生信网-文献期刊

Front Immunol

2022 Oct 7

Murphy AJ, Kelschenbach J, He H

2. Identifying a lactic acid metabolism-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

Front Immunol

2022 Oct 7

Zhao F, Wang Z, Li Z

3. A necroptosis related prognostic model of pancreatic cancer based on single cell sequencing analysis and transcriptome analysis.

Front Immunol

2022 Oct 7

Chen L, Zhang X, Zhang Q

BACKGROUND: As a tumor type with high mortality and poor therapeutic effect, the pathogenesis of pancreatic cancer is still unclear. It is necessary to explore the significance of necroptosis in pancreatic cancer. METHODS: Pancreatic cancer transcriptome data were obtained from the TCGA database, ICGC database, and GSE85916 in the GEO database. The TCGA cohort was set as a training cohort, while the ICGC and GSE85916 cohort were set as the validation cohorts. Single-cell sequencing data of pancreatic cancer were obtained from GSE154778 in the GEO database. The genes most associated with necroptosis were identified by weighted co-expression network analysis and single-cell sequencing analysis. COX regression and Lasso regression were performed for these genes, and the prognostic model was established. By calculating risk scores, pancreatic cancer patients could be divided into NCPTS_high and NCPTS_low groups, and survival analysis, immune infiltration analysis, and mutation analysis between groups were performed. Cell experiments including gene knockdown, CCK-8 assay, clone formation assay, transwell assay and wound healing assay were conducted to explore the role of the key gene EPS8 in pancreatic cancer. PCR assays on clinical samples were further used to verify EPS8 expression. RESULTS: We constructed the necroptosis-related signature in pancreatic cancer using single-cell sequencing analysis and transcriptome analysis. The calculation formula of risk score was as follows: NCPTS = POLR3GL * (-0.404) + COL17A1 * (0.092) + DDIT4 * (0.007) + PDE4C * (0.057) + CLDN1 * 0.075 + HMGA2 * 0.056 + CENPF * 0.198 +EPS8 * 0.219. Through this signature, pancreatic cancer patients with different cohorts can be divided into NCPTS_high and NCPTS_low group, and the NCPTS_high group has a significantly poorer prognosis. Moreover, there were significant differences in immune infiltration level and mutation level between the two groups. Cell assays showed that in CAPAN-1 and PANC-1 cell lines, EPS8 knockdown significantly reduced the viability, clonogenesis, migration and invasion of pancreatic cancer cells. Clinical PCR assay of EPS8 expression showed that EPS8 expression was significantly up-regulated in pancreatic cancer (*P<0.05). CONCLUSION: Our study can provide a reference for the diagnosis, treatment and prognosis assessment of pancreatic cancer.

4. Effects of dietary Clostridium autoethanogenum protein on the growth, disease resistance, intestinal digestion, immunity and microbiota structure of Litopenaeus vannamei reared at different water salinities.

Front Immunol

2022 Oct 7

Chen J, Wang H, Yuan H

The shortage of fishmeal (FM) resources limits the healthy development of aquaculture. Developing new protein sources to replace FM in aquatic feeds is an effective measure to alleviate this situation. However, the application effect of new protein sources is greatly affected by water salinity, which is an important parameter of aquaculture. In this study, the growth, disease resistance, and intestinal digestion, immunity, and microbiota structure of Litopenaeus vannamei (initial weight: 0.38 ± 0.01 g) fed on Clostridium autoethanogenum protein (CAP) or not at three different water salinities (15 ‰, 30 ‰, and 45 ‰) were compared, aiming to explore the effects of dietary CAP on shrimp when suffering different salinity stresses. The results showed that the growth performance, feed utilization, and survival rate (SR) after pathogen challenge of L. vannamei could be significantly improved by dietary CAP when compared with the control at the same salinity and they were also significantly affected by salinity changes when L. vannamei was fed on the same protein source. With the increase in salinity, obvious upregulation was observed in the activities and gene expression of digestive enzymes both in L. vannamei fed on FM and CAP, with significantly higher levels in L. vannamei fed on CAP than in those fed on FM at the same salinity. Meanwhile, the expression levels of immune genes in the CAP group were significantly higher than those in the FM group at different salinities. The intestinal microbiota analysis showed that CAP could increase the relative abundance of beneficial bacteria and decrease the relative abundance of harmful bacteria in the intestine of L. vannamei at the phylum, family, and genus levels, and it was more affected by salinity changes when compared with FM. Besides, the changes in salinity and protein sources led to different changes in the intestinal microflora function of L. vannamei. In sum, this study indicated that CAP could improve the growth, disease resistance, digestive capacity, and intestinal microflora of L. vannamei with a much more intense immune response and enhance its ability to cope with salinity stress.

