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1. Immunogenic change after percutaneous microwave ablation in pulmonary malignancies: Variation in immune cell subsets and cytokines in peripheral blood.

Front Immunol

2022 Dec 9

Zhang L, Zhang M, Wang J

2. A novel technology for home monitoring of lupus nephritis that tracks the pathogenic urine biomarker ALCAM.

Front Immunol

2022 Dec 9

Lei R, Vu B, Kourentzi K

3. Molecular and anatomical roadmap of stroke pathology in immunodeficient mice.

Front Immunol

2022 Dec 9

Weber RZ, Mulders G, Perron P

BACKGROUND: Stroke remains a leading cause of disability and death worldwide. It has become apparent that inflammation and immune mediators have a pre-dominant role in initial tissue damage and long-term recovery. Still, different immunosuppressed mouse models are necessary in stroke research e.g., to evaluate therapies using human cell grafts. Despite mounting evidence delineating the importance of inflammation in the stroke pathology, it is poorly described to what extent immune deficiency influences overall stroke outcome. METHODS: Here, we assessed the stroke pathology of popular genetic immunodeficient mouse models, i.e., NOD scid gamma (NSG) and recombination activating gene 2 (Rag2-/-) mice as well as pharmacologically immunosuppressed mice and compared them to immune competent, wildtype (WT) C57BL/6J mice three weeks after injury. We performed histology, gene expression, blood serum and behavioural analysis to identify the impact of immunosuppression on stroke progression. RESULTS: We detected changes in microglia activation/macrophage infiltration, scar-forming and vascular repair in immune-suppressed mice three weeks after injury. Transcriptomic analysis of stroked tissue revealed the strongest deviation from WT was observed in NSG mice affecting immunological and angiogenic pathways. Pharmacological immunosuppression resulted in the least variation in gene expression compared with the WT. These anatomical and genetic changes did not affect functional recovery in a time course of three weeks. To determine whether timing of immunosuppression is critical, we compared mice with acute and delayed pharmacological immunosuppression after stroke. Mice with delayed immunosuppression (7d) showed increased inflammatory and scarring responses compared to animals acutely treated with tacrolimus, thus more closely resembling WT pathology. Transplantation of human cells in the brains of immunosuppressed mice led to prolonged cell survival in all immunosuppressed mouse models, which was most consistent in NSG and Rag2-/- mice. CONCLUSIONS: We detected distinct anatomical and molecular changes in the stroke pathology between individual immunosuppressed mouse models that should be considered when selecting an appropriate mouse model for stroke research.

4. Editorial: The mechanism and novel strategies of overcoming resistance of hematological malignancies to CAR-T cell killing.

Front Immunol

2022 Dec 9

Zhang T, Yu T, Yang X

5. Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes.

Front Immunol

2022 Dec 9

Wada T, Shiraishi A, Gando S

INTRODUCTION: Trauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients. METHODS: This retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin <80% on hospital arrival, n = 75) in comparison with those who had normal antithrombin activity (antithrombin ≥80%, n = 200). Global markers of coagulation and fibrinolysis, molecular biomarkers for thrombin generation (soluble fibrin [SF]), and markers of anticoagulation (antithrombin) were evaluated to confirm the associations of antithrombin with DIC development and outcomes, including in-hospital mortality and the multiple organ dysfunction syndrome (MODS). RESULTS: Patients with low antithrombin activity had higher prevalence of shock, transfusion requirements, and in-hospital mortality. Higher DIC scores and more severe organ dysfunction were observed in the low AT group compared to that in the normal AT group. Antithrombin activity on arrival at the hospital was an independent predictor of the development of DIC in trauma patients, and levels of SF increased with lower antithrombin values (antithrombin activity > 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values. CONCLUSION: Decreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

6. Nanomaterials targeting macrophages in sepsis: A promising approach for sepsis management.

Front Immunol

2022 Dec 9

Song C, Xu J, Gao C

7. Bidirectional associations between eosinophils, basophils, and lymphocytes with atopic dermatitis: A multivariable Mendelian randomization study.

Front Immunol

2022 Dec 9

Zeng-Yun-Ou Z, Zhong-Yu J, Wei L.

8. Integrated single-cell transcriptome analysis of the tumor ecosystems underlying cervical cancer metastasis.

Front Immunol

2022 Dec 9

Li C, Liu D, Yang S

9. A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility.

Front Immunol

2022 Dec 9

Boer JC, Pan Q, Holien JK

INTRODUCTION: COVID-19 pandemic has been threatening public health and economic development worldwide for over two years. Compared with the original SARS-CoV-2 strain reported in 2019, the Omicron variant (B.1.1.529.1) is more transmissible. This variant has 34 mutations in its Spike protein, 15 of which are present in the Receptor Binding Domain (RBD), facilitating viral internalization via binding to the angiotensin-converting enzyme 2 (ACE2) receptor on endothelial cells as well as promoting increased immune evasion capacity. METHODS: Herein we compared SARS-CoV-2 proteins (including ORF3a, ORF7, ORF8, Nucleoprotein (N), membrane protein (M) and Spike (S) proteins) from multiple ancestral strains. We included the currently designated original Variant of Concern (VOC) Omicron, its subsequent emerged variants BA.1, BA2, BA3, BA.4, BA.5, the two currently emerging variants BQ.1 and BBX.1, and compared these with the previously circulating VOCs Alpha, Beta, Gamma, and Delta, to better understand the nature and potential impact of Omicron specific mutations. RESULTS: Only in Omicron and its subvariants, a bias toward an Asparagine to Lysine (N to K) mutation was evident within the Spike protein, including regions outside the RBD domain, while none of the regions outside the Spike protein domain were characterized by this mutational bias. Computational structural analysis revealed that three of these specific mutations located in the central core region, contribute to a preference for the alteration of conformations of the Spike protein. Several mutations in the RBD which have circulated across most Omicron subvariants were also analysed, and these showed more potential for immune escape. CONCLUSION: This study emphasizes the importance of understanding how specific N to K mutations outside of the RBD region affect SARS-CoV-2 conformational changes and the need for neutralizing antibodies for Omicron to target a subset of conformationally dependent B cell epitopes.

10. Residual tumor model in esophageal squamous cell carcinoma after neoadjuvant immunochemotherapy: Frequently involves the mucosa and/or submucosa.

Front Immunol

2022 Dec 9

Gao L, Hong ZN, Wu L

OBJECTIVES: The efficacy and safety of neoadjuvant immunochemotherapy (nICT) are widely explored in locally advanced esophageal squamous cell carcinoma (ESCC). Whether the "wait-and-see" strategy is applicable in ESCC after nICT is still lacking a theoretical basis. This study aimed to preliminarily explore the distribution of residual tumors and the regression pattern of ESCC after nICT. METHODS: Patients undergoing radical esophagectomy after nICT in Fujian Medical University Union Hospital between January 2020 and March 2022 were identified. The resection specimens were re-evaluated by one experienced pathologist. The pathological response was assessed by tumor regression grade (TRG) (modified Ryan scheme). The TRG grade was divided into grades 0 (pathological complete response), 1, 2, and 3. The pathological stage was evaluated in the Eighth Edition AJCC. In the non-pCR group, the residual model was divided into four types: Type I, regression towards the lumen; type II, regression towards the invasive front; type III, concentric regression; and type IV, scattered regression. RESULTS: A total of 95 consecutive patients were included for analysis. Seventy-six (80.0%) of 95 patients were in non-pCR (pathological complete response), and nine patients (9/76, 11.84%) had isolated residual tumors in lymph nodes. There was no significant difference in baseline characteristics between the pCR group and the non-pCR group (p > 0.05). The overall distribution of TRG for all esophageal wall layers was TRG 0 = 28 (28/95, 29.5%), TRG 1 = 17 (17/95, 17.9%), TRG 2 = 18 (18.9%, 18/95), and TRG 3 = 32 (32/95, 33.7%). In 67 patients with residual tumors in the esophageal wall (TRG ≧1), 63 (63/67, 94.0%) had residual tumor cells in the mucosa and/or submucosa, and four had isolated residual tumors in the muscle layer (4/67, 6.0%). Further analysis showed eight (8/67, 11.9%) patients with submucosal involvement but without mucosal involvement. The distribution of regression patterns was type I (n = 35, 52.2%), type II (n = 3, 4.5%), type III (n = 8, 11.9%), and type IV (n = 21, 31.3%). CONCLUSIONS: The mucosa and/or submucosa are frequently involved in residual malignancy, and the frequent regression models are regression toward the lumen and random regression. There is an opportunity to carefully test the residual tumors in a subgroup of the population with ESCC following nICT. However, some patients had residual tumors only in the muscle layer or lymph nodes. The clinical application of the wait-and-see strategy in ESCC after nICT should be explored using an appropriate evaluation protocol.

11. Sex differences in Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and experimental autoimmune neuritis.

Front Immunol

2022 Dec 9

McCombe PA, Hardy TA, Nona RJ

12. Inflammatory-driven NK cell maturation and its impact on pathology.

Front Immunol

2022 Dec 9

Bourayou E, Golub R.

13. Case report: Nocardia gipuzkoensis infection in an immunocompetent patient diagnosed by metagenomic next-generation sequencing and whole genome sequencing.

Front Immunol

2022 Dec 9

Liu C, Yang J, Huang H

14. Exploring biomarkers for prognosis and neoadjuvant chemosensitivity in rectal cancer: Multi-omics and ctDNA sequencing collaboration.

Front Immunol

2022 Dec 9

Jiang XF, Zhang BM, Du FQ

INTRODUCTION: This study aimed to identified the key genes and sequencing metrics for predicting prognosis and efficacy of neoadjuvant chemotherapy (nCT) in rectal cancer (RC) based on genomic DNA sequencing in samples with different origin and multi-omics association database. METHODS: We collected 16 RC patients and obtained DNA sequencing data from cancer tissues and plasma cell-free DNA before and after nCT. Various gene variations were analyzed, including single nucleotide variants (SNV), copy number variation (CNV), tumor mutation burden (TMB), copy number instability (CNI) and mutant-allele tumor heterogeneity (MATH). We also identified genes by which CNV level can differentiate the response to nCT. The Cancer Genome Atlas database and the Clinical Proteomic Tumor Analysis Consortium database were used to further evaluate the specific role of therapeutic relevant genes and screen out the key genes in multi-omics levels. After the intersection of the screened genes from differential expression analysis, survival analysis and principal components analysis dimensionality reduction cluster analysis, the key genes were finally identified. RESULTS: The genes CNV level of principal component genes in baseline blood and cancer tissues could significantly distinguish the two groups of patients. The CNV of HSP90AA1, EGFR, SRC, MTOR, etc. were relatively gained in the better group compared with the poor group in baseline blood. The CNI and TMB was significantly different between the two groups. The increased expression of HSP90AA1, EGFR, and SRC was associated with increased sensitivity to multiple chemotherapeutic drugs. The nCT predictive score obtained by therapeutic relevant genes could be a potential prognostic indicator, and the combination with TMB could further refine prognostic prediction for patients. After a series of analysis in multi-omics association database, EGFR and HSP90AA1 with significant differences in multiple aspects were identified as the key predictive genes related to prognosis and the sensitivity of nCT. DISCUSSION: This work revealed that effective combined application and analysis in multi-omics data are critical to search for predictive biomarkers. The key genes EGFR and HSP90AA1 could serve as an effective biomarker to predict prognose and neoadjuvant chemosensitivity.

15. Longitudinal serum proteomics analyses identify unique and overlapping host response pathways in Lyme disease and West Nile virus infection.

Front Immunol

2022 Dec 9

Boada P, Fatou B, Belperron AA

16. Efficacy of immune checkpoint inhibitors plus molecular targeted agents after the progression of lenvatinib for advanced hepatocellular carcinoma.

Front Immunol

2022 Dec 9

Xie F, Chen B, Yang X

17. Isolation, structures, bioactivities, application and future prospective for polysaccharides from Tremella aurantialba: A review.

Front Immunol

2022 Dec 8

Yan Y, Wang M, Chen N

18. GLP-1 receptor agonist as a modulator of innate immunity.

Front Immunol

2022 Dec 8

Chen J, Mei A, Wei Y

19. How GRAIL controls Treg function to maintain self-tolerance.

Front Immunol

2022 Dec 8

Fathman CG, Yip L, Gómez-Martín D

Regulatory T cells (Tregs) normally maintain self-tolerance. Tregs recognize "self" such that when they are not working properly, such as in autoimmunity, the immune system can attack and destroy one's own tissues. Current therapies for autoimmunity rely on relatively ineffective and too often toxic therapies to "treat" the destructive inflammation. Restoring defective endogenous immune regulation (self-tolerance) would represent a paradigm shift in the therapy of these diseases. One recent approach to restore self-tolerance is to use "low dose IL-2" as a therapy to increase the number of circulating Tregs. However, studies to-date have not demonstrated that low-dose IL-2 therapy can restore concomitant Treg function, and phase 2 studies in low dose IL-2 treated patients with autoimmune diseases have failed to demonstrate significant clinical benefit. We hypothesize that the defect in self-tolerance seen in autoimmunity is not due to an insufficient number of available Tregs, but rather, due to defects in second messengers downstream of the IL-2R that normally control Treg function and stability. Previous studies from our lab and others have demonstrated that GRAIL (a ubiquitin E3 ligase) is important in Treg function. GRAIL expression is markedly diminished in Tregs from patients with autoimmune diseases and allergic asthma and is also diminished in Tregs of mice that are considered autoimmune prone. In the relevant pathway in Tregs, GRAIL normally blocks cullin ring ligase activity, which inhibits IL-2R desensitization in Tregs and consequently promotes Treg function. As a result of this defect in GRAIL expression, the Tregs of patients with autoimmune diseases and allergic asthma degrade IL-2R-associated pJAK1 following activation with low dose IL-2, and thus cannot maintain pSTAT5 expression. pSTAT5 controls the transcription of genes required for Treg function. Additionally, the GRAIL-mediated defect may also allow the degradation of the mTOR inhibitor, DEP domain-containing mTOR interacting protein (Deptor). This can lead to IL-2R activation of mTOR and loss of Treg stability in autoimmune patients. Using a monoclonal antibody to the remnant di-glycine tag on ubiquitinated proteins after trypsin digestion, we identified a protein that was ubiquitinated by GRAIL that is important in Treg function, cullin5. Our data demonstrate that GRAIL acts a negative regulator of IL-2R desensitization by ubiquitinating a lysine on cullin5 that must be neddylated to allow cullin5 cullin ring ligase activity. We hypothesize that a neddylation inhibitor in combination with low dose IL-2 activation could be used to substitute for GRAIL and restore Treg function and stability in the Tregs of autoimmune and allergic asthma patients. However, the neddylation activating enzyme inhibitors (NAEi) are toxic when given systemically. By generating a protein drug conjugate (PDC) consisting of a NAEi bound, via cleavable linkers, to a fusion protein of murine IL-2 (to target the drug to Tregs), we were able to use 1000-fold less of the neddylation inhibitor drug than the amount required for therapeutically effective systemic delivery. The PDC was effective in blocking the onset or the progression of disease in several mouse models of autoimmunity (type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis) and a mouse model of allergic asthma in the absence of detectable toxicity. This PDC strategy represents targeted drug delivery at its best where the defect causing the disease was identified, a drug was designed and developed to correct the defect, and the drug was targeted and delivered only to cells that needed it, maximizing safety and efficacy.

20. Molecular dissection of Janus kinases as drug targets for inflammatory diseases.

Front Immunol

2022 Dec 8

Kwon S.

21. Neoadjuvant immunotherapy for resectable esophageal cancer: A review.

Front Immunol

2022 Dec 8

Li Q, Liu T, Ding Z.

22. Patients with positive HER-2 amplification advanced gastroesophageal junction cancer achieved complete response with combined chemotherapy of AK104/cadonilimab (PD-1/CTLA-4 bispecific): A case report.

Front Immunol

2022 Dec 8

Peng J, Zhu Q, Peng Z

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is the most prominent therapeutic target for advanced gastric (G)/GEJ cancer. However, targeted therapy did not significantly improve survival. Currently, there are no regimens for the treatment of HER-2 amplification that exclude targeted agents. CASE PRESENTATION: A 42-year-old man was diagnosed with adenocarcinoma of GEJ (stage IV) with liver metastasis and lung metastasis. The patient was enrolled in a trial that excluded patients with known HER2-positivity: AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (mXELOX) as first-line therapy for advanced gastric G/GEJ cancer (NCT03852251). After six cycles of AK104 combined with chemotherapy therapy, immune-related pulmonary toxicity was observed. We rechallenged AK104 after hormone therapy, and no further pulmonary toxicity was observed. Immune-related hepatitis occurred in the patient during immunotherapy combined with single-drug capecitabine therapy. After combining steroid therapy with mycophenolate mofetil, the patient's immune hepatitis improved. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the patient's adverse immune response. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. A complete response was confirmed by PET/CT and the biopsy specimen from gastroscopy on 2020-06-10. Next generation sequencing of biopsy tissue was used to guide subsequent therapy at a recent follow-up visit. The results indicated that ERBB2 mutations occurred at copy number 58.4934 (HER-2), TMB = 3.1, MSS. IHC: EBV (-), PD-L1 CPS = 3, HER-2 (3+). CONCLUSION: Patients with HER-2-positive advanced GEJ cancer received PD-1/CTLA-4 bispecific immunotherapy combined with chemotherapy and achieved complete remission. It offers a novel, highly specific, and highly potent therapeutic option for HER-2-positive patients. Its use should be considered as a new treatment when trastuzumab is not viable. Currently, we are working to overcome this resistance.

23. Editorial: DADA2 and other monogenic vasculitides.

Front Immunol

2022 Dec 8

Lee PY, Batu ED, Ozen S.

24. Intraepithelial lymphocytes in the pig intestine: T cell and innate lymphoid cell contributions to intestinal barrier immunity.

Front Immunol

2022 Dec 8

Wiarda JE, Loving CL.

25. Identification of immune microenvironment subtypes and signature genes for Alzheimer's disease diagnosis and risk prediction based on explainable machine learning.

Front Immunol

2022 Dec 8

Lai Y, Lin P, Lin F

BACKGROUND: Using interpretable machine learning, we sought to define the immune microenvironment subtypes and distinctive genes in AD. METHODS: ssGSEA, LASSO regression, and WGCNA algorithms were used to evaluate immune state in AD patients. To predict the fate of AD and identify distinctive genes, six machine learning algorithms were developed. The output of machine learning models was interpreted using the SHAP and LIME algorithms. For external validation, four separate GEO databases were used. We estimated the subgroups of the immunological microenvironment using unsupervised clustering. Further research was done on the variations in immunological microenvironment, enhanced functions and pathways, and therapeutic medicines between these subtypes. Finally, the expression of characteristic genes was verified using the AlzData and pan-cancer databases and RT-PCR analysis. RESULTS: It was determined that AD is connected to changes in the immunological microenvironment. WGCNA revealed 31 potential immune genes, of which the greenyellow and blue modules were shown to be most associated with infiltrated immune cells. In the testing set, the XGBoost algorithm had the best performance with an AUC of 0.86 and a P-R value of 0.83. Following the screening of the testing set by machine learning algorithms and the verification of independent datasets, five genes (CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12) that were closely associated with AD pathological biomarkers and allowed for the accurate prediction of AD progression were found to be immune microenvironment-related genes. The feature gene-based nomogram may provide clinical advantages to patients. Two immune microenvironment subgroups for AD patients were identified, subtype2 was linked to a metabolic phenotype, subtype1 belonged to the immune-active kind. MK-866 and arachidonyltrifluoromethane were identified as the top treatment agents for subtypes 1 and 2, respectively. These five distinguishing genes were found to be intimately linked to the development of the disease, according to the Alzdata database, pan-cancer research, and RT-PCR analysis. CONCLUSION: The hub genes associated with the immune microenvironment that are most strongly associated with the progression of pathology in AD are CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12. The hypothesized molecular subgroups might offer novel perceptions for individualized AD treatment.

26. Corrigendum: Bibliometric and visual analysis of neutrophil extracellular traps from 2004 to 2022.

Front Immunol

2022 Dec 8

Wan Y, Shen J, Ouyang J

27. Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy.

Front Immunol

2022 Dec 8

Jia L, Chen N, Chen X

28. Age of onset correlates with clinical characteristics and prognostic outcomes in neuromyelitis optica spectrum disorder.

Front Immunol

2022 Dec 8

Hu Y, Sun Q, Yi F

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease preferentially affects the optic nerve and the spinal cord. The first attack usually occurs in the third or fourth decade, though patients with disease onset in the fifties or later are not uncommon. This study aimed to investigate the clinical characteristics and prognosis in patients with different age of onset and to explore the correlations between age of onset and clinical characteristics and prognostic outcomes. METHOD: We retrospectively reviewed the medical records of 298 NMOSD patients diagnosed according to the 2015 updated version of diagnostic criteria. Patients were divided into early-onset NMOSD (EO-NMOSD) (<50 years at disease onset) and late-onset NMOSD (LO-NMOSD) (≥50 years at disease onset) based on the age of disease onset. LO-NMOSD patients were divided into two subgroups: relative-late-onset NMOSD (RLO-NMOSD) (50~70 years at disease onset) and very-late-onset NMOSD (≥70 years at disease onset). Clinical characteristics, laboratory findings, neuroimaging features, and prognostic outcomes were investigated. RESULTS: Compared to EO-NMOSD patients, patients with LO-NMOSD showed more frequent transverse myelitis (TM) (58.20% vs. 36.00%, p = 0.007) while less frequent optic neuritis (ON) (23.10% vs. 34.80%, p = 0.031) and brainstem/cerebral attacks (7.50% vs. 18.30%, p = 0.006) as the first attack. Patients with LO-NMOSD showed less frequent relapses, higher Expanded Disability Status Scale (EDSS) score at the last follow-up, fewer NMOSD-typical brain lesions, and longer segments of spinal cord lesions. Patients with older onset age showed a higher proportion of increased protein levels in cerebrospinal fluid during the acute phase of attacks. Age at disease onset positively correlated with length of spinal cord lesions at first attack and at last follow-up, negatively correlated with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up), irrespective of AQP4-IgG serostatus. Patients with older age at disease onset progressed to severe motor disability sooner, and age of onset positively correlated with EDSS score at the last follow-up, irrespective of AQP4-IgG serostatus. CONCLUSION: Age of disease onset affects clinical characteristics and prognosis outcomes of patients with NMOSD.

29. Time-restricted feeding reduces monocyte production by controlling hematopoietic stem and progenitor cells in the bone marrow during obesity.

Front Immunol

2022 Dec 8

Kim Y, Lee Y, Lee MN

30. Safety and short-term outcomes of laparoscopic surgery for advanced gastric cancer after neoadjuvant immunotherapy: A retrospective cohort study.

Front Immunol

2022 Dec 8

Su J, Guo W, Chen Z

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly used for the treatment of advanced gastric cancer (AGC). However, the safety and the short-term outcomes of laparoscopic gastrectomy for patients with AGC after neoadjuvant immunotherapy (NAI) remain unknown. METHODS: We retrospectively analyzed the patients with AGC who underwent laparoscopic surgery after neoadjuvant therapy between 1 January 2019 and 31 October 2021. We further compared the differences in postoperative complications, overall response rate, adverse events, surgical parameters, and postoperative recovery between two cohorts: the NAI group (NAI plus chemotherapy) and the neoadjuvant chemotherapy (NAC) group. Multivariable regression analyses were used to determine the risk factors for the overall response rate. RESULTS: Overall, 80 patients were enrolled, of whom 30 cases were included in the NAI cohort and 50 were included in the NAC cohort. The overall rate of postoperative complications was 30.0% in both groups (p = 1.000). The overall response rate was 70.0% in the NAI cohort and 40% in the NAC cohort (p = 0.012). The adverse effects were found in 16 cases (53.3%) of the NAI cohort and 23 cases (46.0%) of the NAC cohort (p = 0.645). There was no statistical difference in intraoperative bleeding (50 ml vs. 50 ml, p = 0.983), operation time (320.9 min vs. 303.5 min, p = 0.382), dissected lymph node count (43.5 vs. 40.0, p = 0.364), first postoperative anal aerofluxus (3 days vs. 3 days, p = 0.091), first liquid diet (4 days vs. 5 days, p = 0.213), and postoperative length of stay in the hospital (8 days vs. 7 days, p = 0.508) between the two groups. NAI was estimated to be the independent protective factor [odds ratio (OR) 4.931, 95% confidence interval (CI) (1.385-17.559), p = 0.014] for odds to overall response rate, whereas vessel invasion was found to be the significant risk factor [OR 0.113, 95% CI (0.027-0.475), p = 0.003]. CONCLUSIONS: Laparoscopic surgery after NAI combined with chemotherapy is a safe therapeutic choice for AGC and may bring better short-term outcomes due to a higher overall response rate.

