of corticosteroids for long-term treatment. Patients with an "overlapping syndrome" may require more intense immunotherapy to prevent relapse.

433. Effects of synovial macrophages in osteoarthritis.

Front Immunol

2023 Jul 10

Zhao K, Ruan J, Nie L

434. A risk score combining co-expression modules related to myeloid cells and alternative splicing associates with response to PD-1/PD-L1 blockade in non-small cell lung cancer.

Front Immunol

2023 Jul 10

Han Y, Liu SM, Jin R

BACKGROUND: Comprehensive analysis of transcriptomic profiles of non-small cell lung cancer (NSCLC) may provide novel evidence for biomarkers associated with response to PD-1/PD-L1 immune checkpoint blockade (ICB). METHODS: We utilized weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic data from two NSCLC datasets from Gene Expression Omnibus (GSE135222 and GSE126044) that involved patients received ICB treatment. We evaluated the correlation of co-expression modules with ICB responsiveness and functionally annotated ICB-related modules using pathway enrichment analysis, single-cell RNA sequencing, flow cytometry and alternative splicing analysis. We built a risk score using Lasso-COX regression based on hub genes from ICB-related modules. We investigated the alteration of tumor microenvironment between high- and low- risk groups and the association of the risk score with previously established predictive biomarkers. RESULTS: Our results identified a black with positive correlation and a blue module with negative correlation to ICB responsiveness. The black module was enriched in pathway of T cell activation and antigen processing and presentation, and the genes assigned to it were consistently expressed on myeloid cells. We observed decreased alternative splicing events in samples with high signature scores of the blue module. The Lasso-COX analysis screened out three genes (EVI2B, DHX9, HNRNPM) and constructed a risk score from the hub genes of the two modules. We validated the predictive value of the risk score for poor response to ICB therapy in an in-house NSCLC cohort and a pan-cancer cohort from the KM-plotter database. The low-risk group had more immune-infiltrated microenvironment, with higher frequencies of precursor exhausted CD8+ T cells, tissue-resident CD8+ T cells, plasmacytoid dendritic cells and type 1 conventional dendritic cells, and a lower frequency of terminal exhausted CD8+ T cells, which may explain its superior response to ICB therapy. The significant correlation of the risk score to gene signature of tertiary lymphoid structure also implicated the possible mechanism of this predictive biomarker. CONCLUSIONS: Our study identified two co-expression modules related to ICB responsiveness in NSCLC and developed a risk score accordingly, which could potentially serve as a predictive biomarker for ICB response.

435. Differentiation in TCM patterns of chronic obstructive pulmonary disease by comprehensive metabolomic and lipidomic characterization.

Front Immunol

2023 Jul 10

Li J, Liu X, Shi Y

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