5. Postoperative neutrophil-lymphocyte ratio predicts unfavorable outcome of acute ischemic stroke patients who achieve complete reperfusion after thrombectomy.

Front Immunol

2022 Oct 7

Feng Y, Bai X, Li W

6. Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma.

Front Immunol

2022 Oct 7

Lin L, Lin G, Lin H

BACKGROUND: DERL3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, the correlation of DERL3 expression with the malignant phenotype of lung adenocarcinoma (LUAD) cells is unclear and remains to be elucidated. Herein, we investigated the interaction between the DERL3 and LUAD pathological process. METHODS: The Cancer Genome Atlas (TCGA) database was utilized to determine the genetic alteration of DERL3 in stage I LUAD. Clinical LUAD samples including carcinoma and adjacent tissues were obtained and were further extracted to detect DERL3 mRNA expression via RT-qPCR. Immunohistochemistry was performed to evaluate the protein expression of DERL3 in LUAD tissues. The GEPIA and TIMER website were used to evaluate the correlation between DERL3 and immune cell infiltration. We further used the t-SNE map to visualize the distribution of DERL3 in various clusters at the single-cell level via TISCH database. The potential mechanisms of the biological process mediated by DERL3 in LUAD were conducted via KEGG and GSEA. RESULTS: It was indicated that DERL3 was predominantly elevated in carcinoma compared with adjacent tissues in multiple kinds of tumors from the TCGA database, especially in LUAD. Immunohistochemistry validated that DERL3 was also upregulated in LUAD tissues compared with adjacent tissues from individuals. DERL3 was preliminarily found to be associated with immune infiltration via the TIMER database. Further, the t-SNE map revealed that DERL3 was predominantly enriched in plasma cells of the B cell population. It was demonstrated that DERL3 high-expressed patients presented significantly worse response to chemotherapy and immunotherapy. GSEA and KEGG results indicated that DERL3 was positively correlated with B cell activation and unfolded protein response (UPR). CONCLUSION: Our findings indicated that DERL3 might play an essential role in the endoplasmic reticulum-associated degradation (ERAD) process in LUAD. Moreover, DERL3 may act as a promising immune biomarker, which could predict the efficacy of immunotherapy in LUAD.

7. Resolvin D1 shows osseous-protection via RANK reduction on monocytes during orthodontic tooth movement.

Front Immunol

2022 Oct 7

Klein Y, Levin-Talmor O, Berkstein JG

8. Two novel mollusk short-form ApeC-containing proteins act as pattern recognition proteins for peptidoglycan.

Front Immunol

2022 Oct 7

Li J, Liu S, Zhang Y

The Apextrin C-terminal (ApeC) domain is a new protein domain largely specific to aquatic invertebrates. In amphioxus, a short-form ApeC-containing protein (ACP) family is capable of binding peptidoglycan (PGN) and agglutinating bacteria via its ApeC domain. However, the functions of ApeC in other phyla remain unknown. Here we examined 130 ACPs from gastropods and bivalves, the first and second biggest mollusk classes. They were classified into nine groups based on their phylogenetics and architectures, including three groups of short-form ACPs, one group of apextrins and two groups of ACPs of complex architectures. No groups have orthologs in other phyla and only four groups have members in both gastropods and bivalves, suggesting that mollusk ACPs are highly diversified. We selected one bivalve ACP (CgACP1; from the oyster Crossostrea gigas) and one gastropod ACP (BgACP1; from the snail Biomphalaria glabrata) for functional experiments. Both are highly-expressed, secreted short-form ACPs and hence comparable to the amphioxus ACPs previously reported. We found that recombinant CgACP1 and BgACP1 bound with yeasts and several bacteria with different affinities. They also agglutinated these microbes, but showed no inhibiting or killing effects. Further analyses show that both ACPs had high affinities to the Lys-type PGN from S. aureus but weak or no affinities to the DAP-type PGN from Bacillus subtilis. Both recombinant ACPs displayed weak or no affinities to other microbial cell wall components, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan A, chitin, chitosan and cellulose, as well as to several PGN moieties, including muramyl dipeptide (MDP), N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). Besides, CgACP1 had the highest expression in the gill and could be greatly up-regulated quickly after bacterial challenge. This is reminiscent of the amphioxus ACP1/2 which serve as essential mucus lectins in the gill. Taken together, the current findings from mollusk and amphioxus ACPs suggest several basic common traits for the ApeC domains, including the high affinity to Lys-type PGN, the bacterial binding and agglutinating capacity, and the role as mucus proteins to protect the mucosal surface.

9. A novel medication decision gene signature predicts response to individualized therapy and prognosis outcomes in hepatocellular carcinoma patients.