31. Decidual macrophages in recurrent spontaneous abortion.

Front Immunol

2022 Dec 8

Zhao QY, Li QH, Fu YY

32. Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications.

Front Immunol

2022 Dec 8

Luo L, Zheng Q, Chen Z

33. Overnutrition-induced gout: An immune response to NLRP3 inflammasome dysregulation by XOD activity increased in quail.

Front Immunol

2022 Dec 8

Wu H, Wang Y, Ren Z

BACKGROUND: Gout is a progressive metabolic disease closely related to hyperuricemia and urate deposition, with an increasing prevalence and incidence across the globe. Recent studies have shown that the pathological process of gout includes two stages: asymptomatic hyperuricemia and MSU crystal deposition. However, the immune response during the development of hyperuricemia to gouty arthritis is not fully elucidated. METHODS: Thus, an overnutrition-induced whole-course gout model was established to clarify the immune response and pathological changes in the development from hyperuricemia to gouty arthritis. The quails without urate oxidase were used as experimental animals. And we confirmed that uric acid metabolic targets were changed when quails were in the asymptomatic hyperuricemia stage. RESULTS: When the quail showed gout symptoms, the NLRP3 inflammasome was activated, and the expressions of IL-1β, TNF-α, IL-6, IL-8, and IL-18 were significantly increased. The relationship between the uric acid metabolism target and the NLRP3 inflammasome may be the critical immune response between hyperuricemia and gouty arthritis. Our data showed that, in the process of gout disease, the expression of xanthine oxidase (XOD) has been increasing, which increases the level of uric acid, disrupts the balance of oxidative stress, generates a large amount of ROS, activates the NLRP3 inflammasome, and release IL-1β. Treatment with the XOD inhibitor can reduce uric acid, restore the body's degree of peroxidative damage and antioxidant capacity, and inhibit NLRP3 inflammasome and IL-1β. In vitro, we extracted and identified primary fibroblast-like synoviocytes (FLS) from quail for the first time. Stimulating FLS with uric acid also caused ROS release and NLRP3 inflammasome activation. However, treatment with an XOD inhibitor prevented all these responses in FLS. CONCLUSION: Our results indicate that the immune response between the uric acid metabolism target XOD and NLRP3 inflammasomes plays a crucial role in developing hyperuricemia to gouty arthritis, and inhibition of both XOD and NLRP3 inflammasomes may be an effective treatment for avoiding the development of asymptomatic hyperuricemia to MSU crystal deposition. Meanwhile, this study also provides an advantageous animal model for pathological mechanisms and research and development drugs for gout.

34. Myomedin replicas of gp120 V3 loop glycan epitopes recognized by PGT121 and PGT126 antibodies as non-cognate antigens for stimulation of HIV-1 broadly neutralizing antibodies.

Front Immunol

2022 Dec 8

Daniel Lišková V, Kosztyu P, Kuchař M

35. Successful treatment of rituximab-unresponsive elderly-onset neuromyelitis optica spectrum disorder and hypogammaglobulinemia with ofatumumab plus intravenous immunoglobulin therapy in a patient with mutant FCGR3A genotype: A case report.

Front Immunol

2022 Dec 8

Zhang W, Jiao Y, Jiao J

36. Corrigendum: Decreased expression of programmed death ligand-L1 by seven in absentia homolog 2 in cholangiocarcinoma enhances T-cell-mediated antitumor activity.

Front Immunol

2022 Dec 8

Zheng H, Zheng WJ, Wang ZG

37. Editorial: The interaction of NKG2D and its ligands in health and diseases.

Front Immunol

2022 Dec 8

Gaudieri S, Reyburn HT, Vales-Gomez M

38. The single-cell landscape of cystic echinococcosis in different stages provided insights into endothelial and immune cell heterogeneity.

Front Immunol

2022 Dec 8

Jiang X, Zhang X, Jiang N

INTRODUCTION: Hydatid cysts and angiogenesis are the key characteristics of cystic echinococcosis, with immune cells and endothelial cells mediating essential roles in disease progression. Recent single-cell analysis studies demonstrated immune cell infiltration after Echinococcus granulosus infection, highlighting the diagnostic and therapeutic potential of targeting certain cell types in the lesion microenvironment. However, more detailed immune mechanisms during different periods of E. granulosus infection were not elucidated. METHODS: Herein, we characterized immune and endothelial cells from the liver samples of mice in different stages by single-cell RNA sequencing. RESULTS: We profiled the transcriptomes of 45,199 cells from the liver samples of mice at 1, 3, and 6 months after infection (two replicates) and uninfected wild-type mice. The cells were categorized into 26 clusters with four distinct cell types: natural killer (NK)/T cells, B cells, myeloid cells, and endothelial cells. An SPP1+ macrophage subset with immunosuppressive and pro-angiogenic functions was identified in the late infection stage. Single-cell regulatory network inference and clustering (SCENIC) analysis suggested that Cebpe, Runx3, and Rora were the key regulators of the SPP1+ macrophages. Cell communication analysis revealed that the SPP1+ macrophages interacted with endothelial cells and had pro-angiogenic functions. There was an obvious communicative relationship between SPP1+ macrophages and endothelial cells via Vegfa-Vegfr1/Vegfr2, and SPP1+ macrophages interacted with other immune cells via specific ligand-receptor pairs, which might have contributed to their immunosuppressive function. DISCUSSION: Our comprehensive exploration of the cystic echinococcosis ecosystem and the first discovery of SPP1+ macrophages with infection period specificity provide deeper insights into angiogenesis and the immune evasion mechanisms associated with later stages of infection.

39. Vaginal neutrophil infiltration is contingent on ovarian cycle phase and independent of pathogen infection.

Front Immunol

2022 Dec 8

Latorre MC, Gómez-Oro C, Olivera-Valle I

40. Immunogenicity and safety of an inactivated enterovirus 71 vaccine coadministered with trivalent split-virion inactivated influenza vaccine: A phase 4, multicenter, randomized, controlled trial in China.

Front Immunol

2022 Dec 8

Chen Y, Xiao Y, Ye Y

41. Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy.

Front Immunol

2022 Dec 8

Hara A, Chihara N, Akatani R

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.

42. Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer.

Front Immunol

2022 Dec 8

Peng H, Li L, Zuo C

43. Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2.

Front Immunol

2022 Dec 8

Zhou Y, Chen Y, Zhong X

Gout is a common inflammatory disease. The activation of NLRP3 inflammasome induced by monosodium urate (MSU) crystals has a critical role in gout, and its prevention is beneficial for patients. Lipoxin A4 (LXA4) is an endogenous lipoxygenase-derived eicosanoid mediator with powerful anti-inflammatory properties. However, whether LXA4 can suppress NLRP3 inflammasome activation induced by MSU crystals remains unclear. This study aimed to investigate the protective effect of LXA4 on MSU-crystal-induced NLRP3 inflammasome activation and its underlying molecular mechanisms. We found that LXA4 inhibited MSU-crystal-induced NLRP3 inflammasome activation, interleukin (IL)-1β maturation, and pyroptosis. More specifically, LXA4 suppressed the assembly of the NLRP3 inflammasome, including oligomerization and speck formation of ASC, and ASC-NLRP3 interaction. Furthermore, LXA4 suppressed oxidative stress, the upstream events for NLRP3 inflammasome activation, as evidenced by the fact that LXA4 eliminated total reactive oxygen species (ROS) generation and alleviated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and mitochondrial dysfunction. However, LXA4 also depressed the Nrf2 activation, a critical molecule in the antioxidant pathway, and then exerted an inhibitory impact on Klf9 expression and promotional impact on TXNRD2 expression, two molecules located downstream of Nrf2 in sequence. Knockdown of TXNRD2 reversed the LXA4-induced depression of ROS and NLRP3 inflammasome. Moreover, LXA4 alleviated joint inflammation and decreased the production of cleaved caspase-1 and matured IL-1β in gouty arthritis rats. Taken together, our findings demonstrate that LXA4 can attenuate MSU-crystal-induced NLRP3 inflammasome activation, probably through suppressing Nrf2 activation to increase TXNRD2 expression. The present study highlights the potential of LXA4 as an attractive new gout treatment candidate.

44. Parasite infections, neuroinflammation, and potential contributions of gut microbiota.

Front Immunol

2022 Dec 8

Alloo J, Leleu I, Grangette C

45. Neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer: A new era for anal preservation.

Front Immunol

2022 Dec 8

Wang Y, Shen L, Wan J

46. Tartrate resistant acid phosphatase 5 (TRAP5) mediates immune cell recruitment in a murine model of pulmonary bacterial infection.

Front Immunol

2022 Dec 8

Tanner L, Bergwik J, Bhongir RKV

INTRODUCTION: During airway infection, upregulation of proinflammatory cytokines and subsequent immune cell recruitment is essential to mitigate bacterial infection. Conversely, during prolonged and non-resolving airway inflammation, neutrophils contribute to tissue damage and remodeling. This occurs during diseases including cystic fibrosis (CF) and COPD where bacterial pathogens, not least Pseudomonas aeruginosa, contribute to disease progression through long-lasting infections. Tartrate-resistant acid phosphatase (TRAP) 5 is a metalloenzyme expressed by alveolar macrophages and one of its target substrates is the phosphoglycoprotein osteopontin (OPN). METHODS: We used a knockout mouse strain (Trap5-/-) and BALB/c-Tg (Rela-luc)31Xen mice paired with siRNA administration or functional protein add-back to elucidate the role of Trap5 during bacterial infection. In a series of experiments, Trap5-/- and wild-type control mice received intratracheal administration of P.aerugniosa (Xen41) or LPS, with mice monitored using intravital imaging (IVIS). In addition, multiplex cytokine immunoassays, flow cytometry, multispectral analyses, histological staining were performed. RESULTS: In this study, we found that Trap5-/- mice had impaired clearance of P. aeruginosa airway infection and reduced recruitment of immune cells (i.e. neutrophils and inflammatory macrophages). Trap5 knockdown using siRNA resulted in a decreased activation of the proinflammatory transcription factor NF-κB in reporter mice and a subsequent decrease of proinflammatory gene expression. Add-back experiments of enzymatically active TRAP5 to Trap5-/- mice restored immune cell recruitment and bacterial killing. In human CF lung tissue, TRAP5 of alveolar macrophages was detected in proximity to OPN to a higher degree than in normal lung tissue, indicating possible interactions. DISCUSSION: Taken together, the findings of this study suggest a key role for TRAP5 in modulating airway inflammation. This could have bearing in diseases such as CF and COPD where excessive neutrophilic inflammation could be targeted by pharmacological inhibitors of TRAP5.

47. Chickens, more than humans, focus the diversity of their immunoglobulin genes on the complementarity-determining region but utilise amino acids, indicative of a more cross-reactive antibody repertoire.

Front Immunol

2022 Dec 8

Mallaby J, Ng J, Stewart A

48. Protective role of engineered extracellular vesicles loaded quercetin nanoparticles as anti-viral therapy against SARS-CoV-2 infection: A prospective review.

Front Immunol

2022 Dec 8

Raghav A, Giri R, Agarwal S

49. Body composition parameters for predicting the efficacy of neoadjuvant chemotherapy with immunotherapy for gastric cancer.

Front Immunol

2022 Dec 8

Lin GT, Huang JB, Lin JL

BACKGROUND: Immune checkpoint inhibitors are increasingly used in neoadjuvant therapy for locally advanced gastric cancer. However, the effect of body composition on the efficacy of neoadjuvant therapy has not been reported. METHODS: The computed tomography (CT) images and clinicopathological data of 101 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy (NCI) from 2019 to 2021 were collected. The CT image of L3 vertebral body section was selected, and the body composition before and after the neoadjuvant treatment was calculated using the SliceOmatic software, mainly including skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). The relationship between body composition and the efficacy and adverse events of NCI was analyzed. RESULTS: Of the 101 patients, 81 with evaluable data were included in the analysis. Of the included patients, 77.8% were male; the median age of all the patients was 62 years, and the median neoadjuvant therapy cycle was three. After the neoadjuvant therapy, 62.9% of the tumors were in remission (residual tumor cells ≤ 50%), and 37.1% of the tumors had no remission (residual tumor cells>50%). Moreover, 61.7% of the patients had treatment-related adverse events (TRAEs), and 18.5% had immune-related adverse events (irAEs). After neoadjuvant therapy, the body mass index (from 23 to 22.6 cm2/m2, p=0.042), SAI (from 34.7 to 32.9 cm2/m2, p=0.01) and VAI (from 32.4 to 26.8 cm2/m2, p=0.005) were significantly lower than those before treatment, while the SMI had no significant change (44.7 vs 42.5 cm2/m2, p=0.278). The multivariate logistics regression analysis revealed that low SMI (odds ratio [OR]: 3.23,95% confidence interval [CI]: 1.06-9.81, p=0.047), SMI attenuation (△SMI) ≥ 1.8(OR: 1.45,95%CI: 1.20-3.48, p=0.048), and clinical node positivity (OR: 6.99,95%CI: 2.35-20.82, p=0.001) were independent risk factors for non-remission. Additionally, high SAI is an independent risk factor for irAEs (OR: 14, 95%CI: 1.73-112.7, p=0.013). CONCLUSION: Low SMI and △SMI≥1.8 are independent risk factors for poor tumor regression in patients with advanced gastric cancer receiving NCI. Patients with a high SAI are more likely to develop irAEs.

50. Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells.

Front Immunol

2022 Dec 8

Braband KL, Kaufmann T, Floess S

51. Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance.

Front Immunol

2022 Dec 8

Qin Y, Xu G.

52. A potential antibody repertoire diversification mechanism through tyrosine sulfation for biotherapeutics engineering and production.

Front Immunol

2022 Dec 8

Zhong X, D'Antona AM.

53. Corrigendum: Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses.

Front Immunol

2022 Dec 8

Jeong BS, Jeon JY, Lai CJ

54. Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review.

Front Immunol

2022 Dec 8

Qiu Y, Fang G, Ye F

55. Impact of oral administration of single strain Lactococcus lactis spp. cremoris on immune responses to keyhole limpet hemocyanin immunization and gut microbiota: A randomized placebo-controlled trial in healthy volunteers.

Front Immunol

2022 Dec 7

Saghari M, Gal P, Grievink HW

INTRODUCTION: Lactococcus lactis spp. cremoris has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of L. lactis spp. cremoris (EDP1066) on the immune response to keyhole limpet hemocyanin (KLH). Potential effects on the gut microbiota were also investigated. METHODS: The trial was registered on Netherlands Trial Register (trial ID NL7519, https://trialsearch.who.int). Eighty-one healthy subjects (median 28, range 18-59 years) were randomized to 28 days of enteric-coated capsules at five doses (n = 13) (1.5 * 1012 total cells daily), freeze-dried powder at one dose (n = 12) (3.0 * 1011 total cells daily) or five doses (n = 12), minitablets at one dose (n = 12) or five doses (n = 12), or placebo (n = 20) prior to KLH immunization. Antibody responses and circulating regulatory T cells (Tregs) were measured after KLH immunization, and skin responses were evaluated after a KLH rechallenge by laser speckle contrast imaging and multispectral imaging. Ex vivo lymphocyte (phytohemagglutinin) and monocyte (lipopolysaccharide (LPS)) cytokine release assays were explored in the minitablet-treated groups only. The prevalence of L. lactis spp. cremoris in the gastrointestinal tract and the impact on the fecal microbiota were assessed by qPCR and 16S rRNA sequencing, respectively. RESULTS: Repeated-measures analysis of covariances revealed no significant treatment effects on the antibody responses to KLH, number of Tregs, or KLH skin rechallenge outcomes. Ex vivo LPS-driven cytokine responses in whole blood were lower in the low dose minitablet group compared to placebo: tumor necrosis factor (estimated difference (ED) from placebo: -44.2%, 95% confidence interval (CI) -65.3% to -10.3%), interleukin (IL)-1β (ED -41.4%, 95% CI -63.5% to -5.8%), and IL-6 (ED -39.2%, 95% CI -56.8% to -14.5%). The fecal presence of L. lactis spp. cremoris increased during treatment by all EDP1066 formulations and normalized 5 days after the last dose. Microbiome α-diversity did not change by the treatments compared to placebo. DISCUSSION: The EDP1066 formulations did not affect the immune response to KLH immunization in healthy individuals. However, exposure to L. lactis spp. cremoris in minitablet formulation impacted ex vivo whole blood LPS cytokine response. The clinical impact of these effects awaits further investigations. NETHERLANDS TRIAL REGISTER: trialsearch.who.int, trial ID NL7519.

56. Upregulation of leucine-rich alpha-2 glycoprotein: A key regulator of inflammation and joint fibrosis in patients with severe knee osteoarthritis.

Front Immunol

2022 Dec 7

Sarkar A, Chakraborty D, Kumar V

INTRODUCTION: Osteoarthritis (OA) is a degenerative disease of the joints mainly affecting older individuals. Since the etiology behind the progression of OA is not well understood, several associated consequences, such as synovial joint stiffness and its progression due to joint fibrosis, are still poorly understood. Although a lot of developments have been achieved in the diagnosis and management of OA, synovial fibrosis remains one of the major challenging consequences. The present study was therefore focused on understanding the mechanism of synovial fibrosis, which may further contribute to improving symptomatic treatments, leading to overall improvements in the treatment outcomes of patients with OA. METHODS: We used advanced proteomic techniques including isobaric tag for relative and absolute quantitation and sequential window acquisition of all theoretical mass spectra for the identification of differentially expressed proteins in the plasma samples of patients with OA. An in silico study was carried out to evaluate the association of the identified proteins with their biological processes related to fibrosis and remodeling of the extracellular matrix (ECM). The most significantly upregulated protein was then validated by Western blot and enzyme-linked immunosorbent assay. The target protein was then further investigated for its role in inflammation and joint fibrosis using an in vitro study model. RESULTS: Leucine-rich alpha-2 glycoprotein (LRG1) was found to be the most highly differentially expressed upregulated (9.4-fold) protein in the plasma samples of patients with OA compared to healthy controls. The knockdown of LRG1 followed by in vitro studies revealed that this protein promotes the secretion of the ECM in synovial cells and actively plays a role in wound healing and cell migration. The knockdown of LRG1 further confirmed the reduction of the inflammatory- and fibrosis-related markers in primary cells. CONCLUSION: LRG1 was identified as a highly significant upregulated protein in the plasma samples of patients with OA. It was found to be associated with increased fibrosis and cell migration, leading to enhanced inflammation and joint stiffness in OA pathogenesis.

57. Roles of the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis.

Front Immunol

2022 Dec 7

Zhang TP, Li R, Wang LJ

OBJECTIVE: The aim of the current study was to investigate the contributing role of gene variation and transcription levels among the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis (PTB). METHODS: A case-control study including 461 PTB patients and 467 normal controls was designed for genotyping. Three SNPs in METTL3 (rs1061027, rs1139130, rs1061026), three SNPs in METTL14 (rs62328061, rs4834698, rs1064034), and two SNPs in WTAP (rs1853259, rs11752345) were genotyped via the SNPscan™ technique. METTL3, METTL14, and WTAP transcription levels were determined in 78 PTB patients and 86 controls via quantitative real-time reverse-transcription PCR. RESULTS: Frequencies of the METTL14 rs62328061 GG genotype, WTAP rs11752345 CT genotype, and T allele were significantly increased in PTB patients compared to controls. An increased risk of rs62328061 was detected in a recessive model, and a decreased risk of rs11752345 was detected in a dominant model in the PTB group. METTL3 gene variation was not associated with PTB risk. The METTL3 rs1139130 GG genotype was significantly increased with drug resistance, and the G allele was significantly decreased with drug-induced liver injury in PTB patients. A reduced frequency of the METTL14 rs62328061 G allele was associated with leukopenia, a reduced frequency of the WTAP rs11752345 T allele was associated with sputum smear positivity, and a higher frequency of the METTL14 rs4834698 TC genotype was evident in PTB patients with hypoproteinemia. Compared to controls, METTL3, METTL14, and WTAP transcription levels in PTB patients were significantly decreased, and the level of WTAP was increased in PTB patients with drug resistance. METTL3 level was negatively associated with erythrocyte sedimentation rate and aspartate aminotransferase, and METTL14 level was negatively correlated with alanine aminotransferase and aspartate aminotransferase. CONCLUSION: METTL14 rs62328061 and WTAP rs11752345 variants were associated with the genetic background of PTB, and METTL3, METTL14, and WTAP levels were abnormally decreased, suggesting that these m6A methyltransferases may play important roles in PTB.

58. PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study.

Front Immunol

2022 Dec 7

Chen S, Wei H, Zhao W

BACKGROUND: The aim of this study was to assessment the efficacy and safety of Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer. METHODS: In this study, pre-treatment clinical and laboratory indicators from 73 patients with advanced non-small cell lung cancer were retrieved for retrospective analysis. According to the therapy regimes they received, the patients were separated into groups, PD-1/PD-L1 inhibitors plus chemotherapy group (PC group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents' group (PA group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents plus chemotherapy group (PAC group). Cox's proportional hazards regression model and Kaplan-Meier (KM) curves were used to assess the connection between treatment regimens and progression free survival (PFS) and overall survival (OS). In addition, the association of treatment regimens with the risk of disease progression and death was evaluated by subgroup analysis. RESULTS: The average age of the enrolled patients was 58.2 ± 10.2 years and 75.3% were male. Multivariate analyses showed that patients in PA group (Disease progression: HR 0.4, P=0.005. Death: HR 0.4, P=0.024) and PAC group (Disease progression: HR 0.3, P=0.012. Death: HR 0.3, P=0.045) had a statistically significant lower hazard ratio (HR) for disease progression and death compared to patients in PC group. Kaplan-Meier analysis showed that patients in PA group (mPFS:7.5 vs.3.5, P=0.00052. mOS:33.1 vs.21.8, P=0.093) and PAC group (mPFS:5.1 vs.3.5, P=0.075. mOS:37.3 vs.21.8, P=0.14) had a longer PFS and OS compared to patients in PC group. In all the pre-defined subgroups, patients in PA and PAC groups showed a decreasing trend in the risk of disease progression and death in most subgroups. The patients in PA group (DCR:96.3% vs.58.3%, P=0.001) and PAC group (DCR:100% vs.58.3%, P=0.019) had a better disease control rate (DCR) than patients in PC group. CONCLUSION: PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy were superior to PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment in patients with advanced non-small cell lung cancer.

59. Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.

Front Immunol

2022 Dec 7

Chen YJ, Guo X, Liu ML

BACKGROUND: Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysis‒cholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment. METHODS: Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo. RESULTS: Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysis‒cholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model. CONCLUSIONS: Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.

60. Mechanical high-intensity focused ultrasound creates unique tumor debris enhancing dendritic cell-induced T cell activation.

Front Immunol

2022 Dec 7

van den Bijgaart RJE, Mekers VE, Schuurmans F

61. Identification of B cell marker genes based on single-cell sequencing to establish a prognostic model and identify immune infiltration in osteosarcoma.

Front Immunol

2022 Dec 7

Zhang Z, Zhang J, Duan Y

62. Dengue induces iNOS expression and nitric oxide synthesis in platelets through IL-1R.

Front Immunol

2022 Dec 7

Pinheiro MBM, Rozini SV, Quirino-Teixeira AC

INTRODUCTION: Dengue is an arthropod-born disease caused by dengue virus (DENV), that may manifest as a mild illness or severe form, characterized by hemorrhagic fever and shock. Nitric oxide (NO) is a vasodilator signaling molecule and an inhibitor of platelet aggregation known to be increased in platelets from dengue patients. However, the mechanisms underlying NO synthesis by platelets during dengue are not yet elucidated. IL-1β is a pro-inflammatory cytokine able to induce iNOS expression in leukocytes and present in dengue patients at high levels. Nevertheless, the role of IL-1β in platelet activation, especially regarding iNOS expression, are not clear. METHODS: We prospectively followed a cohort of 28 dengue-infected patients to study NO synthesis in platelets and its relationship with disease outcomes. We used in vitro infection and stimulation models to gain insights on the mechanisms. RESULTS AND DISCUSSION: We confirmed that platelets from dengue patients express iNOS and produce higher levels of NO during the acute phase compared to healthy volunteers, returning to normal levels after recovery. Platelet NO production during acute dengue infection was associated with the presence of warning signs, hypoalbuminemia and hemorrhagic manifestations, suggesting a role in dengue pathophysiology. By investigating the mechanisms, we evidenced increased iNOS expression in platelets stimulated with dengue patients´ plasma, indicating induction by circulating inflammatory mediators. We then investigated possible factors able to induce platelet iNOS expression and observed higher levels of IL-1β in plasma from patients with dengue, which were correlated with NO production by platelets. Since platelets can synthesize and respond to IL-1β, we investigated whether IL-1β induces iNOS expression and NO synthesis in platelets. We observed that recombinant human IL-1β enhanced iNOS expression and dose-dependently increased NO synthesis by platelets. Finally, platelet infection with DENV in vitro induced iNOS expression and NO production, besides the secretion of both IL-1α and IL-1β. Importantly, treatment with IL-1 receptor antagonist or a combination of anti-IL-1α and anti-IL-1β antibodies prevented DENV-induced iNOS expression and NO synthesis. Our data show that DENV induces iNOS expression and NO production in platelets through mechanisms depending on IL-1 receptor signaling.

63. Clinical relevance of genetic polymorphisms in WNT signaling pathway (SFRP1, WNT3A, CTNNB1, WIF-1, DKK-1, LRP5, LRP6) on pulmonary tuberculosis in a Chinese population.

Front Immunol

2022 Dec 7

Huang Q, Wang CC, Liu YG

64. Pyruvate: Ferredoxin oxidoreductase is involved in IgA-related microbiota dysbiosis and intestinal inflammation.

Front Immunol

2022 Dec 7

Wang K, Guo Y, Liu Y

INTRODUCTION: Inflammatory bowel diseases (IBDs) are associated with both immune abnormalities and dysbiosis, characterized by a loss of Faecalibacterium prausnitzii (F. prausnitzii). However, the reason for F. prausnitzii deficiency remains unclear. METHODS: 16S rDNA seque-ncing and IgA enzyme-linked immunosorbent assay (ELISA) were applied to identify bacterial community and IgA changes in ulcerative colitis (UC) patients. Forced immunization with F. prausnitzii in rabbits was conducted. To screen for potential IgA-reactive proteins in F. prausnitzii lysates, we performed western blotting and mass spectrometry analyses. Pyruvate: ferredoxin oxidoreductase (PFOR) was cloned and purified, then the immunoreactivity of PFOR was verified in peripheral blood mononuclear cells (PBMCs) through PCR, ELISpot assay and single-cell sequencing (scRNA-seq). Finally, the UC fecal dysbiosis was re-analyzed in the context of the phylogenetic tree of PFOR. RESULTS: F. prausnitzii was underrepresented in UC patients with elevated F. prausnitzii-reactive IgA in the fecal supernatant. Forced immunization with F. prausnitzii in rabbits led to high interferon-γ (IFN-γ) transcription in the colon, along with beta diversity disturbance and intestinal inflammation. PFOR was identified as an IgA-binding antigen of F. prausnitzii and the immunoreactivity was validated in PBMCs, which showed elevated expression of inflammatory cytokines. The scRNA-seq revealed enhanced signals in both T regulatory cells (Tregs) and monocytes after PFOR incubation. Furthermore, phylogenetic analysis revealed that PFOR was a common but conserved protein among the gut bacteria. DISCUSSION: Our results collectively suggest that PFOR is a bioactive protein in the immune system and may contribute to host-microbial crosstalk. Conserved but bioactive microbial proteins, such as PFOR, warrant more attention in future host-microbial interaction studies.

65. Development and function of natural TCR(+) CD8αα(+) intraepithelial lymphocytes.

Front Immunol

2022 Dec 7

Gui Y, Cheng H, Zhou J

66. Protein re-surfacing of E. coli L-Asparaginase to evade pre-existing anti-drug antibodies and hypersensitivity responses.

Front Immunol

2022 Dec 7

Bootwala A, An HH, Franklin MW

67. Research progress on the role of hormones in ischemic stroke.

Front Immunol

2022 Dec 7

Huang S, Liu L, Tang X

68. B21 DNA vaccine expressing ag85b, rv2029c, and rv1738 confers a robust therapeutic effect against latent Mycobacterium tuberculosis infection.

Front Immunol

2022 Dec 7

Weng S, Zhang J, Ma H

69. IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing differentiation and targeting of plasma cells.

Front Immunol

2022 Dec 7

Alomari N, Totonchy J.

70. Circulatory levels of alarmins in patients with non-segmental vitiligo: Potential biomarkers for disease diagnosis and activity/severity assessment.

Front Immunol

2022 Dec 7

He K, Wu W, Wang X

BACKGROUND: Non-segmental vitiligo (NSV) is an autoimmune skin disorder that is difficult to determine disease activity/severity and thus to treat. Alarmins have emerged as promising biomarkers in various diseases, so further confirmation of their potential roles in NSV would be of considerable value. With the present work, we aimed to determine the serum levels of alarmins in patients with NSV, correlate these alarmins with disease activity and severity, and analyze the predictive value of the combination of these markers. METHODS: 104 NSV patients and 56 healthy controls were enrolled at the Xijing Hospital of Fourth Military Medical University between September 1, 2018, and June 30, 2019. The serum levels of alarmins (including IL-33, IL-1α, S100A9, S100A12, S100B, and HMGB1) were measured with enzyme-linked immunosorbent assays. The predictive performance of these biomarkers was evaluated with the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and other representative statistics. RESULTS: A total of 104 patients with NSV (mean [SD] age, 34.2 [13.0] years; 62 [59.6%] male) and 56 healthy controls (mean [SD] age, 34.8 [13.5] years; 34 [60.7%] male) were enrolled. For vitiligo diagnosis, S100B had the highest sensitivity (92.31%), whereas HMGB1 had the highest specificity (85.71%); the combination of IL-1α, S100B, S100A9, and HMGB1 increased the AUC value to 0.925, with a sensitivity of 87.50% and a specificity of 85.71%. Multivariate logistic regression analysis showed S100B (OR, 1.019; 95% CI, 1.002-1.038; P =0.03), S100A9 (OR, 1.002; 95% CI, 1.001-1.003; P<0.001), and HMGB1 (OR, 1.915; 95% CI, 1.186-3.091; P =0.008) were significantly associated with vitiligo activity. S100A9 had the highest accuracy in discriminating patients at the active stage from the stable stage, with an AUC value of 0.827. The combination of these alarmins had an AUC value of 0.860 to assess disease activity, with a sensitivity of 90.00% and a specificity of 72.97%. Furthermore, S100B (r=0.61, P <0.001), S100A9 (r=0.33, P <0.001), and HMGB1 (r = 0.51, P <0.001) levels were positively correlated with the affected body surface area (BSA) in NSV patients. CONCLUSIONS: Serum S100B, S100A9, and HMGB1 might be biomarkers for diagnosing and assessing the activity/severity of NSV, either used alone or in combination.

71. HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy.

Front Immunol

2022 Dec 7

Zhao L, Song Y, Zhang Y

72. Cooperation between cGAS and RIG-I sensing pathways enables improved innate recognition of HIV-1 by myeloid dendritic cells in elite controllers.

Front Immunol

2022 Dec 7

Martin-Gayo E, Gao C, Calvet-Mirabent M

73. A scalable model for simulating multi-round antibody evolution and benchmarking of clonal tree reconstruction methods.

Front Immunol

2022 Dec 6

Zhang C, Bzikadze AV, Safonova Y

Affinity maturation (AM) of B cells through somatic hypermutations (SHMs) enables the immune system to evolve to recognize diverse pathogens. The accumulation of SHMs leads to the formation of clonal lineages of antibody-secreting b cells that have evolved from a common naïve B cell. Advances in high-throughput sequencing have enabled deep scans of B cell receptor repertoires, paving the way for reconstructing clonal trees. However, it is not clear if clonal trees, which capture microevolutionary time scales, can be reconstructed using traditional phylogenetic reconstruction methods with adequate accuracy. In fact, several clonal tree reconstruction methods have been developed to fix supposed shortcomings of phylogenetic methods. Nevertheless, no consensus has been reached regarding the relative accuracy of these methods, partially because evaluation is challenging. Benchmarking the performance of existing methods and developing better methods would both benefit from realistic models of clonal lineage evolution specifically designed for emulating B cell evolution. In this paper, we propose a model for modeling B cell clonal lineage evolution and use this model to benchmark several existing clonal tree reconstruction methods. Our model, designed to be extensible, has several features: by evolving the clonal tree and sequences simultaneously, it allows modeling selective pressure due to changes in affinity binding; it enables scalable simulations of large numbers of cells; it enables several rounds of infection by an evolving pathogen; and, it models building of memory. In addition, we also suggest a set of metrics for comparing clonal trees and measuring their properties. Our results show that while maximum likelihood phylogenetic reconstruction methods can fail to capture key features of clonal tree expansion if applied naively, a simple post-processing of their results, where short branches are contracted, leads to inferences that are better than alternative methods.

74. Women for science and science for women: Gaps, challenges and opportunities towards optimizing pre-exposure prophylaxis for HIV-1 prevention.

Front Immunol

2022 Dec 6

Karim QA, Archary D, Barré-Sinoussi F

75. Editorial: Immune cells and inflammatory mediators in mucosal pathologies, volume II.

Front Immunol

2022 Dec 6

Leite-de-Moraes M, Chieppa M, Vermeulen M.

76. Tear-derived exosomal biomarkers of Graves' ophthalmopathy.

Front Immunol

2022 Dec 6

Shi TT, Zhao RX, Xin Z

77. Editorial: Immunology of machine perfused organs and tissues.

Front Immunol

2022 Dec 6

Hautz T, Brandacher G, Schneeberger S.

78. Circulating methylation level of HTR2A is associated with inflammation and disease activity in rheumatoid arthritis.

Front Immunol

2022 Dec 6

Zhao J, Xu L, Chang C

79. Monoclonal antibodies in the management of asthma: Dead ends, current status and future perspectives.

Front Immunol

2022 Dec 6

Kardas G, Panek M, Kuna P

80. Graphene quantum dots induce cascadic apoptosis via interaction with proteins associated with anti-oxidation after endocytosis by Trypanosoma brucei.

Front Immunol

2022 Dec 6

Xie Y, Liang H, Jiang N

81. Editorial: Stromal and immune microenvironment in breast cancer metastasis.

Front Immunol

2022 Dec 6

Lu X, Liu X, Celià-Terrassa T

82. Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps.

Front Immunol

2022 Dec 6

Lei T, Chen L, Wang K

83. A therapeutic vaccine strategy to prevent Pneumocystis pneumonia in an immunocompromised host in a non-human primate model of HIV and Pneumocystis co-infection.

Front Immunol

2022 Dec 6

Rabacal W, Schweitzer F, Kling HM

INTRODUCTION: Pneumocystis is a ubiquitous fungal pathogen that causes pneumonia (PCP) and pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. With the success of anti-retroviral therapy for HIV-infected individuals the frequency of PCP in that population has decreased, however, PCP remains a significant cause of morbidity and mortality in individuals with hematologic and solid malignancies, and in individuals treated with immunosuppressive therapies for autoimmune diseases, and following bone marrow and solid organ transplantation. Despite the clinical need, there is no approved vaccine to prevent PCP in vulnerable populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pneumocystis. Toward this goal, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) and identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pneumocystis immunity in immune-competent macaques that is durable and prevents PCP following simian immunodeficiency virus (SIV)-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide B cell help under conditions of reduced CD4+ T cell help. METHODS: In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with the iNKT cell-activating adjuvant α-galactosylceramide (α-GC) and KEX1 (α-GC+KEX1) can effectively boost anti-Pneumocystis humoral immunity following virus-induced immunosuppression. RESULTS: Immunization of antigen-experienced NHPs with α-GC+KEX1 during the early chronic phase of SIV-infection significantly boosted anti-Pneumocystis humoral immunity by increasing memory B cells and antibody titers, and enhanced titer durability during SIV-induced immunosuppression. This therapeutic vaccination strategy boosted anti-Pneumocystis immune responses during SIV-infection and contributed to protection against Pneumocystis co-infection in KEX1-vaccinated macaques. CONCLUSION: These studies present a novel strategy for stimulating durable anti-Pneumocystis humoral immunity in the context of complex, chronic SIV-induced immunosuppression and may be further applied to immunization of other immunosuppressed populations, and toward other common recall antigens.

84. Anti-PD-1 antibodies, a novel treatment option for advanced chemoresistant pulmonary lymphoepithelioma carcinoma.

Front Immunol

2022 Dec 6

Zhou N, Tang H, Yu S

85. Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma.

Front Immunol

2022 Dec 5

Wang Y, Zhang X, Xu C

INTRODUCTION: Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). METHODS: Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment. RESULTS: Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy. DISCUSSION: In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.

86. Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia.

Front Immunol

2022 Dec 5

Yang Y, Yang Y, Liu J

87. Disparities in inflammation between non-Hispanic black and white individuals with lung cancer in the Greater Chicago Metropolitan area.

Front Immunol

2022 Dec 5

Byrne CA, Gomez SL, Kim S

88. Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy.

Front Immunol

2022 Dec 5

Brentville VA, Symonds P, Chua J

INTRODUCTION: Post translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. METHODS: A citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model. RESULTS: We show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide. CONCLUSION: We propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.

89. A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis.

Front Immunol

2022 Dec 5

Tricarico PM, Gratton R, Dos Santos-Silva CA

90. Identification of necroptosis-related subtypes, development of a novel signature, and characterization of immune infiltration in colorectal cancer.

Front Immunol

2022 Dec 5

Sun M, Ji X, Xie M

91. Evaluating IL-6 and IL-10 as rapid diagnostic tools for Gram-negative bacteria and as disease severity predictors in pediatric sepsis patients in the intensive care unit.

Front Immunol

2022 Dec 5

Zhang Y, Li B, Ning B.

BACKGROUND: To explore the diagnostic performance of interleukin (IL)-6 and IL-10 in discriminating Gram bacteria types and predicting disease severity in intensive care unit (ICU)-hospitalized pediatric sepsis patients. METHOD: We retrospectively collected Th1/Th2 cytokine profiles of 146 microbiologically documented sepsis patients. Patients were categorized into Gram-positive (G+) or Gram-negative (G-) sepsis groups, and cytokine levels were compared. Subgroup analysis was designed to eliminate the influence of other inflammatory responses on cytokine levels. RESULTS: After propensity score matching, 78 patients were matched and categorized according to Gram bacteria types. Compared with G+ sepsis, IL-6 and IL-10 were significantly elevated in G- sepsis (p < 0.05). Spearman test proved the linear correlation between IL-6 and IL-10 (r = 0.654, p < 0.001), and their combination indicators (ratio and differences) were effective in identifying G- sepsis. In the subgroup analysis, such cytokine elevation was significant regardless of primary infection site. However, for patients with progressively deteriorating organ function [new or progressive multiple organ dysfunction syndrome (NPMODS)], differences in IL-6 and IL-10 levels were less significant between G+ and G- sepsis. In the receiver operating characteristic (ROC) curves of the G- sepsis group, the area under the curve (AUC) value for IL-6 and IL-10 was 0.679 (95% CI 0.561-0.798) and 0.637 (95% CI 0.512-0.762), respectively. The optimal cutoff value for diagnosing G- sepsis was 76.77 pg/ml and 18.90 pg/ml, respectively. While for the NPMODS group, the AUC for IL-6 and IL-10 was 0.834 (95% CI 0.766-0.902) and 0.781 (95% CI 0.701-0.860), respectively. CONCLUSION: IL-6 and IL-10 are comparably effective in discriminating G+/G- sepsis in pediatric intensive care unit (PICU) patients. The deteriorated organ function observed in ICU patients reveals that complex inflammatory responses might have contributed to the cytokine pattern observed in severe sepsis patients, therefore confounding the discriminating efficacy of Th1/Th2 cytokines in predicting Gram bacteria types.

92. Pathological complete response after neoadjuvant immunotherapy combined with chemotherapy in pediatric rectal carcinoma: A case report.

Front Immunol

2022 Dec 5

Cao X, Luo J, Zhao B

BACKGROUND: Pediatric colorectal carcinoma (PCRC) is a rare non-embryonal tumor with an incidence of 0.1% to 1% of adults. Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) have shown significant efficacy in defective mismatch repair/Microsatellite instability-high (dMMR/MSI-H) metastatic CRC (mCRC). Although several studies have reported neoadjuvant immunotherapy (NIT) in MSI-H/dMMR non-mCRC patients, not all patients achieved pathological complete remission (pCR). There are differences between PCRC and adult colorectal carcinoma (CRC), and the role of NIT in PCRC remains to be further defined. CASE PRESENTATION: We report the case of a 12-year-old child who was admitted to the hospital with abdominal pain and vomiting for more than 3 months. The child's diagnosis was difficult and complex. He was initially diagnosed with intestinal obstruction, eventually diagnosed with a rare PCRC and identified as locally advanced colorectal cancer (LACRC) with genetic sequencing results showing MSI-H. After a thorough evaluation by clinicians, he received 4 cycles of Camrelizumab (anti-PD-1 antibody) + CapeOx (capecitabine and oxaliplatin) NIT combination chemotherapy. Repeat imaging and all tumor markers were unremarkable, and R0 resection was achieved. Postoperative pathology showed a tumor regression grade (TRG) of 0 grade determined as pCR. Postoperative review has not shown any recurrence or metastasis to date and the prognosis is good. CONCLUSION: PCRC should improve the diagnostic efficiency to prevent misdiagnosis and miss the best time for treatment. NIT and or chemotherapy can be a reasonable and effective treatment option for dMMR/MSI-H locally advanced PCRC. Our report provides some support and evidence for neoadjuvant immunotherapy for locally advanced PCRC, while highlighting the importance of preoperative detection of microsatellite status for locally advanced PCRC.

93. COVID-19 vaccinology landscape in Africa.

Front Immunol

2022 Dec 5

Baptista S, Naidoo S, Suliman S

94. Transcriptomic FHIT(low)/pHER2(high) signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer.

Front Immunol

2022 Dec 5

Brisebarre A, Ancel J, Ponchel T

INTRODUCTION: In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance. MATERIALS AND METHODS: We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI). RESULTS: We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts. CONCLUSION: These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.

95. High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells.

Front Immunol

2022 Dec 5

Phetsouphanh C, Khoo WH, Jackson K

96. Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer.

Front Immunol

2022 Dec 5

Boissière-Michot F, Chateau MC, Thézenas S

BACKGROUND: T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy. METHODS: TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed. RESULTS: TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p<0.0001), PD-L1+ tumor cells (p<0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR). CONCLUSIONS: These results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.

97. Milestones in acute GVHD pathophysiology.

Front Immunol

2022 Dec 5

Socie G, Michonneau D.

98. Overexpression of SMS in the tumor microenvironment is associated with immunosuppression in hepatocellular carcinoma.

Front Immunol

2022 Dec 5

Xiang L, Piao L, Wang D

99. Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features.

Front Immunol

2022 Dec 5

Sharifinejad N, Azizi G, Chavoshzadeh Z

BACKGROUND: Combined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions. METHODS: We analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations. RESULTS: A total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity. CONCLUSION: About 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

100. Boolean modeling reveals that cyclic attractors in macrophage polarization serve as reservoirs of states to balance external perturbations from the tumor microenvironment.

Front Immunol

2022 Dec 5

de León UA, Vázquez-Jiménez A, Matadamas-Guzmán M

101. IRF2 is required for development and functional maturation of human NK cells.

Front Immunol

2022 Dec 5

Persyn E, Wahlen S, Kiekens L

102. Editorial: Updates on immunity to influenza A virus in humans and animals.

Front Immunol

2022 Dec 30

Ramos I, Nogales A.

103. Editorial: Metabolic conditions of chronic inflammatory diseases.

Front Immunol

2022 Dec 29

Saalbach A, Kunz M.

104. Editorial: Innate immunity and severe asthma: From microbiome to target therapy.

Front Immunol

2022 Dec 29

Bagnasco D, Caminati M.

105. Erratum: Rheumatoid factor IgM autoantibodies control IgG homeostasis.

Front Immunol

2022 Dec 29

Frontiers Production Office.

106. Gut mycobiome dysbiosis contributes to the development of hypertension and its response to immunoglobulin light chains.

Front Immunol

2022 Dec 29

Zou Y, Ge A, Lydia B

OBJECTIVES: Human gut microbiome has gained great attention for its proposed roles in the development of hypertension. The fungal microbiome in the human gut (i.e. the mycobiome) is beginning to gain recognition as a fundamental part of our microbiome. However, the existing knowledge of human mycobiome has never revealed the association between gut mycobiome and hypertension. It is known that inflammation and immunity contribute to human hypertension. Here, we sought to investigate whether gut mycobiome could predict the development of hypertension and its association with immunoglobulin light chains. METHODS AND MATERIALS: Participants were classified into three cohorts: prehypertension (pre-HTN), hypertension (HTN), and normal-tension (NT) based on their blood pressure. Fresh samples were collected, and the ITS transcribed spacer ribosomal RNA gene sequence was performed. An immunoturbidimetric test was used to examine the serum levels of immunological light chains. RESULTS: Subjects in both of the states of pre-HTN and HTN had different fungal microbiome community compared to the NT group (FDR<0.05). Slightly higher levels of fungal richness and diversity were observed in the groups of pre-HTN and HTN. The relative abundance of Malassezia increased in the HTN group compared to that in the NT group, and the relative abundance of Mortierella enriched in the NT group. For the pre-HTN group, the relative abundance of Malassezia was positively associated with serum the concentration of light chain (LC) κ (r=0.510, P=0.044); for the HTN group, the relative abundance of Mortierella was positively associated with the serum concentration of LC κ (P<0.05), the relative abundance of Malassezia was positively associated with both the serum concentrations of LC κ and LC λ (r>0.30, P<0.05). CONCLUSIONS: Our present study demonstrated that gut fungal dysbiosis occurred in the state of prehypertension, and fungal dysbiosis can predict the dysregulation of serum light chains in hypertension patients. Further study on modulating gut fungal community should be focused on balancing the immunological features in hypertension.

107. PvML1 suppresses bacterial infection by recognizing LPS and regulating AMP expression in shrimp.

Front Immunol

2022 Dec 28

Wang Y, Yang LG, Feng GP

Toll and Toll-like receptors (TLRs) play essential roles in the innate immunity of Drosophila and mammals. Recent studies have revealed the presence of Toll-mediated immune signaling pathways in shrimp. However, the recognition and activation mechanism of Toll signaling pathways in crustaceans remain poorly understood due to the absence of key recognition molecules, such as peptidoglycan recognition proteins. Here, a novel MD2-related lipid-recognition (ML) member named PvML1 was characterized in Penaeus vannamei. We found that PvML1 shared a similar 3D structure with human MD2 that could specifically recognize lipopolysaccharides (LPS) participating in LPS-mediated TLR4 signaling. PvML1 was highly expressed in hemocytes and remarkably upregulated after Vibrio parahemolyticus challenge. Furthermore, the binding and agglutinating assays showed that PvML1 possessed strong binding activities to LPS and its key portion lipid A as well as Vibrio cells, and the binding of PvML1 with bacterial cells led to the agglutination of bacteria, suggesting PvML1 may act as a potential pathogen recognition protein upon interaction with LPS. Besides, coating V. parahemolyticus with recombinant PvML1 promoted bacterial clearance in vivo and increased the survival rate of bacterium-challenged shrimp. This result was further confirmed by RNAi experiments. The knockdown of PvML1 remarkably suppressed the clearance of bacteria in hemolymph and decreased the survival rate of infected shrimp. Meanwhile, the silencing of PvML1 severely impaired the expression of a few antimicrobial peptides (AMPs). These results demonstrated the significant correlation of bacterial clearance mediated by PvML1 with the AMP expression. Interestingly, we found that PvML1 interacted with the extracellular region of PvToll2, which had been previously shown to participate in bacterial clearance by regulating AMP expression. Taken together, the proposed antibacterial model mediated by PvML1 might be described as follows. PvML1 acted as a potential recognition receptor for Gram-negative bacteria by binding to LPS, and then it activated PvToll2-mediated signaling pathway by interacting with PvToll2 to eliminate invading bacteria through producing specific AMPs. This study provided new insights into the recognition and activation mechanism of Toll signaling pathways of invertebrates and the defense functions of ML members.

108. A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration.

Front Immunol

2022 Dec 28

Hallam TM, Cox TE, Smith-Jackson K

109. Soluble TREM2 is a potential biomarker for the severity of primary angiitis of the CNS.

Front Immunol

2022 Dec 27

Guo T, Ma J, Sun J

110. Case report: Challenges in immune reconstitution following hematopoietic stem cell transplantation for CTLA-4 insufficiency-like primary immune regulatory disorders.

Front Immunol

2022 Dec 27

Margarit-Soler A, Deyà-Martínez À, Canizales JT

111. No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment.

Front Immunol

2022 Dec 23

Fang Q, Stehr AM, Naschberger E

112. Hcp1-loaded staphylococcal membrane vesicle vaccine protects against acute melioidosis.

Front Immunol

2022 Dec 23

Zhu K, Li G, Li J

113. Prognostic value of TMEM59L and its genomic and immunological characteristics in cancer.

Front Immunol

2022 Dec 23

Shi C, Zhang L, Chen D

BACKGROUND: TMEM59L is a newly discovered transmembrane protein; its functions in cancer remain unknown. This study was designed to reveal the prognostic value and the functional role of TMEM59L in cancer. METHODS: The gene expression profiles, methylation data, and corresponding clinical data of TMEM59L were retrieved from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression database. Survival analysis was employed to calculate the pan-cancer prognostic value of TMEM59L. The correlation between TMEM59L expression and tumor immune microenvironment, as well as DNA methylation dynamics and genomic heterogeneity across cancers were assessed based on data from TCGA. RESULTS: Our findings revealed that distinct differences of TMEM59L mRNA expression were observed in different cancer types and that higher TMEM59L expression was observed in the advanced pathological stage and associated with worse prognosis in kidney renal papillary cell carcinoma, bladder urothelial carcinoma, colon adenocarcinoma, and kidney renal clear cell carcinoma. Pathway analysis indicated that TMEM59L exerted a key influence in cancer development and in immune- and cancer-associated pathways such as epithelial-mesenchymal transition and TGF-β signaling. Moreover, correlation analysis hinted at a negative correlation of TMEM59L expression with CD8 T cells, activated CD4 T cells, and several immunomodulators, including IDO1, TIGIT, PD-L1, CTLA-4, and BTLA in various cancers. Survival analysis indicated that the hypermethylation of TMEM59L gene was associated with longer survival times. A significant correlation was also observed between TMEM59L expression and immunophenoscore, homologous recombination deficiency, loss of heterozygosity, tumor stemness score, and neoantigens in various cancers. Importantly, we also identified numerous potential agents that may target TMEM59L. CONCLUSION: Our study revealed the prognostic value as well as the genomic and immunological characteristics of TMEM59L in cancers, highlighting the promising potential for TMEM59L as a prognostic cancer biomarker and a therapeutic target.

114. Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Front Immunol

2022 Dec 23

Dovrolis N, Filidou E, Tarapatzi G

115. Comprehensive analysis of a glycolysis and cholesterol synthesis-related genes signature for predicting prognosis and immune landscape in osteosarcoma.

Front Immunol

2022 Dec 23

Xu F, Yan J, Peng Z

BACKGROUND: Glycolysis and cholesterol synthesis are crucial in cancer metabolic reprogramming. The aim of this study was to identify a glycolysis and cholesterol synthesis-related genes (GCSRGs) signature for effective prognostic assessments of osteosarcoma patients. METHODS: Gene expression data and clinical information were obtained from GSE21257 and TARGET-OS datasets. Consistent clustering method was used to identify the GCSRGs-related subtypes. Univariate Cox regression and LASSO Cox regression analyses were used to construct the GCSRGs signature. The ssGSEA method was used to analyze the differences in immune cells infiltration. The pRRophetic R package was utilized to assess the drug sensitivity of different groups. Western blotting, cell viability assay, scratch assay and Transwell assay were used to perform cytological validation. RESULTS: Through bioinformatics analysis, patients diagnosed with osteosarcoma were classified into one of 4 subtypes (quiescent, glycolysis, cholesterol, and mixed subtypes), which differed significantly in terms of prognosis and tumor microenvironment. Weighted gene co-expression network analysis revealed that the modules strongly correlated with glycolysis and cholesterol synthesis were the midnight blue and the yellow modules, respectively. Both univariate and LASSO Cox regression analyses were conducted on screened module genes to identify 5 GCSRGs (RPS28, MCAM, EN1, TRAM2, and VEGFA) constituting a prognostic signature for osteosarcoma patients. The signature was an effective prognostic predictor, independent of clinical characteristics, as verified further via Kaplan-Meier analysis, ROC curve analysis, univariate and multivariate Cox regression analysis. Additionally, GCSRGs signature had strong correlation with drug sensitivity, immune checkpoints and immune cells infiltration. In cytological experiments, we selected TRAM2 as a representative gene to validate the validity of GCSRGs signature, which found that TRAM2 promoted the progression of osteosarcoma cells. Finally, at the pan-cancer level, TRAM2 had been correlated with overall survival, progression free survival, disease specific survival, tumor mutational burden, microsatellite instability, immune checkpoints and immune cells infiltration. CONCLUSION: Therefore, we constructed a GCSRGs signature that efficiently predicted osteosarcoma patient prognosis and guided therapy.

116. High-intensity chemotherapy improved the prognosis of patients with high-grade B-cell lymphoma.

Front Immunol

2022 Dec 23

Chen Y, Cai Q, Chang Y

117. Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review.

Front Immunol

2022 Dec 23

Mei WJ, Mi M, Qian J

118. Frequent somatic mosaicism in T lymphocyte subsets in individuals with and without multiple sclerosis.

Front Immunol

2022 Dec 23

Van Horebeek L, Dedoncker N, Dubois B

119. Effect of dietary soybean saponin Bb on the growth performance, intestinal nutrient absorption, morphology, microbiota, and immune response in juvenile Chinese soft-shelled turtle (Pelodiscus sinensis).

Front Immunol

2022 Dec 23

Wang Y, Jia X, Guo Z

Soybean meal is widely applied in the aquafeeds due to the limitation of fish meal resources. Numerous studies have manifested that dietary soybean saponin, an anti-nutrient factor in soybean meal, may slow growth and induce intestinal inflammation in aquatic animals, but the possible causes are unclear. The juvenile Pelodiscus sinensis (mean initial body weight: 6.92 ± 0.03 g) were fed basal diet (CON group) and 2.46% soybean saponin Bb-supplemented diet (SAP group) for 35 days to further explore the effects of dietary soybean saponin Bb on the growth performance, apparent digestibility coefficients, intestinal morphology, the gut microbiota, intestinal transporters/channels, and immune-related gene expression. The results indicated that dietary soybean saponin Bb significantly decreased final body weight, specific growth rate, protein deposition ratio, and apparent digestibility coefficients (dry matter, crude protein, and crude lipid) of nutrients in Pelodiscus sinensis, which may be closely correlated with markedly atrophic villus height and increased lamina propria width in the small intestine. In addition, plasma contents of cholesterol, calcium, phosphorus, potassium, lysozyme, and C3 were significantly decreased in the SAP group compared with the control group. Soybean saponin Bb significantly downregulated the mRNA levels of glucose transporter 2, fatty acid binding protein 1 and fatty acid binding protein 2, amino acid transporter 2, b0,+-type amino acid transporter 1, and sodium-dependent phosphate transport protein 2b in the small intestine. At the same time, the expressions of key transcription factors (STAT1, TBX21, FOS), chemokines (CCL3), cytokines (TNF-α, IL-8), and aquaporins (AQP3, AQP6) in the inflammatory response were increased by soybean saponin Bb in the large intestine of a turtle. Additionally, dietary supplementation of SAP significantly reduced the generic abundance of beneficial bacteria (Lactobacillus, Bifidobacterium, and Bacillus) and harmful bacteria (Helicobacter and Bacteroides). In a nutshell, dietary supplementation of 2.46% soybean saponin not only hindered the growth performance by negatively affecting the macronutrients absorption in the small intestine but also induced an inflammatory response in the large intestine possibly by damaging the intestinal morphology, disturbing the intestinal microbiota and decreasing intestinal epithelial cell membrane permeability.

120. Unraveling the role of Breg cells in digestive tract cancer and infectious immunity.

Front Immunol

2022 Dec 23

Moreira H, Dobosz A, Cwynar-Zając Ł

121. Case report: A report of the complete pathological response of intrahepatic cholangiocarcinoma after conversion therapy.

Front Immunol

2022 Dec 23

Zhang X, Tang H, Fan J

122. Cuproptosis related genes associated with Jab1 shapes tumor microenvironment and pharmacological profile in nasopharyngeal carcinoma.

Front Immunol

2022 Dec 23

Wang L, Wang D, Yang L

123. Editorial: Deciphering the role of macrophages in lung homeostasis and diseases.

Front Immunol

2022 Dec 22

Jiang Z.

124. Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment.

Front Immunol

2022 Dec 22

Wu D, Luo Y, Li T

125. Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics.

Front Immunol

2022 Dec 22

Jia Q, Li S, Li XJ

126. Inflammatory checkpoints in amyotrophic lateral sclerosis: From biomarkers to therapeutic targets.

Front Immunol

2022 Dec 22

Jiang Z, Wang Z, Wei X

127. AbAgIntPre: A deep learning method for predicting antibody-antigen interactions based on sequence information.

Front Immunol

2022 Dec 22

Huang Y, Zhang Z, Zhou Y.

128. CCR7/dendritic cell axis mediates early bacterial dissemination in Orientia tsutsugamushi-infected mice.

Front Immunol

2022 Dec 22

Liang Y, Wang H, Gonzales C

129. ALFA-PRF: a novel approach to detect murine perforin release from CTLs into the immune synapse.

Front Immunol

2022 Dec 22

Rudd-Schmidt JA, Laine RF, Noori T

130. Variations in dynamic tumor-associated antigen-specific T cell responses correlate with HCC recurrence after thermal ablation.

Front Immunol

2022 Dec 22

Zang C, Zhao Y, Liu G

131. Serum cytokine profiling reveals different immune response patterns during general and severe Mycoplasma pneumoniae pneumonia.

Front Immunol

2022 Dec 22

Zhang Z, Dou H, Tu P

132. A pan-cancer and single-cell sequencing analysis of CD161, a promising onco-immunological biomarker in tumor microenvironment and immunotherapy.

Front Immunol

2022 Dec 22

Li H, Zhou K, Wang K

133. Long-term sialidase-specific immune responses after natural infection with cholera: Findings from a longitudinal cohort study in Bangladesh.

Front Immunol

2022 Dec 22

Chowdhury F, Akter A, Bhuiyan TR

BACKGROUND: Immune responses that target sialidase occur following natural cholera and have been associated with protection against cholera. Sialidase is a neuraminidase that facilitates the binding of cholera toxin (CT) to intestinal epithelial cells. Despite this, little is known about age-related sialidase-specific immune responses and the impact of nutritional status and co-infection on sialidase-specific immunity. METHODS: We enrolled 50 culture-confirmed Vibrio cholerae O1 cholera cases presenting to the icddr,b Dhaka hospital with moderate to severe dehydration. We evaluated antibody responses out to 18 months (day 540) following cholera. We assessed immune responses targeting sialidase, lipopolysaccharide (LPS), cholera toxin B subunit (CtxB), and vibriocidal responses. We also explored the association of sialidase-specific immune responses to nutritional parameters and parasitic co-infection of cases. RESULTS: This longitudinal cohort study showed age-dependent differences in anti-sialidase immune response after natural cholera infection. Adult patients developed plasma anti-sialidase IgA and IgG responses after acute infection (P<0.05), which gradually decreased from day 30 on. In children, no significant anti-sialidase IgA, IgM, and IgG response was seen with the exception of a late IgG response at study day 540 (p=0.05 compared to adults). There was a correlation between anti-sialidase IgA with vibriocidal titers, as well as anti-sialidase IgA and IgG with anti-LPS and anti-CtxB antibody responses in adult patients, whereas in children, a significant positive correlation was seen only between anti-sialidase IgA and CtxB IgA responses. Stunted children showed significantly lower anti-sialidase IgA, IgG, and IgM antibody responses and higher LPS IgG and IgM antibody responses than healthy children. The anti-sialidase IgA and IgG responses were significantly higher in cases with concomitant parasitic infection. CONCLUSION: Our data suggest that cholera patients develop age-distinct systemic and mucosal immune responses against sialidase. The stunted children have a lower anti-sialidase antibody response which may be associated with gut enteropathy and the neuraminidase plays an important role in augmented immune response in cholera patients infected with parasites.

134. Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Front Immunol

2022 Dec 22

Bai KH, Zhu MJ, Zhang YY

135. Monoclonal antibodies constructed from COVID-19 convalescent memory B cells exhibit potent binding activity to MERS-CoV spike S2 subunit and other human coronaviruses.

Front Immunol

2022 Dec 22

Peng Y, Liu Y, Hu Y

INTRODUCTION: The Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly contagious coronaviruses causing MERS and COVID-19, respectively, without an effective antiviral drug and a long-lasting vaccine. Approaches for diagnosis, therapeutics, prevention, etc., particularly for SARS-CoV-2 that is continually spreading and evolving, are urgently needed. Our previous study discovered that >60% of sera from convalescent COVID-19 individuals, but <8% from general population, showed binding activity against the MERS-CoV spike protein, indicating that SARS-CoV-2 infection boosted antibodies cross-reactive with MERS-CoV. METHODS: To generate antibodies specific to both SARS-CoV-2 and MERS-CoV, here we screened 60 COVID-19 convalescent sera against MERS-CoV spike extracellular domain and S1 and S2 subunits. We constructed and characterized monoclonal antibodies (mAbs) from COVID-19 convalescent memory B cells and examined their binding and neutralizing activities against human coronaviruses. RESULTS AND DISCUSSION: Of 60 convalescent serum samples, 34 showed binding activity against MERS-CoV S2, with endpoint titers positively correlated with the titers to SARS-CoV-2 S2. By sorting single memory B cells from COVID-19 convalescents, we constructed 38 mAbs and found that 11 mAbs showed binding activity with MERS-CoV S2, of which 9 mAbs showed potent cross-reactivity with all or a proportion of spike proteins of alphacoronaviruses (229E and NL63) and betacoronaviruses (SARS-CoV-1, SARS-CoV-2, OC43, and HKU1). Moreover, 5 mAbs also showed weak neutralization efficiency against MERS-CoV spike pseudovirus. Epitope analysis revealed that 3 and 8 mAbs bound to linear and conformational epitopes in MERS-CoV S2, respectively. In summary, we have constructed a panel of antibodies with broad-spectrum reactivity against all seven human coronaviruses, thus facilitating the development of diagnosis methods and vaccine design for multiple coronaviruses.

136. Epithelial-derived galectin-9 containing exosomes contribute to the immunomodulatory effects promoted by 2'-fucosyllactose and short-chain galacto- and long-chain fructo-oligosaccharides.

Front Immunol

2022 Dec 22

Ayechu-Muruzabal V, de Boer M, Blokhuis B

INTRODUCTION: Early life exposure to non-digestible oligosaccharides (NDO) or microbial components is known to affect immune development. NDO in combination with a TLR9 agonist mimicking bacterial triggers (CpG) promoted the secretion of galectins through unknown pathways. We aimed to study the contribution of exosomes in epithelial galectin secretion and subsequent immunoregulation upon exposure to a mixture of NDO by inhibiting exosome biogenesis. METHODS: Human intestinal epithelial cells (IEC) (FHs 74 Int or HT-29) were apically exposed to 2'-fucosyllactose (2'FL) and short-chain galacto- and long-chain fructo-oligosaccharides (GF), alone or with CpG. Basolaterally, non-activated or αCD3/CD28-activated peripheral blood mononuclear cells (PBMC) were added. After 24 h incubation, IEC were washed and incubated in fresh medium to analyze epithelial-derived galectin secretion. Additionally, before exposure to NDO and CpG, IEC were exposed to GW4869 to inhibit exosome biogenesis. After 24 h of incubation, IEC were washed and incubated for additional 24 h in the presence of GW4869, after which epithelial-derived galectin secretion was studied. Also, epithelial-derived exosomes were isolated to study the presence of galectins within the exosomes. RESULTS: Compared to CpG alone, exposure to 2'FL/GF mixture and CpG, significantly enhanced Th1-type IFNγ, and regulatory IEC-derived galectin-9 secretion in the HT-29/PBMC model. Similarly, in the FHs 74 Int/PBMC co-culture, 2'FL/GF induced immunomodulatory effects in the absence of CpG. Interestingly, galectin-9 and -4 were present in CD63-expressing exosomes isolated from HT-29 supernatants after IEC/PBMC co-culture. Exposure to GW4869 suppressed 2'FL/GF and CpG induced epithelial-derived galectin-9 secretion, which subsequently prevented the rise in IL-10 and reduction in IL-13 secretion observed in the HT-29/PBMC co-culture model upon exposure to 2'FL/GF and CpG. DISCUSSION: Exposure to 2'FL/GF and CpG or 2'FL/GF promoted Th1-type regulatory effects in HT-29/PBMC or FHs 74 Int/PBMC co-culture respectively, while Th2-type IL-13 was reduced in association with increased galectin-9 release. Galectin-9 and -4 were present in exosomes from HT-29 and the inhibition of exosome biogenesis inhibited epithelial-derived galectin secretion. This, also affected immunomodulatory effects in IEC/PBMC co-culture suggesting a key role of galectin expressing IEC-derived exosomes in the mucosal immune regulation induced by NDO.

137. The safety of COVID-19 vaccines in patients with myasthenia gravis: A scoping review.

Front Immunol

2022 Dec 22

Peng S, Tian Y, Meng L

BACKGROUND: COVID-19 vaccines are required for individuals with myasthenia gravis (MG), as these patients are more likely to experience severe pneumonia, myasthenia crises, and higher mortality rate. However, direct data on the safety of COVID-19 vaccines in patients with MG are lacking, which results in hesitation in vaccination. This scoping was conducted to collect and summarize the existing evidence on this issue. METHODS: PubMed, Cochrane Library, and Web of Science were searched for studies using inclusion and exclusion criteria. Article titles, authors, study designs, demographics of patients, vaccination information, adverse events (AEs), significant findings, and conclusions of included studies were recorded and summarized. RESULTS: Twenty-nine studies conducted in 16 different countries in 2021 and 2022 were included. Study designs included case report, case series, cohort study, cross-sectional study, survey-based study, chart review, and systemic review. A total of 1347 patients were included. The vaccines used included BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, inactivated vaccines, and recombinant subunit vaccines. Fifteen case studies included 48 patients reported that 23 experienced new-onset, and five patients experienced flare of symptoms. Eleven other types of studies included 1299 patients reported that nine patients experienced new-onset, and 60 participants experienced flare of symptoms. Common AEs included local pain, fatigue, asthenia, cephalalgia, fever, and myalgia. Most patients responded well to treatment without severe sequelae. Evidence gaps include limited strength of study designs, type and dose of vaccines varied, inconsistent window of risk and exacerbation criteria, limited number of participants, and lack of efficacy evaluation. CONCLUSION: COVID-19 vaccines may cause new-onset or worsening of MG in a small proportion of population. Large-scale, multicenter, prospective, and rigorous studies are required to verify their safety.

138. Arm race between Rift Valley fever virus and host.

Front Immunol

2022 Dec 22

Wang X, Yuan Y, Liu Y

139. Advances in pathogenesis and nanoparticles (NPs)-mediated treatment of psoriasis.

Front Immunol

2022 Dec 22

Shen Q, Liu R, Tan S

140. A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii.

Front Immunol

2022 Dec 22

He Y, Xu D, Yan Z

BACKGROUND: Neurodegenerative diseases including AD is currently one of intractable problems globally due to the insufficiency of intervention strategies. Long-term infection of Toxoplasma gondii (T. gondii) can induce cognitive impairment in hosts, which is closely implicated in the pathogenesis of neurodegenerative diseases. Aconitate decarboxylase 1 (Acod1) and its produced metabolite itaconate (termed Acod1/itaconate axis), have recently attracted extensive interests due to its anti-inflammatory role in macrophages. However, whether the axis can influence cognitive function remains unknown. METHODS: A chronic T. gondii-infected mice (C57BL/6J) model was established via administration of cysts by gavage. Novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests were used to evaluate the behavior performance. Transmission electron microscopy, immunofluorescence, RT-PCR, western-blotting and RNA sequencing were utilized to determine the pathological changes, neuroinflammation and transcription profile in hippocampus tissues post infection, respectively. Moreover, the protective effect of Acod1/itaconate axis in T. gondii-induced cognitive deficits was evaluated. RESULTS: We found that the latent infection of the parasite impaired the cognitive function, which was assessed behaviorally by novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests. RNA sequencing of hippocampus showed that the infection downregulated the expression of genes related to synaptic plasticity, transmission and cognitive behavior. To our attention, the infection robustly upregulated the expression of genes associated with pro-inflammatory responses, which was characterized by microglia activation and disorder of Acod1/itaconate axis. Interestingly, administration of dimethyl itaconate (DI, an itaconate derivative with cell membrane permeability) could significantly ameliorate the cognitive deficits induced by T. gondii, which was proved by improvement of behavior performance and synaptic ultrastructure impairment, and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a potential therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection. CONCLUSIONS: Overall, these findings provide a novel insight for the pathogenesis of T. gondii-related cognitive deficits in hosts, and also provide a novel clue for the potential therapeutic strategies.

141. Endothelial glycocalyx in hepatopulmonary syndrome: An indispensable player mediating vascular changes.

Front Immunol

2022 Dec 22

Li L, Cook C, Liu Y

142. The game between host antiviral innate immunity and immune evasion strategies of senecavirus A - A cell biological perspective.

Front Immunol

2022 Dec 22

Zhao K, Zhang S, Liu X

143. CARMA3: A potential therapeutic target in non-cancer diseases.

Front Immunol

2022 Dec 22

Gui Z, Zhang Y, Zhang A

144. Novel neutralizing chicken IgY antibodies targeting 17 potent conserved peptides identified by SARS-CoV-2 proteome microarray, and future prospects.

Front Immunol

2022 Dec 22

Li J, Liang T, Hei A

145. IκB(NS)-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6C(high) monocytes and preventing exaggerated innate immune responses.

Front Immunol

2022 Dec 22

Frentzel S, Jeron A, Pausder A

IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6Chigh inflammatory monocytes prompted us to further characterize the specific contribution of IκBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chigh monocytes primed during Lm infection in the absence of IκBNS displayed a blunted response compared to wild type-derived Ly6Chigh monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNS during Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chigh monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNS as molecular driver of inflammation in listeriosis.

146. Editorial: Factors determining long term anti-tumor responses to immune checkpoint blockade therapy.

Front Immunol

2022 Dec 21

Zappasodi R, Cook GP, Taylor A.

147. Therapeutic potential of paeoniflorin in atherosclerosis: A cellular action and mechanism-based perspective.

Front Immunol

2022 Dec 21

Yu W, Ilyas I, Hu X

148. The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells.

Front Immunol

2022 Dec 21

Wöhner M, Pinter T, Bönelt P

149. Pan-cancer analysis of ASB3 and the potential clinical implications for immune microenvironment of glioblastoma multiforme.

Front Immunol

2022 Dec 21

Mu L, Han Z, Yu S

BACKGROUND: Ankyrin repeat and SOCS Box containing 3 (ASB3) is an E3 ubiquitin ligase. It has been reported to regulate the progression of some cancers, but no systematic pan-cancer analysis has been conducted to explore its function in prognosis and immune microenvironment. METHOD: In this study, mRNA expression data were downloaded from TCGA and GTEx database. Next generation sequencing data from 14 glioblastoma multiforme (GBM) samples by neurosurgical resection were used as validation dataset. Multiple bioinformatics methods (ssGSEA, Kaplan-Meier, Cox regression analysis, GSEA and online tools) were applied to explore ASB3 expression, gene activity, prognosis of patients in various cancers, and its correlation with clinical information, immune microenvironment and pertinent signal pathways in GBM. The biological function of ASB3 in tumor-infiltrating lymphocytes (TILs) was verified using an animal model. RESULTS: We found that ASB3 was aberrant expressed in a variety of tumors, especially in GBM, and significantly correlated with the prognosis of cancer patients. The level of ASB3 was related to the TMB, MSI and immune cell infiltration in some cancer types. ASB3 had a negative association with immune infiltration and TME, including regulatory T cells (Tregs), cancer-associated fibroblasts, immunosuppressors and related signaling pathways in GBM. ASB3 overexpression reduced the proportion of Tregs in TILs. GSEA and PPI analysis also showed negative correlation between ASB3 expression and oncogenetic signaling pathways in GBM. CONCLUSION: A comprehensive pan-cancer analysis of ASB3 showed its potential function as a biomarker of cancer prognosis and effective prediction of immunotherapy response. This study not only enriches the understanding of the biological function of ASB3 in pan-cancer, especially in GBM immunity, but also provides a new reference for the personalized immunotherapy of GBM.

150. Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.

Front Immunol

2022 Dec 21

Chen YT, Chang YH, Pathak N

151. In-depth analysis of T cell immunity and antibody responses in heterologous prime-boost-boost vaccine regimens against SARS-CoV-2 and Omicron variant.

Front Immunol

2022 Dec 21

Heinen N, Marheinecke CS, Bessen C

152. Effects of replacing fishmeal with cottonseed protein concentrate on growth performance, blood metabolites, and the intestinal health of juvenile rainbow trout (Oncorhynchus mykiss).

Front Immunol

2022 Dec 21

Liu Y, Ma S, Lv W

153. HLA-G 3'UTR polymorphism diplotypes and soluble HLA-G plasma levels impact cervical cancer susceptibility and prognosis.

Front Immunol

2022 Dec 21

Gan J, Di XH, Yan ZY

BACKGROUND: Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with relevance in several cancers. The aim of this study was to evaluate the potential role of soluble HLA-G (sHLA-G), its genetic polymorphisms and its haplotype structure in the susceptibility and prognosis of primary cervical cancer in a Chinese Han population. METHODS: We investigated sHLA-G plasma levels and 3' untranslated region (3'UTR) polymorphisms through ELISA and direct DNA sequencing, respectively, in cervical cancer patients (120 cases) and healthy control women (96 cases). The data were analyzed for associations using PowerMarker, Haploview, and GraphPad Prism. RESULTS: In this study, 8 polymorphic sites, 16 haplotypes and 23 diplotypes in the HLA-G 3'UTR were identified in our study population. We observed that each pair of 8 polymorphic sites exhibited linkage disequilibrium. The heterozygote CT genotype at position +3422 (rs17875408) was more common in cervical cancer patients than in healthy women (OR=5.285, P<0.05). Haplotypes UTR-1, UTR-3, and UTR-7 accounted for more than 85% of both groups, but no significant difference was found. The frequency of the UTR-1/UTR-3 diplotype in patients was significantly higher than that in controls (P<0.05). In addition, we further observed that HLA-G 3'UTR polymorphisms may influence the sHLA-G plasma level in patients' peripheral blood, especially 14 bp Ins/Del (rs371194629) and +3142 C/G (rs1063320). A receiver operating characteristic (ROC) curve analysis showed that the sHLA-G level had good diagnostic performance in differentiating patients with cervical cancer from healthy women (AUC>0.7). Among patients, mean sHLA-G levels increased with increasing FIGO stages but were not related to the overall survival time. CONCLUSIONS: The results of the present study enhance our understanding of how HLA-G 3'UTR polymorphisms can influence the peripheral sHLA-G plasma level and play a key role in cervical carcinogenesis. This study further confirmed that sHLA-G may represent a novel plasma biomarker for the prognosis and potential therapeutic target of cervical cancer.

154. Polo-like kinase 1 is related with malignant characteristics and inhibits macrophages infiltration in glioma.

Front Immunol

2022 Dec 21

Luo L, Zhang XY, Zhen YW

BACKGROUND: Tumor immune microenvironment (TIM) plays a critical role in tumorigenesis and progression. Recently, therapies based on modulating TIM have made great breakthroughs in cancer treatment. Polo-like kinase 1 (PLK1) is a crucial regulatory factor of the cell cycle process and its dysregulations often cause various pathological processes including tumorigenesis. However, the detailed mechanisms surrounding the regulation of PLK1 on glioma immune microenvironment remain undefined. METHODS: Public databases and online datasets were used to extract data of PLK1 expression, clinical features, genetic alterations, and biological functions. The EdU, flow cytometry, and macrophage infiltration assays as well as xenograft animal experiments were performed to determine the relationship between PLK1 and glioma immune microenvironment in vivo and in vitro. RESULTS: PLK1 is always highly expressed in multiple cancers especially in glioma. Univariable and Multivariate proportional hazard Cox analysis showed that PLK1 was a prognostic biomarker for glioma. Simultaneously, highly expressed PLK1 is significantly related to prognosis, histological and genetic features in glioma by analyzing public databases. In addition, the enrichment analysis suggested that PLK1 might related to "immune response", "cell cycle", "DNA replication", and "mismatch repair" in glioma. Immune infiltration analysis demonstrated that highly expressed PLK1 inhibited M1 macrophages infiltration to glioblastoma immune microenvironment by Quantiseq and Xcell databases and negatively related to some chemokines and marker genes of M1 macrophages in glioblastoma. Subsequent experiments confirmed that PLK1 knockdown inhibited the proliferation of glioma cells but increased the M1 macrophages infiltration and polarization. Furthermore, in glioma xenograft mouse models, we showed that inhibiting PLK1 blocked tumor proliferation and increased the M1 macrophages infiltration. Finally, PLK1 methylation analysis and lncRNA-miRNA network revealed the potential mechanism of abnormal PLK1 expression in glioma. CONCLUSIONS: PLK1 inhibits M1 macrophages infiltration into glioma immune microenvironment and is a potential biomarker for glioma.

155. Chicken CSF2 and IL-4-, and CSF2-dependent bone marrow cultures differentiate into macrophages over time.

Front Immunol

2022 Dec 21

Borowska D, Sives S, Vervelde L

156. Predicting the prognosis in patients with sepsis by a pyroptosis-related gene signature.

Front Immunol

2022 Dec 21

Liang S, Xing M, Chen X

BACKGROUND: Sepsis remains a life-threatening disease with a high mortality rate that causes millions of deaths worldwide every year. Many studies have suggested that pyroptosis plays an important role in the development and progression of sepsis. However, the potential prognostic and diagnostic value of pyroptosis-related genes in sepsis remains unknown. METHODS: The GSE65682 and GSE95233 datasets were obtained from Gene Expression Omnibus (GEO) database and pyroptosis-related genes were obtained from previous literature and Molecular Signature Database. Univariate cox analysis and least absolute shrinkage and selection operator (LASSO) cox regression analysis were used to select prognostic differentially expressed pyroptosis-related genes and constructed a prognostic risk score. Functional analysis and immune infiltration analysis were used to investigate the biological characteristics and immune cell enrichment in sepsis patients who were classified as low- or high-risk based on their risk score. Then the correlation between pyroptosis-related genes and immune cells was analyzed and the diagnostic value of the selected genes was assessed using the receiver operating characteristic curve. RESULTS: A total of 16 pyroptosis-related differentially expressed genes were identified between sepsis patients and healthy individuals. A six-gene-based (GZMB, CHMP7, NLRP1, MYD88, ELANE, and AIM2) prognostic risk score was developed. Based on the risk score, sepsis patients were divided into low- and high-risk groups, and patients in the low-risk group had a better prognosis. Functional enrichment analysis found that NOD-like receptor signaling pathway, hematopoietic cell lineage, and other immune-related pathways were enriched. Immune infiltration analysis showed that some innate and adaptive immune cells were significantly different between low- and high-risk groups, and correlation analysis revealed that all six genes were significantly correlated with neutrophils. Four out of six genes (GZMB, CHMP7, NLRP1, and AIM2) also have potential diagnostic value in sepsis diagnosis. CONCLUSION: We developed and validated a novel prognostic predictive risk score for sepsis based on six pyroptosis-related genes. Four out of the six genes also have potential diagnostic value in sepsis diagnosis.

157. Actin depolymerizing factor-based nanomaterials: A novel strategy to enhance E. mitis-specific immunity.

Front Immunol

2022 Dec 21

Yu Z, Xu L, He K

158. Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work?

Front Immunol

2022 Dec 20

Zhang Y, Lin J, You Z

BACKGROUND: Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity. METHODS: A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR). RESULTS: From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; p < 0.001) and 0.91 (SIR 0.91; 0.72-1.14; p = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; p < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; p < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26-2.36; p = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively. CONCLUSION: We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA. INTERPRETATION: Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.

159. Corrigendum: Clinical efficacy, safety and tolerability of a new subcutaneous immunoglobulin 16.5% (Octanorm [Cutaquig(®)]) in the treatment of patients with primary immunodeficiencies.

Front Immunol

2022 Dec 20

Kobayashi RH, Gupta S, Melamed I

160. HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes.

Front Immunol

2022 Dec 20

Karnaukhov V, Paes W, Woodhouse IB

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others - ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs.

161. Systematic analysis of brain and skull ischemic injury expression profiles reveals associations of the tumor immune microenvironment and cell death with ischemic stroke.

Front Immunol

2022 Dec 20

Zhang C, Wang L, Guo Y

BACKGROUND: Previous studies have shown that stroke is a potential first sign of neoplasia, but the relationship between stroke and cancer remains unclear. As a complex brain disease, ischemic stroke involves cell death and immunity. Thus, it is necessary to investigate the association of the tumor immune microenvironment and cell death with ischemic stroke. METHODS: We established a photothrombosis-induced ischemic injury model in mouse brain and skull. Subsequently, we sequenced the whole transcriptome of the injured mouse brain and skull and analyzed the expression profiles. To investigate the association of stroke with cell death and cancer, we systematically performed gene set enrichment analysis in pan-cell death (i.e., apoptosis, cuproptosis, ferroptosis, necroptosis, and pyroptosis) and the cancer hallmark pathways. The time-dependent immune cell abundance variations after ischemic injury were estimated. Furthermore, pan-cancer genomic and prognostic analyses of the ischemic injury-related gene sets were also performed. RESULTS: In this study, we found that there exist temporal and spatial differences in the gene expression patterns of both the brain and skull with ischemic injury. The skull ischemic injury-induced changes in the brain transcriptome were particularly great, but could recover in a short period, while the skull transcriptome variation resulting from brain ischemic injury was long-lasting. In addition, the expression of the genes related to ischemic injury was also associated with pan-cell death and the cancer hallmark pathways. The changes in the abundance of immune cells indicate that brain ischemic injury may disrupt the immune microenvironment for a longer time, while the skull can balance the stability of the immune microenvironment better. Moreover, the brain ischemic injury-related gene sets were highly correlated with a variety of tumors, particularly glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM), which carry a greater mortality risk after stroke. CONCLUSION: This systematic analysis not only helps in the understanding of the changes in the gene expression profiles of both the brain and skull with ischemic injury but also reveals the association of the tumor immune microenvironment and cell death with ischemic stroke.

162. Corrigendum: Mettl14-mediated m6A modification enhances the function of Foxp3(+) regulatory T cells and promotes allograft acceptance.

Front Immunol

2022 Dec 20

Liu Y, Yuan Y, Zhou Z

163. Anti-PD-1 immune-related adverse events are associated with high therapeutic antibody fixation on T cells.

Front Immunol

2022 Dec 20

Gazzano M, Parizot C, Psimaras D

164. Topical Skullcapflavone II attenuates atopic dermatitis in a mouse model by directly inhibiting associated cytokines in different cell types.

Front Immunol

2022 Dec 20

Lee Y, Oh JH, Li N

165. The 2000HIV study: Design, multi-omics methods and participant characteristics.

Front Immunol

2022 Dec 20

Vos WAJW, Groenendijk AL, Blaauw MJT

BACKGROUND: Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets. METHODS: The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort. RESULTS: Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine. CONCLUSION: The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

166. Precision-cut rat placental slices as a model to study sex-dependent inflammatory response to LPS and Poly I:C.

Front Immunol

2022 Dec 20

Anandam KY, Abad C, Synova T

167. Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation.

Front Immunol

2022 Dec 20

Pavliuchenko N, Duric I, Kralova J

INTRODUCTION: Autoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo . In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1. METHODS: To address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers. RESULTS: Our data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues. CONCLUSIONS: We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

168. A distinct M2 macrophage infiltrate and transcriptomic profile decisively influence adipocyte differentiation in lipedema.

Front Immunol

2022 Dec 20

Wolf S, Rannikko JH, Virtakoivu R

Lipedema is a chronic and progressive adipose tissue disorder, characterized by the painful and disproportionate increase of the subcutaneous fat in the lower and/or upper extremities. While distinct immune cell infiltration is a known hallmark of the disease, its role in the onset and development of lipedema remains unclear. To analyze the macrophage composition and involved signaling pathways, anatomically matched lipedema and control tissue samples were collected intra-operatively from gender- and BMI-matched patients, and the Stromal Vascular Fraction (SVF) was used for Cytometry by Time-of-Flight (CyTOF) and RNA sequencing. The phenotypic characterization of the immune component of lipedema versus control SVF using CyTOF revealed significantly increased numbers of CD163 macrophages. To gain further insight into this macrophage composition and molecular pathways, RNA sequencing of isolated CD11b+ cells was performed. The analysis suggested a significant modification of distinct gene ontology clusters in lipedema, including cytokine-mediated signaling activity, interleukin-1 receptor activity, extracellular matrix organization, and regulation of androgen receptor signaling. As distinct macrophage populations are known to affect adipose tissue differentiation and metabolism, we evaluated the effect of M2 to M1 macrophage polarization in lipedema using the selective PI3Kγ inhibitor IPI-549. Surprisingly, the differentiation of adipose tissue-derived stem cells with conditioned medium from IPI-549 treated SVF resulted in a significant decreased accumulation of lipids in lipedema versus control SVF. In conclusion, our results indicate that CD163+ macrophages are a critical component in lipedema and re-polarization of lipedema macrophages can normalize the differentiation of adipose-derived stem cells in vitro evaluated by the cellular lipid accumulation. These data open a new chapter in understanding lipedema pathophysiology and may indicate potential treatment options.

169. A novel ganglioside-related risk signature can reveal the distinct immune landscape of neuroblastoma and predict the immunotherapeutic response.

Front Immunol

2022 Dec 20

Yang J, Han L, Sha Y

INTRODUCTION: Gangliosides play an essential role in cancer development and progression. However, the involvement of gangliosides in the prognosis and tumor microenvironment (TME) of neuroblastoma is not entirely understood. METHODS: Consensus clustering analysis was performed to identify ganglioside-mediated molecular subtypes. LASSO-Cox analysis was conducted to identify independent prognostic genes, and a novel risk signature was constructed. The risk signature was validated internally and externally. We further explored the independent prognosis value, immune landscape, drug susceptibility, and tumor dedifferentiation of the risk signature. The role of the signature gene B3GALT4 in neuroblastoma was explored in vitro. RESULTS: Seventeen ganglioside-related genes were differentially expressed between INSS stage 4 and other stages, and two ganglioside-related clusters with distinct prognoses were identified. A novel risk signature integrating ten ganglioside-related prognostic genes was established. Across the train set and external validation sets, the risk signature presented high predictive accuracy and discrimination. The risk signature was an independent prognostic factor and constructed a nomogram combining multiple clinical characteristics. In the high-score group, the deficiency in antigen processing and presenting machinery, lack of immune cell infiltration, and escaping NK cells contributed substantially to immune escape. The low-score group was more responsive to immune checkpoint blockade therapy, while the high-score group showed substantial sensitivity to multiple chemotherapeutic drugs. Besides, the risk score was significantly positively correlated with the stemness index and reduced considerably in all-trans retinoic acid-treated neuroblastoma cell lines, indicating high dedifferentiation in the high-score group. Additionally, neuroblastoma cells with downregulation of B3GALT4 present with increased proliferation, invasion, and metastasis abilities in vitro. CONCLUSION: The novel ganglioside-related risk signature highlights the role of ganglioside in neuroblastoma prognosis and immune landscape and helps optimize chemotherapy and immunotherapy for neuroblastoma.

170. Embryonic ILC-poiesis across tissues.

Front Immunol

2022 Dec 20

Hernández-Torres DC, Stehle C.

171. Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma.

Front Immunol

2022 Dec 20

Xu J, Hu Z, Cao H

BACKGROUND: The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed. METHODS: Thirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro. RESULTS: FDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients' tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC. CONCLUSION: Our analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.

172. Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma.

Front Immunol

2022 Dec 2

Shi Y, Huang G, Jiang F

173. Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels.

Front Immunol

2022 Dec 2

Trevisan B, Rodriguez M, Medder H

174. Impact of exposure to malaria and nutritional status on responses to the experimental malaria vaccine ChAd63 MVA ME-TRAP in 5-17 month-old children in Burkina Faso.

Front Immunol

2022 Dec 2

Morter R, Tiono AB, Nébié I

The experimental malaria vaccine ChAd63 MVA ME-TRAP previously showed protective efficacy against Plasmodium falciparum infection in Phase IIa sporozoite challenge studies in adults in the United Kingdom and in a Phase IIb field efficacy trial in Kenyan adults. However, it failed to demonstrate efficacy in a phase IIb trial in 5-17 month-old children in an area of high malaria transmission in Burkina Faso. This secondary analysis investigated whether exposure to malaria or nutritional status might be associated with reduced responses to vaccination in this cohort. Parasite blood smears and anti-AMA-1 IgG titres were used to assess history of exposure to malaria and weight-for-length Z scores were calculated to assess nutritional status. Differences in vaccine-specific anti-TRAP IgG titre and ex vivo IFNγ ELISpot response were measured between groups. In total, n = 336 volunteers randomised to receive the experimental vaccine regimen were included in this analysis. A positive smear microscopy result was associated with reduced anti-TRAP IgG titre (geometric mean titre: 2775 (uninfected) vs 1968 (infected), p = 0.025), whilst anti-AMA-1 IgG titres were weakly negatively correlated with reduced ex vivo IFNγ ELISpot response (r = -0.18, p = 0.008). Nutritional status was not associated with either humoral or cellular immunogenicity. Vaccine efficacy was also measured separately for vaccinees with positive and negative blood smears. Although not significant in either group compared to controls, vaccine efficacy measured by Cox hazard ratio was higher in uninfected compared to infected individuals (19.8% [p = 0.50] vs 3.3% [p = 0.69]). Overall, this data suggests exposure to malaria may be associated with impaired vaccine immunogenicity. This may have consequences for the testing and eventual deployment of various vaccines, in areas with high endemicity for malaria. TRIAL REGISTRATION: Pactr.org, identifier PACTR201208000404131; ClinicalTrials.gov, identifier NCT01635647.

175. Single-cell transcriptomics reveals cell type-specific immune regulation associated with anti-NMDA receptor encephalitis in humans.

Front Immunol

2022 Dec 2

Jiang Y, Dai S, Jia L

176. Kinetics of free and ligand-bound atacicept in human serum.

Front Immunol

2022 Dec 2

Eslami M, Willen D, Papasouliotis O

177. Bidirectional two-sample Mendelian randomization study of causality between rheumatoid arthritis and myocardial infarction.

Front Immunol

2022 Dec 2

Guo HY, Wang W, Peng H

178. Viral infectious diseases severity: co-presence of transcriptionally active microbes (TAMs) can play an integral role for disease severity.

Front Immunol

2022 Dec 2

Yadav A, Pandey R.

Humans have been challenged by infectious diseases for all of their recorded history, and are continually being affected even today. Next-generation sequencing (NGS) has enabled identification of, i) culture independent microbes, ii) emerging disease-causing pathogens, and iii) understanding of the genome architecture. This, in turn, has highlighted that pathogen/s are not a monolith, and thereby allowing for the differentiation of the wide-ranging disease symptoms, albeit infected by a primary pathogen. The conventional 'one disease - one pathogen' paradigm has been positively revisited by considering limited yet important evidence of the co-presence of multiple transcriptionally active microbes (TAMs), potential pathogens, in various infectious diseases, including the COVID-19 pandemic. The ubiquitous microbiota presence inside humans gives reason to hypothesize that the microbiome, especially TAMs, contributes to disease etiology. Herein, we discuss current evidence and inferences on the co-infecting microbes particularly in the diseases caused by the RNA viruses - Influenza, Dengue, and the SARS-CoV-2. We have highlighted that the specific alterations in the microbial taxonomic abundances (dysbiosis) is functionally connected to the exposure of primary infecting pathogen/s. The microbial presence is intertwined with the differential host immune response modulating differential disease trajectories. The microbiota-host interactions have been shown to modulate the host immune responses to Influenza and SARS-CoV-2 infection, wherein the active commensal microbes are involved in the generation of virus-specific CD4 and CD8 T-cells following the influenza virus infection. Furthermore, COVID-19 dysbiosis causes an increase in inflammatory cytokines such as IL-6, TNF-α, and IL-1β, which might be one of the important predisposing factors for severe infection. Through this article, we aim to provide a comprehensive view of functional microbiomes that can have a significant regulatory impact on predicting disease severity (mild, moderate and severe), as well as clinical outcome (survival and mortality). This can offer fresh perspectives on the novel microbial biomarkers for stratifying patients for severe disease symptoms, disease prevention and augmenting treatment regimens.

179. S1PR(4) deficiency results in reduced germinal center formation but only marginally affects antibody production.

Front Immunol

2022 Dec 2

Riese J, Hähnel C, Menz J

180. Corrigendum: Mouse models of lung-specific SARS-CoV-2 infection with moderate pathological traits.

Front Immunol

2022 Dec 2

Kim SH, Kim J, Jang JY

181. Predicting diagnostic gene expression profiles associated with immune infiltration in patients with lupus nephritis.

Front Immunol

2022 Dec 2

Wang L, Yang Z, Yu H

OBJECTIVE: To identify potential diagnostic markers of lupus nephritis (LN) based on bioinformatics and machine learning and to explore the significance of immune cell infiltration in this pathology. METHODS: Seven LN gene expression datasets were downloaded from the GEO database, and the larger sample size was used as the training group to obtain differential genes (DEGs) between LN and healthy controls, and to perform gene function, disease ontology (DO), and gene set enrichment analyses (GSEA). Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), were applied to identify candidate biomarkers. The diagnostic value of LN diagnostic gene biomarkers was further evaluated in the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from LN patients and to analyze their correlation with diagnostic markers. RESULTS: Thirty and twenty-one DEGs were screened in kidney tissue and peripheral blood, respectively. Both of which covered macrophages and interferons. The disease enrichment analysis of DEGs in kidney tissues showed that they were mainly involved in immune and renal diseases, and in peripheral blood it was mainly enriched in cardiovascular system, bone marrow, and oral cavity. The machine learning algorithm combined with external dataset validation revealed that C1QA(AUC = 0.741), C1QB(AUC = 0.758), MX1(AUC = 0.865), RORC(AUC = 0.911), CD177(AUC = 0.855), DEFA4(AUC= 0.843)and HERC5(AUC = 0.880) had high diagnostic value and could be used as diagnostic biomarkers of LN. Compared to controls, pathways such as cell adhesion molecule cam, and systemic lupus erythematosus were activated in kidney tissues; cell cycle, cytoplasmic DNA sensing pathways, NOD-like receptor signaling pathways, proteasome, and RIG-1-like receptors were activated in peripheral blood. Immune cell infiltration analysis showed that diagnostic markers in kidney tissue were associated with T cells CD8 and Dendritic cells resting, and in blood were associated with T cells CD4 memory resting, suggesting that CD4 T cells, CD8 T cells and dendritic cells are closely related to the development and progression of LN. CONCLUSION: C1QA, C1QB, MX1, RORC, CD177, DEFA4 and HERC5 could be used as new candidate molecular markers for LN. It may provide new insights into the diagnosis and molecular treatment of LN in the future.

182. Editorial: Dysregulation of immunity predisposing to severe COVID-19 infection.

Front Immunol

2022 Dec 2

Halwani R, Pulvirenti F, Al-Muhsen S.

183. Commentary: Serum hepatitis B virus large and medium surface proteins as novel tools for predicting HBsAg clearance.

Front Immunol

2022 Dec 2

Pfefferkorn M, van Bömmel F.

184. Editorial: Frontiers on innate immunity and intercellular communication.

Front Immunol

2022 Dec 19

Xiao Y, Zhang Y, Yin H

185. Neurotrophic and immunomodulatory effects of olfactory ensheathing cells as a strategy for neuroprotection and regeneration.

Front Immunol

2022 Dec 19

Denaro S, D'Aprile S, Alberghina C

186. Aryl hydrocarbon receptor: The master regulator of immune responses in allergic diseases.

Front Immunol

2022 Dec 19

Riaz F, Pan F, Wei P.

187. The role and mechanism of gut microbiota-derived short-chain fatty in the prevention and treatment of diabetic kidney disease.

Front Immunol

2022 Dec 19

Tao P, Ji J, Wang Q

188. Radiomic models based on magnetic resonance imaging predict the spatial distribution of CD8(+) tumor-infiltrating lymphocytes in breast cancer.

Front Immunol

2022 Dec 19

Jeon SH, Kim SW, Na K

189. Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study.

Front Immunol

2022 Dec 19

Bellan M, Apostolo D, Albè A

190. Case report: Variable response to immunotherapy in ovarian cancer: Our experience within the current state of the art.

Front Immunol

2022 Dec 19

Provinciali N, Greppi M, Pesce S

191. Circulating brain-derived extracellular vesicles expressing neuroinflammatory markers are associated with HIV-related neurocognitive impairment.

Front Immunol

2022 Dec 19

de Menezes EGM, Liu JS, Bowler SA

BACKGROUND: Neurocognitive impairment remains prevalent in people with HIV (PWH) despite long term virological suppression by antiretroviral therapy (ART) regimens. Systemic and neuro-inflammatory processes are suggested to contribute to the complex pathology leading to cognitive impairment in this population, yet the underlying mechanisms remain unresolved. Extracellular vesicles (EVs) play a central role in intracellular communication and have emerged as key modulators of immunological and inflammatory responses. In this report, we examined the impact of EVs in PWH experiencing cognitive deficits to determine their relevance in HIV associated neuropathology. METHODS: EV phenotypes were measured in plasma samples from 108 PWH with either cognitive impairment (CI, n=92) or normal cognition (NC, n=16) by flow cytometry. Matched cerebrospinal fluid (CSF)-derived EVs were similarly profiled from a subgroup of 84 individuals who underwent a lumbar puncture. Peripheral blood mononuclear cells were assayed by flow cytometry to measure monocyte frequencies in a subset of 32 individuals. RESULTS: Plasma-EVs expressing CD14, CD16, CD192, C195, and GFAP were significantly higher in HIV-infected individuals with cognitive impairment compared to individuals with normal cognition. Increased CSF-EVs expressing GFAP and CD200 were found in the cognitive impairment group compared to the normal cognition group. Frequencies of patrolling monocytes correlated with plasma-EVs expressing CD14, CD66b, MCSF, MAP2, and GFAP. Frequencies of CD195 expression on monocytes correlated positively with plasma-EVs expressing CD41a, CD62P, and CD63. Expression of CD163 on monocytes correlated positively with CSF-EVs expressing GFAP and CD200. Finally, the expression of CD192 on total monocytes correlated with CSF-EVs expressing CD200, CD62P, and CD63. CONCLUSIONS: EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment, suggesting that distinct EV subsets may serve as novel biomarkers of neuronal injury in HIV infection. Further circulating platelet EV levels were linked to monocyte activation indicating a potential novel interaction in the pathogenesis of HIV-related cognitive impairment.

192. Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer.

Front Immunol

2022 Dec 19

Li F, Liu S.

193. Expounding the role of tick in Africa swine fever virus transmission and seeking effective prevention measures: A review.

Front Immunol

2022 Dec 16

Lv T, Xie X, Song N

194. Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling.

Front Immunol

2022 Dec 16

Schreibing F, Hannani MT, Kim H

195. Editorial: Macrophage immunity and metabolism in cancer: Novel diagnostic and therapeutic strategies.

Front Immunol

2022 Dec 16

Leavenworth JW, Lai X, Miao H

196. Density dependent regulation of inflammatory responses in macrophages.

Front Immunol

2022 Dec 16

Vaughan-Jackson A, Stodolak S, Ebrahimi KH

197. A transient receptor potential channel-related model based on machine learning for evaluating tumor microenvironment and immunotherapeutic strategies in acute myeloid leukemia.

Front Immunol

2022 Dec 16

Hua J, Ding T, Shao Y.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy. Transient receptor potential (TRP) channels in AML still need to be further explored. A TRP channel-related model based on machine learning was established in this study. METHODS: The data were downloaded from TCGA-LAML and Genome-Tissue Expression (GTEx). TRP-related genes (TRGs) were extracted from previous literature. With the use of Single-Sample Gene Set Enrichment Analysis (ssGSEA), TRP enrichment scores (TESs) were calculated. The limma package was used to identify differentially expressed genes (DEGs), and univariate Cox regression analysis was performed to identify prognostic DEGs. The above prognostic DEGs were analyzed by Random Survival Forest and least absolute shrinkage and selection operator (Lasso) analysis to create the TRP signature. The Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to investigate the efficiency and accuracy of prognostic prediction. Moreover, genomic mutation analysis was based on GISTIC analysis. Based on ESTIMATE, TIMER, MCPcounter, and ssGSEA, the tumor microenvironment and immunological characteristics were expressly evaluated to explore immunotherapeutic strategies. Enrichment analysis for TRP signature was based on the Kyoto Encyclopedia of Genes Genomes (KEGG), Gene Ontology (GO), over-representation analysis (ORA), and Gene Set Enrichment Analysis (GSEA). Genomics of Drug Sensitivity in Cancer (GDSC) and pRRophetic were used to carry out drug sensitivity analysis. Conclusively, SCHIP1 was randomly selected to perform in vitro cyto-functional experiments. RESULTS: The worse clinical outcomes of patients with higher TESs were observed. There were 107 differentially expressed TRGs identified. Our data revealed 57 prognostic TRGs. Eight TRGs were obtained to establish the prognostic TRP signature, and the worse clinical outcomes of patients with higher TRP scores were found. The efficiency and accuracy of TRP signature in predicting prognosis were confirmed by ROC curves and five external validation datasets. Our data revealed that the mutation rates of DNMT3A, IDH2, MUC16, and TTN were relatively high. The level of infiltrating immune cell populations, stromal, immune, and ESTIMATE scores increased as the TRP scores increased. Nevertheless, AML patients with lower TRP scores exhibited more tumor purity. The TRP scores were found to be correlated with immunomodulators and immune checkpoints, thus revealing immune characteristics and immunotherapeutic strategies. The IC50 values of six chemotherapeutics were lower in the high TRP score (HTS) group. Finally, it was found that SCHIP1 may be the oncogenic gene. CONCLUSION: The results of this study will help in understanding the role of TRP and SCHIP1 in the prognosis and development of AML.

198. Pasteurella multocida toxin - lessons learned from a mitogenic toxin.

Front Immunol

2022 Dec 16

Kubatzky KF.

The gram-negative, zoonotic bacterium Pasteurella multocida was discovered in 1880 and found to be the causative pathogen of fowl cholera. Pasteurella-related diseases can be found in domestic and wild life animals such as buffalo, sheep, goat, deer and antelope, cats, dogs and tigers and cause hemorrhagic septicemia in cattle, rhinitis or pneumonia in rabbits or fowl cholera in poultry and birds. Pasteurella multocida does not play a major role in the immune-competent human host, but can be found after animal bites or in people with close contact to animals. Toxigenic strains are most commonly found in pigs and express a phage-encoded 146 kDa protein, the Pasteurella multocida toxin (PMT). Toxin-expressing strains cause atrophic rhinitis where nasal turbinate bones are destroyed through the inhibition of bone building osteoblasts and the activation of bone resorbing osteoclasts. After its uptake through receptor-mediated endocytosis, PMT specifically targets the alpha subunit of several heterotrimeric G proteins and constitutively activates them through deamidation of a glutamine residue to glutamate in the alpha subunit. This results in cytoskeletal rearrangement, proliferation, differentiation and survival of cells. Because of the toxin's mitogenic effects, it was suggested that it might have carcinogenic properties, however, no link between Pasteurella infections and cell transformation could be established, neither in tissue culture models nor through epidemiological data. In the recent years it was shown that the toxin not only affects bone, but also the heart as well as basically all cells of innate and adaptive immunity. During the last decade the focus of research shifted from signal transduction processes to understanding how the bacteria might benefit from a bone-destroying toxin. The primary function of PMT seems to be the modulation of immune cell activation which at the same time creates an environment permissive for osteoclast formation. While the disease is restricted to pigs, the implications of the findings from PMT research can be used to explore human diseases and have a high translational potential. In this review our current knowledge will be summarized and it will be discussed what can be learned from using PMT as a tool to understand human pathologies.

199. Detrimental effects of simulated microgravity on mast cell homeostasis and function.

Front Immunol

2022 Dec 16

Kim M, Jang G, Kim KS

200. The microRNA processing subunit DGCR8 is required for a T cell-dependent germinal center response.

Front Immunol

2022 Dec 16

Daum P, Ottmann SR, Meinzinger J

201. Delineating the molecular landscape of different histopathological growth patterns in colorectal cancer liver metastases.

Front Immunol

2022 Dec 16

Hu M, Chen Z, Hu D

202. Behavioral factors to modulate immunotherapy efficacy in cancer.

Front Immunol

2022 Dec 16

Jongerius C, Vermeulen L, van Egmond M

203. Tumor necrosis factor-α-primed mesenchymal stem cell-derived exosomes promote M2 macrophage polarization via Galectin-1 and modify intrauterine adhesion on a novel murine model.

Front Immunol

2022 Dec 16

Li J, Pan Y, Yang J

BACKGROUND: Intrauterine adhesion (IUA) is a condition caused due to damage or infection of the endometrium. It is characterized by continuous inflammation and following fibrosis and dysfunction. However, the current animal IUA models have several disadvantages, including complex operation, high mortality, and many extra distractions owing to opening of the abdominal cavity to expose the uterus. Mesenchymal stem cells (MSCs), which have been used in treatment of IUA, are heterogeneous and immunosuppressive. However, their therapeutic effect is not as good as expected. METHODS: Here, we successfully built a new murine IUA model, called electric tool-scratching IUA model, and applied it in our experiments to investigate the efficacy of tumor necrosis factor-α (TNF-α) primed MSCs (T-MSCs). In the new model, we used a self-made electric tool that can cause mechanical damage to the endometrium without opening the abdominal cavity. ELISA and histological staining analysis were performed to evaluate pathological features of IUA. qRT-PCR, flow cytometry and immunofluoresence staining were performed to detect the phenotypes of macrophages. TMT proteomics quantification and western blotting assay were performed to analyze the differentially expressed proteins of MSC exosomes. RESULTS: Based on the new IUA model, we found TNF-α pretreatment could enhance the ability of MSCs to relieve inflammation and reduce endometrium fibrosis. Mechanistically, T-MSC promoted macrophage polarization to M2 phenotype through exosomes. Subsequently, we found the expression of Galectin-1 was increased in T-MSC exosomes. Finally, we analyzed the gene expression pattern of Galectin-1 treated macrophages and found Galectin-1 promoted macrophage polarization to M2 phenotype mainly through the Jak-STAT signaling pathway. CONCLUSIONS: Our studies proposed an innovative mouse model and a better MSC treatment strategy for IUA.

204. Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein.

Front Immunol

2022 Dec 15

Kuźniewska A, Thiel M, Kowalska D

205. The immunological characteristics of TSPAN1 expressing B cells in autoimmune hepatitis.

Front Immunol

2022 Dec 15

Ou Y, Chen R, Qian Q

206. Prognostic prediction and immune infiltration analysis based on ferroptosis and EMT state in hepatocellular carcinoma.

Front Immunol

2022 Dec 15

Liu Z, Wang J, Li S

BACKGROUND: Ferroptosis is one of the main mechanisms of sorafenib against hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) plays an important role in the heterogeneity, tumor metastasis, immunosuppressive microenvironment, and drug resistance of HCC. However, there are few studies looking into the relationship between ferroptosis and EMT and how they may affect the prognosis of HCC collectively. METHODS: We downloaded gene expression and clinical data of HCC patients from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for prognostic model construction and validation respectively. The Least absolute shrinkage and selection operator (LASSO) Cox regression was used for model construction. The predictive ability of the model was assessed by Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve. We performed the expression profiles analysis to evaluate the ferroptosis and EMT state. CIBERSORT and single-sample Gene Set Enrichment Analysis (ssGSEA) methods were used for immune infiltration analysis. RESULTS: A total of thirteen crucial genes were identified for ferroptosis-related and EMT-related prognostic model (FEPM) stratifying patients into two risk groups. The high-FEPM group had shorter overall survivals than the low-FEPM group (p<0.0001 in the TCGA cohort and p<0.05 in the ICGC cohort). The FEPM score was proved to be an independent prognostic risk factor (HR>1, p<0.01). Furthermore, the expression profiles analysis suggested that the high-FEPM group appeared to have a more suppressive ferroptosis status and a more active EMT status than the low- FEPM group. Immune infiltration analysis showed that the myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were highly enriched in the high-FEPM group. Finally, a nomogram enrolling FEPM score and TNM stage was constructed showing outstanding predictive capacity for the prognosis of patients in the two cohorts. CONCLUSION: In conclusion, we developed a ferroptosis-related and EMT-related prognostic model, which could help predict overall survival for HCC patients. It might provide a new idea for predicting the response to targeted therapies and immunotherapies in HCC patients.

207. Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.

Front Immunol

2022 Dec 15

Lv Z, Cui J, Zhang J.

208. Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2(hi) osteoclast progenitors.

Front Immunol

2022 Dec 15

Filipović M, Flegar D, Aničić S

INTRODUCTION: The existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior. METHODS: In order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation. RESULTS: A disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis. CONCLUSION: Our approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.

209. Cysteine-specific (89)Zr-labeled anti-CD25 IgG allows immuno-PET imaging of interleukin-2 receptor-α on T cell lymphomas.

Front Immunol

2022 Dec 15

Lee JH, Jung KH, Kim M

INTRODUCTION: Positron emission tomography (PET) using radiolabeled Abs as imaging tracer is called immuno-PET. Immuno-PET can verify therapeutic Ab delivery and can noninvasively quantify global levels of target expression in tumors of living subjects. The interleukin-2 receptor α chain (IL-2Rα; CD25) is a promising target for immune therapy and radioimmunotherapy of lymphomas. Immuno-PET could facilitate this approach by visualizing CD25 expression in vivo. METHODS: We prepared 89Zr-anti-CD25 IgG specifically labeled to sulfhydryl moieties by maleimide-deferoxamine conjugation. RESULTS AND DISCUSSION: CD25(+) SUDHL1 human T-cell lymphoma cells showed high anti-human 89Zr-CD25 IgG binding that reached 32-fold of that of CD25(-) human lymphoma cells and was completely blocked by excess unlabeled Ab. In SUDHL1 tumor-bearing nude mice, pharmacokinetic studies demonstrated exponential reductions of whole blood and plasma activity following intravenous 89Zr-anti-CD25 IgG injection, with half-lives of 26.0 and 23.3 h, respectively. SUDHL1 tumor uptake of 89Zr-CD25 IgG was lower per weight in larger tumors, but blood activity did not correlate with tumor size or blood level of human CD25, indicating minimal influence by circulating soluble CD25 protein secreted from the lymphoma cells. 89Zr-CD25 IgG PET allowed high-contrast SUDHL1 lymphoma visualization at five days. Biodistribution studies confirmed high tumor 89Zr-CD25 IgG uptake (8.7 ± 0.9%ID/g) that was greater than blood (5.2 ± 1.6%ID/g) and organ uptakes (0.7 to 3.5%ID/g). Tumor CD25-specific targeting was confirmed by suppression of tumor uptake to 4.3 ± 0.2%ID by excess unlabeled CD25 IgG, as well as by low tumor uptake of 89Zr-labeled IgG2a isotype control Ab (3.6 ± 0.9%ID). Unlike CD25(+) lymphocytes from mouse thymus that showed specific uptake of anti-mouse 89Zr-CD25 IgG, EL4 mouse lymphoma cells had low CD25 expression and showed low uptake. In immunocompetent mice bearing EL4 tumors, anti-mouse 89Zr-CD25 IgG displayed low uptakes in normal organs as well as in the tumor. Furthermore, the biodistribution was not influenced by Ab blocking, indicating that specific uptake in nontumor tissues was minimal. 89Zr-CD25 IgG immuno-PET may thus be useful for imaging of T-cell lymphomas and noninvasive assessment of CD25 expression on target cells in vivo.

210. cGAS in nucleus: The link between immune response and DNA damage repair.

Front Immunol

2022 Dec 15

Song JX, Villagomes D, Zhao H

211. Infiltration of LPAR5(+) macrophages in osteosarcoma tumor microenvironment predicts better outcomes.

Front Immunol

2022 Dec 15

He Y, Zhou H, Huang X

INTRODUCTION: Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. METHODS: Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. RESULTS: Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. CONCLUSION: We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.

212. Can G-quadruplex become a promising target in HBV therapy?

Front Immunol

2022 Dec 15

Teng Y, Zhu M, Chi Y

213. Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations.

Front Immunol

2022 Dec 15

Bonetto V, Pasetto L, Lisi I

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications. METHODS: Blood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection. RESULTS: Blood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels. DISCUSSION: The overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

214. Immune system modulation in aging: Molecular mechanisms and therapeutic targets.

Front Immunol

2022 Dec 15

Cisneros B, García-Aguirre I, Unzueta J

215. The extrinsic factors important to the homeostasis of allergen-specific memory CD4 T cells.

Front Immunol

2022 Dec 15

Choi A, Jung YW, Choi H.

216. Evaluation of dendritic cell-targeting T7 phages as a vehicle to deliver avian influenza virus H5 DNA vaccine in SPF chickens.

Front Immunol

2022 Dec 15

Xu H, Li L, Li R

217. The blood pressure targets in sepsis patients with acute kidney injury: An observational cohort study of multiple ICUs.

Front Immunol

2022 Dec 15

Zhao L, Fan Y, Wang Z

218. Essential immune functions of fibroblasts in innate host defense.

Front Immunol

2022 Dec 15

Cavagnero KJ, Gallo RL.

Front Immunol

2022 Dec 15

Jiang ST, Liu YG, Zhang L

220. Computational analysis to define efficacy & molecular mechanisms of 7, 4'- Dihydroxyflavone on eosinophilic esophagitis: Ex-vivo validation in human esophagus biopsies.

Front Immunol

2022 Dec 15

Maskey AR, Wang ZZ, Chen X

INTRODUCTION: Eosinophilic Esophagitis (EoE) is a chronic condition characterized by eosinophilic inflammation of the esophagus which leads to esophageal dysfunction with common symptoms including vomiting, feeding difficulty, dysphagia, abdominal pain. Current main treatment options of EoE include dietary elimination and swallowed steroids. Diet elimination approach could lead to identifying the trigger food(s), but it often requires repeated upper endoscopy with general anesthesia and potentially could negatively affect nutrition intake and growth of the child and individuals' quality of life. Although the swallowed steroid treatment of effective, the EoE will universally recur after discontinuation of the treatment. Digestive Tea formula (DTF) has been used by the Traditional Chinese Medicine (TCM) practice to improve GI symptoms in EoE patients, including abdominal pain, GE reflux, and abnormal bowel movement. Previously, a flavonoid small molecule compound 7, 4 dihydroxy flavone (DHF) from Glycyrrhiza uralensis in DTF inhibited eotaxin, Th2 cytokine and IgE production in vitro and in vivo. METHOD: This study comprehensively evaluates the potential therapeutic and immunological mechanisms underlying DHF improvement of symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses, in silico molecular docking and dynamic simulation followed by ex-vivo target validation by qRT-PCR using cultured human esophagus biopsy specimen with or without DHF from patients with EoE. RESULTS: Computational analyses defined 29 common targets of DHF on EoE, among which TNF-α, IL-6, IL1β, MAPK1, MAPK3 and AKT1 were most important. Docking analysis and dynamic simulation revealed that DHF directly binds TNF-α with a free binding energy of -7.7 kcal/mol with greater stability and flexibility. Subsequently, in the human esophagus biopsy culture system, significant reduction in levels of TNF-α, IL-6, IL-8 and IL1-β was found in the supernatant of biopsy sample cultured with DHF. Furthermore, the gene expression profile showed significant reduction in levels of TNF-α, IL1-β, IL-6, CCND and MAPK1 in the esophagus biopsy sample cultured with DHF. DISCUSSION: Taken together, the current study provides us an insight into the molecular mechanisms underlying multi-targeted benefits of DHF in the treatment of EoE and paves the way for facilitating more effective EoE therapies.

221. Histone lysine-specific demethylase 1 regulates the proliferation of hemocytes in the oyster Crassostrea gigas.

Front Immunol

2022 Dec 15

Gu X, Qiao X, Yu S

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is an essential epigenetic regulator of hematopoietic differentiation, which can specifically mono-methylate H3K4 (H3K4me1) and di-methylate H3K4 (H3K4me2) as a transcriptional corepressor. Previous reports have been suggested that it participated in hematopoiesis and embryonic development process. Here, a conserved LSD1 (CgLSD1) with a SWIRM domain and an amino oxidase (AO) domain was identified from the Pacific oyster Crassostrea gigas. METHODS: We conducted a comprehensive analysis by various means to verify the function of CgLSD1 in hematopoietic process, including quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, immunofluorescence assay, RNA interference (RNAi) and flow cytometry. RESULTS: The qRT-PCR analysis revealed that the transcripts of CgLSD1 were widely expressed in oyster tissues with the highest level in the mantle. And the transcripts of CgLSD1 were ubiquitously expressed during larval development with the highest expression level at the early D-veliger larvae stage. In hemocytes after Vibrio splendidus stimulation, the transcripts of CgLSD1 were significantly downregulated at 3, 6, 24, and 48 h with the lowest level at 3 h compared to that in the Seawater group (SW group). Immunocytochemical analysis showed that CgLSD1 was mainly distributed in the nucleus of hemocytes. After the CgLSD1 was knocked down by RNAi, the H3K4me1 and H3K4me2 methylation level significantly increased in hemocyte protein. Besides, the percentage of hemocytes with EdU-positive signals in the total circulating hemocytes significantly increased after V. splendidus stimulation. After RNAi of CgLSD1, the expression of potential granulocyte markers CgSOX11 and CgAATase as well as oyster cytokine-like factor CgAstakine were increased significantly in mRNA level, while the transcripts of potential agranulocyte marker CgCD9 was decreased significantly after V. splendidus stimulation. CONCLUSION: The above results demonstrated that CgLSD1 was a conserved member of lysine demethylate enzymes that regulate hemocyte proliferation during the hematopoietic process.

222. Role of macrophage scavenger receptor MSR1 in the progression of non-alcoholic steatohepatitis.

Front Immunol

2022 Dec 15

Sheng W, Ji G, Zhang L.

223. Case report: Durable response after pembrolizumab in combination with radiation - induced abscopal effect in platinum - refractory metastatic endometrial clear cell carcinoma.

Front Immunol

2022 Dec 15

Kao CH, Liu CT, Lin H

224. Methylation changes induced by a glycodendropeptide immunotherapy and associated to tolerance in mice.

Front Immunol

2022 Dec 14

Núñez R, Rodríguez MJ, Lebrón-Martín C

225. Case report: Eculizumab plus obinutuzumab induction in a deceased donor kidney transplant recipient with DEAP-HUS.

Front Immunol

2022 Dec 14

Favi E, Molinari P, Alfieri C

226. Microglial Pten safeguards postnatal integrity of the cortex and sociability.

Front Immunol

2022 Dec 14

Zhou X, Wei J, Li L

227. Assessment of immunotherapy response in intracranial malignancy using semi-automatic segmentation on magnetic resonance images.

Front Immunol

2022 Dec 14

Tan J, Liu C, Li Y

OBJECTIVE: To explore multi-aspect radiologic assessment of immunotherapy response in intracranial malignancies based on a semi-automatic segmentation technique, and to explore volumetric thresholds with good performance according to RECIST 1.1 thresholds. METHODS: Patients diagnosed with intracranial malignancies and treated with immunotherapy were included retrospectively. In all MR images, target lesions were measured using a semi-automatic segmentation technique that could intelligently generate visual diagrams including RECIST 1.1, total volume, and max. 3D diameter. The changes in parameters were calculated for each patient after immunotherapy. The ROC curve was used to analyze the sensitivity and specificity of the size change of the legion. This was useful to find new volumetric thresholds with better efficiency in response assessment. The changes in total volume were assessed by conventional volumetric thresholds, while RECIST 1.1 thresholds were for the max. 3D diameter. A chi-square test was used to compare the concordance and diagnostic correlation between the response assessment results of the three criteria. RESULTS: A total of 20 cases (average age, 58 years; range, 23 to 84 years) and 58 follow-up MR examinations after immunotherapy were included in the analysis. The P-value of the chi-square test between RECIST 1.1 and total volume is 0 (P <0.05), same as that in RECIST 1.1 and max. 3D diameter. The kappa value of the former two was 0.775, and the kappa value for the latter two was 0.742. The above results indicate a significant correlation and good concordance for all three criteria. In addition, we also found that the volumetric assessment had the best sensitivity and specificity for the immunotherapy response in intracranial malignancies, with a PR threshold of -64.9% and a PD threshold of 21.4%. CONCLUSIONS: Radiologic assessment of immunotherapy response in intracranial malignancy can be performed by multiple criteria based on semi-automatic segmentation technique on MR images, such as total volume, max. 3D diameter and RECIST 1.1. In addition, new volumetric thresholds with good sensitivity and specificity were found by volumetric assessment.

228. Fatty acid metabolism is related to the immune microenvironment changes of gastric cancer and RGS2 is a new tumor biomarker.

Front Immunol

2022 Dec 14

Yang S, Sun B, Li W

BACKGROUND: Alterations in lipid metabolism promote tumor progression. However, the role of lipid metabolism in the occurrence and development of gastric cancer have not been fully clarified. METHOD: Here, genes that are related to fatty acid metabolism and differentially-expressed between normal and gastric cancer tissues were identified in the TCGA-STAD cohort. The intersection of identified differentially-expressed genes with Geneset was determined to obtain 78 fatty acid metabolism-related genes. The ConsensusClusterPlus R package was used to perform differentially-expressed genes, which yielded divided two gastric cancer subtypes termed cluster 1 and cluster 2. RESULTS: Patients in cluster 2 was found to display poorer prognosis than patients in cluster 1. Using machine learning method to select 8 differentially expressed genes among subtypes to construct fatty acid prognostic risk score model (FARS), which was found to display good prognostic efficacy. We also identified that certain anticancer drugs, such as bortezomib, elesclomol, GW843682X, and nilotinib, showed significant sensitivity in the high FARS score group. RGS2 was selected as the core gene upon an analysis of the gastric cancer single-cell, and Western blotting and immunofluorescence staining results revealed high level of expression of this gene in gastric cancer cells. The results of immunohistochemical staining showed that a large amount of RGS2 was deposited in the stroma in gastric cancer. A pan-cancer analysis also revealed a significant association of RGS2 with TMB, TIDE, and CD8+ T-cell infiltration in other cancer types as well. RGS2 may thus be studied further as a new target for immunotherapy in future studies on gastric cancer. CONCLUSION: In summary, the FARS model developed here enhances our understanding of lipid metabolism in the TME in gastric cancer, and provides a theoretical basis for predicting tumor prognosis and clinical treatment.

229. Biology and clinical relevance of follicular cytotoxic T cells.

Front Immunol

2022 Dec 14

Lv Y, Ricard L, Gaugler B

230. Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment.

Front Immunol

2022 Dec 14

Balta E, Janzen N, Kirchgessner H

231. T cell repertoire profiling in allografts and native tissues in recipients with COVID-19 after solid organ transplantation: Insight into T cell-mediated allograft protection from viral infection.

Front Immunol

2022 Dec 14

Fu J, Rust D, Fang Z

INTRODUCTION: The effects of the SARS-CoV-2 virus on the body, and why the effects are more severe in certain patients, remain incompletely understood. One population of special interest is transplant recipients because of their immunosuppressed state. Understanding the pathophysiology of graft dysfunction in transplant patients with the COVID-19 viral syndrome is important for prognosticating the risk to the graft as well as understanding how best to prevent and, if necessary, treat graft injury in these patients. METHODS: We analyzed multiple types of solid organ transplant recipients (liver, kidney, heart or lung) at our institution who died from SARS-CoV-2 and underwent autopsy (n = 6) or whose grafts were biopsied during active SARS-CoV-2 infection (n = 8). Their serum inflammatory markers were examined together with the histological appearance, viral load, and TCR repertoire of their graft tissue and, for autopsy patients, several native tissues. RESULTS: Histology and clinical lab results revealed a systemic inflammatory pattern that included elevated inflammatory markers and diffuse tissue damage regardless of graft rejection. Virus was detected throughout all tissues, although most abundant in lungs. The TCR repertoire was broadly similar throughout the tissues of each individual, with greater sharing of dominant clones associated with more rapid disease course. There was no difference in viral load or clonal distribution of overall, COVID-associated, or putative SARS-CoV-2-specific TCRs between allograft and native tissue. We further demonstrated that SARSCoV-2-specific TCR sequences in transplant patients lack a donor HLArestricted pattern, regardless of distribution in allograft or native tissues,suggesting that recognition of viral antigens on infiltrating recipient cells can effectively trigger host T cell anti-viral responses in both the host and graft. DISCUSSION: Our findings suggest a systemic immune response to the SARS-CoV-2 virus in solid organ transplant patients that is not associated with rejection and consistent with a largely destructive effect of recipient HLA-restricted T cell clones that affects donor and native organs similarly.

232. Case report: JAKi and TNFi dual therapy is a potential treatment strategy for difficult-to-treat rheumatoid arthritis.

Front Immunol

2022 Dec 14

Chen JW, Zhang WS, Lin CS

233. Mesangial cell: A hub in lupus nephritis.

Front Immunol

2022 Dec 14

Liu M, Zhang L, Wang Y

234. Efficacy and safety of belimumab for the treatment of refractory childhood-onset systemic lupus erythematosus: A single-center, real-world, retrospective study.

Front Immunol

2022 Dec 14

Wang D, Shan C, Liu J

OBJECTIVE: This study aimed to investigate the efficacy and safety of belimumab for treating children with refractory childhood-onset systemic lupus erythematosus (cSLE). METHODS: Twenty-six cSLE patients who received belimumab treatment in our hospital from January 2020 to September 2021 (23 of them for more than 52 weeks) were enrolled in this study. Their clinical and laboratory data, assessment of disease activity, glucocorticoid dosage, and treatment-emergent adverse events (TEAEs) were retrieved for analysis. The paired samples t-test and the nonparametric test were used to compare the baseline and post-treatment data. RESULTS: The mean age of onset was 10.3 ± 2.4 years old; the mean disease duration was 41.6 ± 37.4 months; the median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 10 (P 25, P 75: 3, 17); and the mean Physician's Global Assessment (PGA) score at baseline was 1.9 ± 1.0. Compared with the baseline values, there was a significant decrease in the 24-h urine protein quantifications at 24 and 52 weeks of treatment (P<0.05) as well as an elevated complement (C) 3 and C4 levels at 4, 12, 24, and 52 weeks of treatment. In addition, the SLEDAI-2K and PGA scores as well as the percentage of CD19+ B cells were significantly decreased at 12, 24, and 52 weeks of treatment compared with the baseline values (P<0.05). The dosage of glucocorticoid at 4, 12, 24, and 52 weeks of treatment was significantly less than that at baseline or the previous follow-up (P<0.05). At 52 weeks, 14 subjects (53.8%) achieved Lupus Low Disease Activity State (LLDAS), and 4 subjects (15.4%) reached clinical remission (CR). At the last follow-up, 16 subjects (61.5%) achieved LLDAS, and 10 subjects (38.5%) reached CR. CONCLUSIONS: Belimumab treatment can significantly improve laboratory indicators, reduce disease activity, and decrease the dosage of glucocorticoid required in children with cSLE. Moreover, it has a good safety profile.

235. Altered serum human cytomegalovirus microRNA levels are common and closely associated with the inflammatory status in patients with fever.

Front Immunol

2022 Dec 14

Wang C, Zhu Y, Chen P

BACKGROUND: Fever has a complicated etiology, and diagnosing its causative factor is clinically challenging. Human cytomegalovirus (HCMV) infection causes various diseases. However, the clinical relevance, prevalence, and significance of HCMV microRNAs (miRNA) in association with fever remain unclear. In the present study, we analyzed the HCMV miRNA expression pattern in the serum of patients with fever and evaluate its clinical associations with occult HCMV infection status in immune disorders. METHODS: We included serum samples from 138 patients with fever and 151 age-gender-matched controls in this study. First, the serum levels of 24 HCMV miRNAs were determined using a hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay in the training set. The markedly altered miRNAs were verified in the validation and testing sets. The serum HCMV IgG/IgM and DNA titers in the testing cohort were also assessed using enzyme-linked immunosorbent assay (ELISA) and RT-qPCR, respectively. RESULTS: The majority of HCMV miRNAs were markedly upregulated in the serum of fever patients. We selected the five most significantly altered HCMV miRNAs: hcmv-miR-US4-3p, hcmv-miR-US29-3p, hcmv-miR-US5-2-3p, hcmv-miR-UL112-3p, and hcmv-miR-US33-3p for validation. These miRNAs were also significantly elevated in the serum of fever patients in the validation and testing sets compared with the controls. Logistic regression analysis revealed that the five miRNAs were novel potential risk factors for fever. Notably, the serum levels of four of the five confirmed HCMV miRNAs were significantly associated with blood C-reaction protein concentrations. Moreover, the five HCMV miRNA levels were closely correlated with the HCMV DNA titers in the testing cohort. CONCLUSION: HCMV infection and activation are common in fever patients and could be novel risk factors for fever. These differentially expressed HCMV miRNAs could enable HCMV activation status monitoring in immune disorders.

236. Editorial: Insights in autoimmune and autoinflammatory disorders: 2021.

Front Immunol

2022 Dec 14

Goldbach-Mansky R, Diamond B.

237. EPC infusion ameliorates acute graft-versus-host disease-related endothelial injury after allogeneic bone marrow transplantation.

Front Immunol

2022 Dec 14

Wang W, Ye Y, Du Y

INTRODUCTION: Graft-versus-host disease (GVHD) damages vascular endothelium. Endothelial progenitor cell (EPC) can differentiate to endothelial cell and promote angiogenesis, but its role in endothelial damage in GVHD is unclear. METHODS: In this study, we intend to assess whether EPC infusion promotes the repair of endothelial injury in GVHD mouse model. Male BALB/c mice were randomly divided into 5 groups: control group, total body irradiation group (TBI group), allogeneic bone marrow transplantation group (Allo-BMT group), acute graft versus host disease group (GVHD group), EPC infusion group (GVHD+EPC group) followed by analysis of mice survival, acute GVHD (aGVHD) score, T cell infiltration by immunofluorescence, as well as continuity of vascular endothelium in liver. RESULTS: Compared with Allo-BMT group, the clinical and pathological score of aGVHD mice were higher. On day 21 after transplantation, a large number of mononuclear cell infiltrations were seen in the target tissues of aGVHD mice and mice died within 30 days. In addition, aGVHD group also presented increased subendothelial infiltration of CD3+ T cells in the liver, decreased VE-cadherin expression and elevated major histocompatibility complex (MHC) II molecule expression in the endothelium. Moreover, expression of MHC-II molecule increased in endothelial cell after irradiation injury and LPS stimulation, indicating abnormally activated endothelial cell with antigen-presenting function. Interestingly, infusion of EPC reduced the clinical and pathological score of aGVHD, decreased infiltration of mononuclear cells, improved survival as well as upregulated VE-cadherin and downregulated MHC-II molecule. DISCUSSION: EPC infusion can mobilize to affected endothelium to decrease the infiltration of T cells and pathological endothelial activation contributing to ameliorating the damage of endothelium. EPC infusion combined with bone marrow transplantation might be a perspective strategy for the prevention and treatment of aGVHD.

238. 3D tumor explant as a novel platform to investigate therapeutic pathways and predictive biomarkers in cancer patients.

Front Immunol

2022 Dec 14

Rodolfo M, Huber V, Cossa M

239. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses.

Front Immunol

2022 Dec 14

Llibre A, Smith N, Rouilly V

240. Increased CEACAM1 expression on peripheral blood neutrophils in patients with rheumatoid arthritis.

Front Immunol

2022 Dec 14

Matsumoto H, Fujita Y, Onizawa M

241. Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU).

Front Immunol

2022 Dec 14

Hosen SMZ, Uddin MN, Xu Z

BACKGROUND: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition. METHODS: This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. RESULTS: Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis. CONCLUSION: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU.

242. New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition.

Front Immunol

2022 Dec 14

Zhang Y, Guo M, Li N

β-glucan is widely used in aquaculture due to its immunostimulatory effects, but the specific effect and potential regulatory mechanism on largemouth bass (Micropterus salmoides) are still unclear. Here, we evaluated the effects of β-glucan on growth, resistance to Aeromonas schubertii, intestinal health, and transcriptome of largemouth bass to reveal the potential regulators, metabolic pathways, and altered differential microbiota. Four experimental diets were designed with β-glucan supplementation levels of 0 (control), 100 (LA-100), 200 (MA-200), and 300 (HA-300) mg kg-1, and each diet was fed to largemouth bass (79.30 ± 0.50 g) in triplicate for 70 days, followed by a 3-day challenge experiment. Results showed that different β-glucan supplementations had no significant effects on growth performance and whole-body composition. Fish fed a diet with 300 mg kg-1 β-glucan significantly increased the activity of lysozyme than those fed diets with 0 and 100 mg kg-1 β-glucan. In addition, the survival rate of largemouth bass in β-glucan supplementation groups was significantly higher than the control group at 12- and 24-h challenge by Aeromonas schubertii. Transcriptome analysis showed that a total of 1,245 genes were differentially expressed [|log2(fold change)| ≥1, q-value ≤0.05], including 109 immune-related differentially expressed genes (DEGs). Further analysis revealed that significantly upregulated and downregulated DEGs associated with immunity were mapped into 12 and 24 pathways, respectively. Results of intestinal microflora indicated that fish fed a diet with 300 mg kg-1 β-glucan had higher bacterial richness and diversity as evaluated by Sobs, Chao, Ace, and Simpson indices, but no significant differences were found in the comparison groups. Furthermore, 300 mg kg-1 β-glucan significantly increased the relative abundance of Mycoplasma and decreased Proteobacteria (mainly Escherichia-Shigella and Escherichia coli) and Bacillus anthracis in largemouth bass intestinal microflora. The findings of this study provided new insights that will be valuable in future studies to elucidate the mechanism of immunity enhancement by β-glucan.

243. Corrigendum: Editorial: Immunological role of the maternal microbiome in pregnancy.

Front Immunol

2022 Dec 14

Di Simone N, Barnea ER, Mueller M.

244. Successful treatment of dupilumab in Kimura disease independent of IgE: A case report with literature review.

Front Immunol

2022 Dec 14

Yang B, Yu H, Jia M

245. Editorial: Host immune response and protective immune responses during filarial infections.

Front Immunol

2022 Dec 13

Ritter M, Hübner MP.

246. High-risk genotypes for type 1 diabetes are associated with the imbalance of gut microbiome and serum metabolites.

Front Immunol

2022 Dec 13

Yue T, Tan H, Wang C

247. Application of B cell immortalization for the isolation of antibodies and B cell clones from vaccine and infection settings.

Front Immunol

2022 Dec 13

Boswell KL, Watkins TA, Cale EM

248. The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications.

Front Immunol

2022 Dec 13

Yue T, Shi Y, Luo S

249. Corrigendum: Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects.

Front Immunol

2022 Dec 13

Huang Y, Zhu M, Liu Z

250. Diagnostic model constructed by nine inflammation-related genes for diagnosing ischemic stroke and reflecting the condition of immune-related cells.

Front Immunol

2022 Dec 13

Ren P, Wang JY, Chen HL

BACKGROUND: Ischemic cerebral infarction is the most common type of stroke with high rates of mortality, disability, and recurrence. However, the known diagnostic biomarkers and therapeutic targets for ischemic stroke (IS) are limited. In the current study, we aimed to identify novel inflammation-related biomarkers for IS using machine learning analysis and to explore their relationship with the levels of immune-related cells in whole blood samples. METHODS: Gene expression profiles of healthy controls and patients with IS were download from the Gene Expression Omnibus. Analysis of differentially expressed genes (DEGs) was performed in healthy controls and patients with IS. Single-sample gene set enrichment analysis was performed to calculate inflammation scores, and weighted gene co-expression network analysis was used to analyze genes in significant modules associated with inflammation scores. Key DEGs in significant modules were then analyzed using LASSO regression analysis for constructing a diagnostic model. The effectiveness and specificity of the diagnostic model was verified in healthy controls and patients with IS and with cerebral hemorrhage (CH) using qRT-PCR. The relationship between diagnostic score and the levels of immune-related cells in whole blood were analyzed using Pearson correlations. RESULTS: A total of 831 DEGs were identified. Both chronic and acute inflammation scores were higher in patients with IS, while 54 DEGs were also clustered in the gene modules associated with chronic and acute inflammation scores. Among them, a total of 9 genes were selected to construct a diagnostic model. Interestingly, RT-qPCR showed that the diagnostic model had better diagnostic value for IS but not for CH. The levels of lymphocytes were lower in blood of patients with IS, while the levels of monocytes and neutrophils were increased. The diagnostic score of the model was negatively associated with the levels of lymphocytes and positively associated with levels of monocytes and neutrophils. CONCLUSIONS: Taken together, the diagnostic model constructed using the inflammation-related genes TNFSF10, ID1, PAQR8, OSR2, PDK4, PEX11B, TNIP1, FFAR2, and JUN exhibited high and specific diagnostic value for IS and reflected the condition of lymphocytes, monocytes, and neutrophils in the blood. The diagnostic model may contribute to the diagnosis of IS.

251. Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer.

Front Immunol

2022 Dec 13

Piening A, Ebert E, Khojandi N

Vaccination against SARS-CoV-2 has been successful in protecting patients with cancer from severe infections, but how immune responses against COVID-19 vaccination interact with those elicited during cancer immunotherapy has not been fully described. Immune checkpoint blockade (ICB) disrupts inhibitory pathways in immune cells to improve function and induce tumor immunity but can often cause serious immune related adverse events (IRAEs). Because COVID-19 vaccination and ICB both boost immune responses, it is imperative to understand if combining these regimens causes synergistic enhancement of the immune system. Specifically, whether ICB impacts anti-vaccine immunity in previously vaccinated patients is important since a large percentage of newly diagnosed cancer patients eligible for immunotherapy will have already been vaccinated against COVID-19. To address this, we investigated the influence of ICB on SARS-CoV-2-spike protein (SP) antibody titers and T cell responses in cancer patients previously vaccinated against COVID-19. Human blood samples were collected from 29 vaccinated patients and 12 unvaccinated control patients at baseline (prior to ICB) and following two rounds of ICB infusion. Anti-SARS-CoV-2-SP IgG titers and T cell responses were quantified. Compared to responses at baseline, there was no significant difference in these immune responses after immunotherapy in vaccinated individuals (P=0.4583, P=0.4571, respectively). We interpret these results as evidence that ICB immunotherapy does not significantly enhance SARS-CoV-2-specific antibody titers or T cell responses. Although our study lacks corresponding IRAE rates, the results provide humoral and cellular immunological data that support recent reports documenting the clinical safety and efficacy of COVID-19 vaccination in patients receiving ICB. Additional longitudinal prospective studies, such as the VOICE study (ClinicalTrials.gov identifier NCT04715438) and CAPTURE study (ClinicalTrials.gov identifier NCT03226886), are warranted and will provide broader safety and immunological data defining the effect of systemic cancer therapies on COVID-19 immunity.

252. Enhanced Spike-specific, but attenuated Nucleocapsid-specific T cell responses upon SARS-CoV-2 breakthrough versus non-breakthrough infections.

Front Immunol

2022 Dec 13

Ahmed MIM, Diepers P, Janke C

253. Editorial: Updates on the role of surfactant proteins A and D in innate immune responses.

Front Immunol

2022 Dec 13

Madan T, Thielens NM.

Front Immunol

2022 Dec 13

Liang Z, Sun R, Tu P

INTRODUCTION: Colorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients. METHODS: To identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan-Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results. RESULTS: The IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan-Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signature. DISCUSSION: Thus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.

255. MYCBP2 expression correlated with inflammatory cell infiltration and prognosis immunotherapy in thyroid cancer patients.

Front Immunol

2022 Dec 13

Wang G, Miao C, Mo L

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have shown promising results for the treatment of multiple cancers. ICIs and related therapies may also be useful for the treatment of thyroid cancer (TC). In TC, Myc binding protein 2 (MYCBP2) is correlated with inflammatory cell infiltration and cancer prognosis. However, the relationship between MYCBP2 expression and ICI efficacy in TC patients is unclear. METHODS: We downloaded data from two TC cohorts, including transcriptomic data and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict the efficacy of ICIs in TC patients. MCPcounter, xCell, and quanTIseq were used to calculate immune cell infiltration scores. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to evaluate signaling pathway scores. Immunohistochemical (IHC) analysis and clinical follow up was used to identify the MYCBP2 protein expression status in patients and associated with clinical outcome. RESULTS: A higher proportion of MYCBP2-high TC patients were predicted ICI responders than MYCBP2-low patients. MYCBP2-high patients also had significantly increased infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients had higher expression of genes associated with B cells, CD8+ T cells, macrophages, plasmacytoid dendritic cells (pDCs), antigen processing and presentation, inflammatory stimulation, and interferon (IFN) responses. GSEA and ssGSEA also showed that MYCBP2-high patients had significantly increased activity of inflammatory factors and signaling pathways associated with immune responses.In addiation, Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy while compared to patients with low MYCBP2 expression after six months clinic follow up. CONCLUSIONS: In this study, we found that MYCBP2 may be a predictive biomarker for ICI efficacy in TC patients. High MYCBP2 expression was associated with significantly enriched immune cell infiltration. MYCBP2 may also be involved in the regulation of signaling pathways associated with anti-tumor immune responses or the production of inflammatory factors.

256. The role of immune cells in modulating chronic inflammation and osteonecrosis.

Front Immunol

2022 Dec 13

Zheng J, Yao Z, Xue L

257. Thrombotic microangiopathy mediates poor prognosis among lupus nephritis via complement lectin and alternative pathway activation.

Front Immunol

2022 Dec 13

Zhang B, Xing G.

258. Maintenance therapy of low-dose nivolumab, S-1, and leucovorin in metastatic pancreatic adenocarcinoma with a germline mutation of MSH6: A case report.

Front Immunol

2022 Dec 13

Peng SH, Chen BB, Kuo TC

259. Editorial: Host immune evasion by Mycobacterium tuberculosis: Current updates.

Front Immunol

2022 Dec 13

Habtamu M, Miheret A, Spurkland A.

260. Erratum: Assessment of plasma Catestatin in COVID-19 reveals a hitherto unknown inflammatory activity with impact on morbidity-mortality.

Front Immunol

2022 Dec 13

Frontiers Production Office.

261. Corrigendum: CD317-Positive Immune Stromal Cells in Human "Mesenchymal Stem Cell" Populations.

Front Immunol

2022 Dec 13

Kay AG, Fox JM, Hewitson JP

262. Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma.

Front Immunol

2022 Dec 13

Li Y, Mo H, Jia S

INTRODUCTION: Metabolic rewiring satisfies increased nutritional demands and modulates many oncogenic processes in tumors. Amino acid metabolism is abnormal in many malignancies. Metabolic reprogramming of amino acids not only plays a crucial role in sustaining tumor cell proliferation but also influences the tumor immune microenvironment. Herein, the aim of our study was to elucidate the metabolic signature of amino acids in hepatocellular carcinoma (HCC). METHODS: Transcriptome profiles of HCC were obtained from the TCGA and ICGC databases. Based on the expression of amino acid metabolism-related genes (AAMRGs), we clustered the HCC samples into two molecular subtypes using the non-negative matrix factorization algorithm. Then, we constructed the amino acid metabolism-related gene signature (AAMRGS) by Cox regression and LASSO regression. Afterward, the clinical significance of the AAMRGS was evaluated. Additionally, we comprehensively analyzed the differences in mutational profiles, immune cell infiltration, immune checkpoint expression, and drug sensitivity between different risk subgroups. Furthermore, we examined three key gene expressions in liver cancer cells by quantitative real-time PCR and conducted the CCK8 assay to evaluate the influence of two chemotherapy drugs on different liver cancer cells. RESULTS: A total of 81 differentially expressed AAMRGs were screened between the two molecular subtypes, and these AAMRGs were involved in regulating amino acid metabolism. The AAMRGS containing GLS, IYD, and NQO1 had a high value for prognosis prediction in HCC patients. Besides this, the two AAMRGS subgroups had different genetic mutation probabilities. More importantly, the immunosuppressive cells were more enriched in the AAMRGS-high group. The expression level of inhibitory immune checkpoints was also higher in patients with high AAMRGS scores. Additionally, the two AAMRGS subgroups showed different susceptibility to chemotherapeutic and targeted drugs. In vitro experiments showed that gemcitabine significantly reduced the proliferative capacity of SNU449 cells, and rapamycin remarkedly inhibited Huh7 proliferation. The five HCC cells displayed different mRNA expression levels of GLS, IYD, and NQO1. CONCLUSIONS: Our study explored the features of amino acid metabolism in HCC and identified the novel AAMRGS to predict the prognosis, immune microenvironment, and drug sensitivity of HCC patients. These findings might help to guide personalized treatment and improve the clinical outcomes of HCC.

263. Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells.

Front Immunol

2022 Dec 13

Davey BC, Pampusch MS, Cartwright EK

T cells expressing a simian immunodeficiency (SIV)-specific chimeric antigen receptor (CAR) and the follicular homing molecule, CXCR5, were infused into antiretroviral therapy (ART) suppressed, SIV-infected rhesus macaques to assess their ability to localize to the lymphoid follicle and control the virus upon ART interruption. While the cells showed evidence of functionality, they failed to persist in the animals beyond 28 days. Development of anti-CAR antibodies could be responsible for the lack of persistence. Potential antigenic sites on the anti-SIV CAR used in these studies included domains 1 and 2 of CD4, the carbohydrate recognition domain (CRD) of mannose-binding lectin (MBL), and an extracellular domain of the costimulatory molecule, CD28, along with short linker sequences. Using a flow cytometry based assay and target cells expressing the CAR/CXCR5 construct, we examined the serum of the CD4-MBL CAR/CXCR5-T cell treated animals to determine that the animals had developed an anti-CAR antibody response after infusion. Binding sites for the anti-CAR antibodies were identified by using alternative CARs transduced into target cells and by preincubation of the target cells with a CD4 blocking antibody. All of the treated animals developed antibodies in their serum that bound to CD4-MBL CAR/CXCR5 T cells and the majority were capable of inducing an ADCC response. The CD4 antibody-blocking assay suggests that the dominant immunogenic components of this CAR are the CD4 domains with a possible additional site of the CD28 domain with its linker. This study shows that an anti-drug antibody (ADA) response can occur even when using self-proteins, likely due to novel epitopes created by abridged self-proteins and/or the self-domain of the CAR connection to a small non-self linker. While in our study, there was no statistically significant correlation between the ADA response and the persistence of the CD4-MBL CAR/CXCR5-T cells in rhesus macaques, these findings suggest that the development of an ADA response could impact the long-term persistence of self-based CAR immunotherapies.

264. Immune-mediated inflammatory diseases and risk of venous thromboembolism: A Mendelian randomization study.

Front Immunol

2022 Dec 13

Lv X, Gao X, Liu J

265. Novel potential biomarkers for severe alcoholic liver disease.

Front Immunol

2022 Dec 13

Huang J, Yu J, Wang J

BACKGROUND: Alcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring. METHODS: Label-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers. RESULTS: A total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target. CONCLUSION: This proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.

266. Longevity of memory B cells and antibodies, as well as the polarization of effector memory helper T cells, are associated with disease severity in patients with COVID-19 in Bangladesh.

Front Immunol

2022 Dec 12

Akhtar M, Basher SR, Nizam NN

The longevity of immune responses induced by different degrees of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provides information important to understanding protection against coronavirus disease 2019 (COVID-19). Here, we report the persistence of SARS-CoV-2 spike receptor-binding domain (RBD) specific antibodies and memory B cells recognizing this antigen in sequential samples from patients in Bangladesh with asymptomatic, mild, moderate and severe COVID-19 out to six months following infection. Since the development of long-lived memory B cells, as well as antibody production, is likely to be dependent on T helper (Th) cells, we also investigated the phenotypic changes of Th cells in COVID-19 patients over time following infection. Our results show that patients with moderate to severe COVID-19 mounted significant levels of IgG antibodies out to six months following infection, while patients with asymptomatic or mild disease had significant levels of IgG antibodies out to 3 months following infection, but these then fell more rapidly at 6 months than in patients with higher disease severity. Patients from all severity groups developed circulating memory B cells (MBCs) specific to SARS-CoV-2 spike RBD by 3 months following infection, and these persisted until the last timepoint measured at 6 months. A T helper cell response with an effector memory phenotype was observed following infection in all symptomatic patients, while patients with asymptomatic infection had no significant increases in effector Th1, Th2 and Th17 effector memory cell responses. Our results suggest that the strength and magnitude of antibody and memory B cells induced following SARS-CoV-2 infection depend on the severity of the disease. Polarization of the Th cell response, with an increase in Th effector memory cells, occurs in symptomatic patients by day 7 following infection, with increases seen in Th1, Th2, Th17 and follicular helper T cell subsets.

267. Basophils from allergy to cancer.

Front Immunol

2022 Dec 12

Poto R, Gambardella AR, Marone G

268. The intragraft vascularized bone marrow induces secondary donor-specific mystacial pad allograft tolerance.

Front Immunol

2022 Dec 12

Lin CH, Anggelia MR, Cheng HY

269. Inhibition of the different complement pathways has varying impacts on the serum bactericidal activity and opsonophagocytosis against Haemophilus influenzae type b.

Front Immunol

2022 Dec 12

Muri L, Schubart A, Thorburn C

Defense against Haemophilus influenzae type b (Hib) is dependent on antibodies and complement, which mediate both serum bactericidal activity (SBA) and opsonophagocytosis. Here we evaluated the influence of capsule-specific antibodies and complement inhibitors targeting the central component C3, the alternative pathway (AP; fB, fD), the lectin pathway (LP; MASP-2) and the terminal pathway (C5) on both effector functions. Findings may be relevant for the treatment of certain diseases caused by dysregulation of the complement system, where inhibitors of complement factors C3 or C5 are used. Inhibitors against other complement components are being evaluated as potential alternative treatment options that may carry a reduced risk of infection by encapsulated bacteria. Serum and reconstituted blood of healthy adults were tested for bactericidal activity before and after vaccination with the Hib capsule-conjugate vaccine ActHIB. Most sera had bactericidal activity prior to vaccination, but vaccination significantly enhanced SBA titers. Independently of the vaccination status, both C3 and C5 inhibition abrogated SBA, whereas inhibition of the LP had no effect. AP inhibition had a major inhibitory effect on SBA of pre- vaccination serum, but vaccination mitigated this inhibition for all disease isolates tested. Despite this, SBA-mediated killing of some Hib isolates remained retarded. Even for the most serum-resistant isolate, SBA was the dominating defense mechanism in reconstituted whole blood, as addition of blood cells to the serum did not enhance bacterial killing. Limited Fc receptor-mediated opsonophagocytosis was unmasked when bacterial killing by the membrane attack complex was blocked. In the presence of C3 or C5 inhibitors, addition of post-vaccination, but not of pre-vaccination serum to the blood cells triggered opsonophagocytosis, leading to suppression of bacterial multiplication. Taken together, our data indicate that for host defense against Hib, killing by SBA is more efficient than by blood cell opsonophagocytosis. However, additional defense mechanisms, such as bacterial clearance by spleen and liver, may play an important role in preventing Hib-mediated sepsis, in particular for Hib isolates with increased serum-resistance. Results indicate potentially improved safety profile of AP inhibitors over C3 and C5 inhibitors as alternative therapeutic agents in patients with increased susceptibility to Hib infection.

270. Potentiating pneumococcal glycoconjugate vaccine PCV13 with saponin adjuvant VSA-1.

Front Immunol

2022 Dec 12

Kim H, Yu J, Bai D

271. Circulating monocytes in acute pancreatitis.

Front Immunol

2022 Dec 12

Liu S, Szatmary P, Lin JW

272. Innate immune function during antineoplastic treatment is associated with 12-months survival in non-small cell lung cancer.

Front Immunol

2022 Dec 12

Ryssel H, Egebjerg K, Nielsen SD

273. Mendelian randomization study reveals a causal relationship between rheumatoid arthritis and risk for pre-eclampsia.

Front Immunol

2022 Dec 12

Zhang D, Hu Y, Guo W

274. Machine learning-based predictive and risk analysis using real-world data with blood biomarkers for hepatitis B patients in the malignant progression of hepatocellular carcinoma.

Front Immunol

2022 Dec 12

Nan Y, Zhao S, Zhang X

275. Serological, fragmentomic, and epigenetic characteristics of cell-free DNA in patients with lupus nephritis.

Front Immunol

2022 Dec 12

Wang F, Miao HB, Pei ZH

276. Using mass cytometry for the analysis of samples of the human airways.

Front Immunol

2022 Dec 12

Rocha-Hasler M, Müller L, Wagner A

277. Derivation and external validation of dendritic cell-related gene signatures for predicting prognosis and immunotherapy efficacy in bladder urothelial carcinoma.

Front Immunol

2022 Dec 12

An B, Guo Z, Wang J

278. Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression.

Front Immunol

2022 Dec 12

Dong S, Li W, Li X

279. Chikungunya patient transcriptional signatures faithfully recapitulated in a C57BL/6J mouse model.

Front Immunol

2022 Dec 12

Bishop CR, Caten FT, Nakaya HI

280. Development and validation of the prognostic model based on autophagy-associated genes in idiopathic pulmonary fibrosis.

Front Immunol

2022 Dec 12

Fan G, Liu J, Wu Z

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. Many studies suggest that autophagy may be related to disease progression and prognosis in IPF. However, the mechanisms involved have not been fully elucidated. METHODS: We incorporated 232 autophagy-associated genes (AAGs) and two datasets, GSE28042 and GSE27957, from the GEO database. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression were used to construct the autophagy-associated prognostic model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of these autophagy-associated genes. CIBERSORT algorithm was used to calculate the immune cell infiltration between patients in the high-risk score and low-risk score groups. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to explore the mRNA expression of five genes in the autophagy-associated risk model. RESULTS: We constructed a 5-autophagy-associated genes signature based on Univariate Cox analysis and LASSO regression. In our autophagy-associated risk model, IPF patients in the high-risk group demonstrated a poor overall survival rate compared to patients in the low-risk group. For 1-, 2-, and 3-year survival rates, the AUC predictive value of the AAG signature was 0.670, 0.787, and 0.864, respectively. These results were validated in the GSE27957 cohort, confirming the good prognostic effect of our model. GO and KEGG pathway analyses enriched immune-related pathways between the high-risk and low-risk groups. And there was also a significant difference in immune cell infiltration between two groups. And the results of qRT-PCR showed that the expression levels of FOXO1, IRGM, MYC, and PRKCQ were significantly decreased in the Peripheral Blood Mononuclear Cell (PBMC) of IPF patient samples. CONCLUSION: Our study constructed and validated an autophagy-associated risk model based on MYC, MAPK1, IRGM, PRKCQ, and FOXO1. And those five genes may influence the progression of IPF by regulating immune responses and immune cells.

281. SOX chemotherapy with anti-PD-1 and iNKT cell immunotherapies for stage IV gastric adenocarcinoma with liver metastases: A case report.

Front Immunol

2022 Dec 12

Li D, Liu M, Wang J

Gastric cancer (GC) is the fourth most common cancer worldwide, with overall 5-year survival rate of approximate 20%. Although multimodal treatments that combine surgery with chemotherapy and immunotherapy have been shown to improve survival, pathological complete response (pCR) is rare in advanced GC patients with liver metastases. Pre-clinical studies and clinical trials have demonstrated the antitumor efficacy of invariant natural killer T (iNKT) cells in various malignancies, including GC. While multimodal therapy comprised of chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy have not been reported in GC patients. This case report describes the treatment of an early 60s patient diagnosed with advanced stage IVB (T1N1M1) adenocarcinomas of gastric cardia with liver metastases who received multimodal therapy comprised of SOX chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy followed by surgical resection. Dramatic decreases in tumor area were observed in both the primary tumor and metastatic lesions following six cycles of SOX chemotherapy and iNKT cell immunotherapy, and four cycles of anti-PD-1 therapy. This combined treatment resulted in the transformation of a remarkably large, unresectable liver metastases into a resectable tumor, and the patient received total gastrectomy with D2 lymph node dissection and liver metastasectomy. Subsequent pathological examination detected no cancer cells in either the primary site or liver metastatic lesions, supporting the likelihood that this treatment achieved pCR. To our knowledge, this report represents the first case of a metastatic gastric cancer patient displaying pCR after six months of multimodal therapy, thus supporting that a SOX chemotherapy, anti-PD-1 therapy, and iNKT cell immunotherapy combination strategy may be effective for treating, and potentially curing, patients with advanced gastric adenocarcinoma.

282. Comprehensive assessment of SARS-CoV-2 antibodies against various antigenic epitopes after naive COVID-19 infection and vaccination (BNT162b2 or ChAdOx1 nCoV-19).

Front Immunol

2022 Dec 12

Lee J, Lee DG, Jung J

283. Prevalence of parent-reported food allergy among children in China: A population-based cross-sectional survey.

Front Immunol

2022 Dec 12

Feng H, Luo N, Lu Y

OBJECTIVE: The prevalence of food allergy (FA) has been increasing in recent years and has become an important public health, food safety, and clinical nutrition problem. However, population-based studies on the prevalence of FA are very limited in China. This study aims to determine the prevalence and pattern of parent-reported FA among school children in Jiangxi Province, China. METHODS: A multicenter cross-sectional study on FA was conducted on primary school children aged 6-11 years old using random cluster sampling with a questionnaire survey. Parent-reported FA was used and defined as individual-reported FA by parent or guardian through a questionnaire in this study. RESULT: Among the total of 8,856 (96.36%) complete questionnaires received, 727 (8.2%) children had adverse reactions to food (ARF). The prevalence rates of parent-reported FA and doctor-diagnosed FA were 6.2% and 3.3%, respectively. Animal-derived foods were the main causative source of FA, and the three leading allergenic foods were shrimp, mango, and mollusks. Skin reactions were the most common clinical manifestations of FA, accounting for 63.7%, and 45.32% of the subjects with parent-reported FA experienced severe allergic reactions. There was a significant difference in parent-reported FA between different survey centers, and FA risk increased significantly in children with other allergic diseases (P<0.001) and small family size (P=0.026). The FA prevalence was significantly higher among children aged 8-11 years than those aged 6-7 years (P=0.020). CONCLUSIONS: A high prevalence of parent-reported FA was observed among children in general primary schools in Jiangxi Province, China. Shrimp, mango, and mollusks were the most common causative foods. The main common symptoms of FA were adverse reactions relating to the skin system. The rate of severe allergic reactions was also high in Jiangxi Children with reported FA. Local standards and policies for the prevention and management of FA need to be adjusted on a timely basis according to actual local conditions.

284. Fc receptor engagement of HIV-1 Env-specific antibodies in mothers and infants predicts reduced vertical transmission.

Front Immunol

2022 Dec 12

Barrows BM, Krebs SJ, Jian N

285. Identification of renal ischemia reperfusion injury subtypes and predictive strategies for delayed graft function and graft survival based on neutrophil extracellular trap-related genes.

Front Immunol

2022 Dec 1

Wu J, Zhang F, Zheng X

BACKGROUND: Ischemia reperfusion injury (IRI) is an inevitable process in renal transplantation, which is closely related to serious postoperative complications such as delayed graft function (DGF), acute rejection and graft failure. Neutrophil extracellular traps (NETs) are extracellular DNA structures decorated with various protein substances released by neutrophils under strong signal stimulation. Recently, NETs have been found to play an important role in the process of IRI. This study aimed to comprehensively analyze the expression landscape of NET-related genes (NRGs) during IRI, identify clusters with different degrees of IRI and construct robust DGF and long-term graft survival predictive strategies. METHODS: The microarray and RNA-seq datasets were obtained from the GEO database. Differentially expressed NRGs (DE-NRGs) were identified by the differential expression analysis, and the NMF algorithm was used to conduct a cluster analysis of IRI samples. Machine learning algorithms were performed to screen DGF-related hub NRGs, and DGF and long-term graft survival predictive strategies were constructed based on these hub NRGs. Finally, we verified the expression of Cxcl1 and its effect on IRI and NETs generation in the mouse IRI model. RESULTS: This study revealed two IRI clusters (C1 and C2 clusters) with different molecular features and clinical characteristics. Cluster C1 was characterized by active metabolism, mild inflammation and lower incidence of DGF, while Cluster C2 was inflammation activated subtype with a higher incidence of DGF. Besides, based on DGF-related hub NRGs, we successfully constructed robust DGF and long-term graft survival predictive strategies. The mouse renal IRI model verified that Cxcl1 was significantly upregulated in renal tissues after IRI, and using a CXCL8/CXCL1 inhibitor could significantly improve renal function, alleviate renal tubular necrosis, tissue inflammatory response, and NET formation. CONCLUSION: This study identified two distinct IRI clusters based on DE-NRGs and constructed robust prediction methods for DGF and graft survival, which can provide references for early prevention and individualized treatment of various postoperative complications after renal transplantation.

286. Rapid response in relapsed follicular lymphoma with massive chylous ascites to anti-CD19 CAR T therapy using Piggy Bac: A case report.

Front Immunol

2022 Dec 1

Zhang Y, Lin Z, Zhang F

287. Integrated analysis from multi-center studies identities m7G-derived modification pattern and risk stratification system in skin cutaneous melanoma.

Front Immunol

2022 Dec 1

Zhang X, Miao Y, Sun HW

288. COVID-19 vaccination and Atypical hemolytic uremic syndrome.

Front Immunol

2022 Dec 1

Bouwmeester RN, Bormans EMG, Duineveld C

289. Interferon and interferon-stimulated genes in HBV treatment.

Front Immunol

2022 Dec 1

Li Q, Sun B, Zhuo Y

290. Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6(+) natural killer T cells.

Front Immunol

2022 Dec 1

Li T, Lin X, Shen B

291. Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan.

Front Immunol

2022 Dec 1

Fattizzo B, Versino F, Zaninoni A

292. Radiotherapy induced immunogenic cell death by remodeling tumor immune microenvironment.

Front Immunol

2022 Dec 1

Zhu S, Wang Y, Tang J

293. Assessment of a diverse panel of transmitted/founder HIV-1 infectious molecular clones in a luciferase based CD8 T-cell mediated viral inhibition assay.

Front Immunol

2022 Dec 1

Fernandez N, Hayes P, Makinde J

294. Multiple sclerosis-disease modifying therapies affect humoral and T-cell response to mRNA COVID-19 vaccine.

Front Immunol

2022 Dec 1

Dominelli F, Zingaropoli MA, Tartaglia M

BACKGROUND: The mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination. METHODS: The aim of the study was to evaluate humoral and specific T-cell response, as well as B-cell activation and survival factors, in people with MS (pwMS) under DMTs before (T0) and after two months (T1) from the third dose of vaccine, comparing the obtained findings to healthy donors (HD). All possible combinations of intracellular IFNγ, IL2 and TNFα T-cell production were evaluated, and T-cells were labelled "responding T-cells", those cells that produced at least one of the three cytokines of interest, and "triple positive T-cells", those cells that produced simultaneously all the three cytokines. RESULTS: The cross-sectional evaluation showed no significant differences in anti-S antibody titers between pwMS and HD at both time-points. In pwMS, lower percentages of responding T-cells at T0 (CD4: p=0.0165; CD8: p=0.0022) and triple positive T-cells at both time-points compared to HD were observed (at T0, CD4: p=0.0007 and CD8: p=0.0703; at T1, CD4: p=0.0422 and CD8: p=0.0535). At T0, pwMS showed higher plasma levels of APRIL, BAFF and CD40L compared to HD (p<0.0001, p<0.0001 and p<0.0001, respectively) and at T1, plasma levels of BAFF were still higher in pwMS compared to HD (p=0.0022).According to DMTs, at both T0 and T1, lower anti-S antibody titers in the depleting/sequestering-out compared to the enriching-in pwMS subgroup were found (p=0.0410 and p=0.0047, respectively) as well as lower percentages of responding CD4+ T-cells (CD4: p=0.0394 and p=0.0004, respectively). Moreover, the depleting/sequestering-out subgroup showed higher percentages of IFNγ-IL2-TNFα+ T-cells at both time-points, compared to the enriching-in subgroup in which a more heterogeneous cytokine profile was observed (at T0 CD4: p=0.0187; at T0 and T1 CD8: p =0.0007 and p =0.0077, respectively). CONCLUSION: In pwMS, humoral and T-cell response to vaccination seems to be influenced by the different DMTs. pwMS under depleting/sequestering-out treatment can mount cellular responses even in the presence of a low positive humoral response, although the cellular response seems qualitatively inferior compared to HD. An understanding of T-cell quality dynamic is needed to determine the best vaccination strategy and in general the capability of immune response in pwMS under different DMT.

295. The CARDS toxin of Mycoplasma pneumoniae induces a positive feedback loop of type 1 immune response.

Front Immunol

2022 Dec 1

Wang T, Sun H, Lu Z

BACKGROUND: Within the past 3-5 years, Mycoplasma pneumoniae has become a major pathogen of community-acquired pneumonia in children. The pathogenic mechanisms involved in M. pneumoniae infection have not been fully elucidated. METHODS: Previous protein microarray studies have shown a differential expression of CXCL9 after M. pneumoniae infection. Here, we conducted a hospital-based study to explore the clinical significance of the type 1 immune response inflammatory factors interferon (IFN)-γ and CXCL9 in patients with M. pneumoniae pneumonia (MPP). Then, through in vitro experiments, we explored whether CARDS toxin stimulated F-DCs (dendritic cells incubated with Flt3L) to promote Th-cell differentiation; we also investigated the IFN-γ-induced CXCL9 secretion pathway in macrophages and the role of CXCL9 in promoting Th1 cell migration. RESULTS: The CXCL9 expression level was upregulated among patients with a higher fever peak, fever duration of greater than 7 days, an imaging manifestation of lobar or segmental, or combined pleural effusion (P<0.05). The peripheral blood levels of IFN-γ and CXCL9, which were higher in patients than in the healthy control group, were positively correlated with each other (r=0.502, P<0.05). In patients, the CXCL9 expression level was significantly higher in the bronchoalveolar lavage fluid (BALF) than in the peripheral blood, and the BALF CXCL9 expression level was higher than that in the healthy control group (all P<0.05). Our flow cytometry analysis revealed that M1-phenotype macrophages (CD16 + CD64 + CD163-) were predominant in the BALF from children with MPP. In in vitro experiments, F-DCs stimulated with CARDS toxin promoted the differentiation of CD4 + IFN-γ + Th (Th1) cells (P<0.05). Moreover, IFN-γ induced high levels of CXCL9 expression in M1-type macrophages in a dose-dependent and time-dependent manner. Additionally, macrophages transfection with STAT1-siRNA-1 downregulated the expression of CXCL9 (P<0.05), and CXCL9 promoted Th1 cell migration (P<0.05). CONCLUSIONS: Our findings suggest that CARDS toxin induces a type 1 immune response positive feedback loop during M. pneumoniae infection; this putative mechanism may be useful in future investigations of immune intervention approaches for M. pneumoniae pneumonia.

296. STXBP3 and GOT2 predict immunological activity in acute allograft rejection.

Front Immunol

2022 Dec 1

Yao Q, Wang C, Wang Y

297. Near-infrared upconversion multimodal nanoparticles for targeted radionuclide therapy of breast cancer lymphatic metastases.

Front Immunol

2022 Dec 1

Zhang C, Zhang Y, Liang M

298. Prognostic model of immune checkpoint inhibitors combined with anti-angiogenic agents in unresectable hepatocellular carcinoma.

Front Immunol

2022 Dec 1

Li X, Sun W, Ding X

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents has shown promising efficacy in unresectable hepatocellular carcinoma (HCC), but until now no clinical prognostic models or predictive biomarkers have been established. METHODS: From 2016 to 2021, a total of 258 HCCs treated with ICIs and tyrosine kinase inhibitors (TKIs) were retrospectively enrolled, as the study cohort. Patients' baseline data was extracted by least absolute and shrinkage selection operator (LASSO) and Cox regression. Finally, a prognostic model in the form of nomogram was developed. Model performance was assessed in terms of discrimination, calibration, and clinical utility. A 5-fold cross-validation was used to evaluate the internal repeatability of the model. In addition, the patient cohort was divided into three subgroups according to nomogram scores. Their survivals were estimated by Kaplan-Meier methods and the differences were analyzed using log-rank tests. RESULTS: Seven clinical parameters were selected: Eastern Cooperative Oncology Group performance status (ECOG PS), combination of transarterial chemoembolization (TACE), extrahepatic metastasis (EHM), platelet to lymphocyte ratio (PLR), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and Child-Pugh score. The model had an area under the curve (AUC) of 0.777 at 1 year and 0.772 at 2 years. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) showed that the discrimination, consistency and applicability of the model were good. In addition, cross-validation validated the discrimination of the model, and the C index value of the model is 0.7405. The median overall survival (OS) of the high-, medium- and low-risk subgroups was 7.58, 17.50 and 53.17 months, respectively, with a significant difference between the groups (P < 0.0001). CONCLUSION: We developed a comprehensive and simple prognostic model for the combination of ICIs plus TKIs. And it may predict the efficacy of the combination regimen for unresectable HCC.

299. SARS-CoV-2 infection of phagocytic immune cells and COVID-19 pathology: Antibody-dependent as well as independent cell entry.

Front Immunol

2022 Dec 1

Matveeva O, Nechipurenko Y, Lagutkin D

300. Alternative pre-mRNA splicing as a mechanism for terminating Toll-like Receptor signaling.

Front Immunol

2022 Dec 1

Lee FFY, Alper S.

301. High-dimensional intravital microscopy reveals major changes in splenic immune system during postnatal development.

Front Immunol

2022 Dec 1

Porto-Pedrosa MLM, de Miranda CDM, Lopes ME

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Newmer生物