Front Immunol

2022 Oct 7

Yuan J, Liu Z, Wu Z

10. Immunogenicity and protective efficacy of the recombinant Pasteurella multocida lipoproteins VacJ and PlpE, and outer membrane protein H from P. multocida A:1 in ducks.

Front Immunol

2022 Oct 7

Li Y, Xiao J, Chang YF

11. Case Report: Rheumatoid meningitis with positive NMDAR antibody: A case treated with intravenous immunoglobulin.

Front Immunol

2022 Oct 7

Zhang H, Wan Y, Mei Z

12. The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease.

Front Immunol

2022 Oct 6

Habenicht LKL, Wang Z, Zhang X

We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer's Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling protein of the classical complement cascade (CCC), which occupies a key role in multiple acute and chronic inflammatory tissue responses. C1q is largely produced by myeloid cells including Kupffer cells (KCs) and subsequently secreted into the circulation as an inactive preprotein. Its binding partner, Apolipoprotein E (ApoE), is produced by KCs and hepatocytes and it is also secreted into the circulation, where it regulates essential steps of lipid transport. In addition to its major source, ApoE can be produced by non-liver cells including immune cells and multiple other cells depending on local tissue contexts. To initiate the CCC cascade, C1q must be activated by molecules as varied as oxidized lipids, amyloid fibrils, and immune complexes. However, ApoE is mute towards inactive C1q but binds at high-affinity to its activated form. Specifically, our studies revealed that ApoE is a CCC-specific checkpoint inhibitor via the formation of the C1q-ApoE complex. We proposed that it may arise in multiple if not all CCC-associated diseases and that its presence indicates ongoing CCC activity. Here, we turned to the liver to examine C1q-ApoE complexes in human B- and C-viral hepatitis and nonalcoholic fatty liver disease (NAFLD). In addition, we used multidrug-resistance-2 gene-knockout (Mdr2-KO) mice as a model for inflammatory liver disease and hepatocellular carcinoma (HCC) pathogenesis. In normal murine and human livers, KCs were the major C1q-producing cell type while hepatocytes were the primary ApoE-forming cell type though the C1q-ApoE complex was rare or nonexistent. However, significant numbers of C1q-ApoE complexes formed in both Mdr2-KO, human viral hepatitis, and NAFLD around portal triads where immune cells had infiltrated the liver. Additionally, high numbers of C1q-ApoE complexes emerged in human livers in areas of extracellular lipid droplets across the entire liver parenchyma in NAFLD-affected patients. Thus, the C1q-ApoE complex is a new pathological hallmark of viral hepatitis B and C and NAFLD.

13. Corrigendum: Systematic pattern analyses of Vδ2(+) TCRs reveal that shared "public" Vδ2(+) γδ T cell clones are a consequence of rearrangement bias and a higher expansion status.

Front Immunol

2022 Oct 6

Deng L, Harms A, Ravens S

14. Four clinical phenotypes of cow's milk protein allergy based on dairy product specific IgE antibody types in North China.

Front Immunol

2022 Oct 6

Tang R, Lyu X, Liu Y

15. Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice.

Front Immunol

2022 Oct 6

Hatamnejad MR, Baradaran Ghavami S, Shirvani M

16. Comprehensive investigation into cuproptosis in the characterization of clinical features, molecular characteristics, and immune situations of clear cell renal cell carcinoma.

Front Immunol

2022 Oct 6

Wang B, Song Q, Wei Y

17. Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia.

Front Immunol

2022 Oct 6

Pan B, Li Y, Xu Z

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Although the treatment landscape for CLL is rapidly evolving, there are still some patients who develop drug resistance or disease refractory. Ferroptosis is a type of lipid peroxidation-induced cell death and has been suggested to have prognostic value in several cancers. Our research aims to build a prognostic model to improve risk stratification in CLL patients and facilitate more accurate assessment for clinical management. METHODS: The differentially expressed ferroptosis-related genes (FRGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Least absolute shrinkage and selection operator (LASSO) Cox algorithms were performed to construct a prognostic risk model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were performed to estimate the immune infiltration score and immune-related pathways. A total of 36 CLL patients in our center were enrolled in this study as a validation cohort. Moreover, a nomogram model was established to predict the prognosis. RESULTS: A total of 15 differentially expressed FRGs with prognostic significance were screened out. After minimizing the potential risk of overfitting, we constructed a novel ferroptosis-related prognostic score (FPS) model with nine FRGs (AKR1C3, BECN1, CAV1, CDKN2A, CXCL2, JDP2, SIRT1, SLC1A5, and SP1) and stratified patients into low- and high-risk groups. Kaplan-Meier analysis showed that patients with high FPS had worse overall survival (OS) (P<0.0001) and treatment-free survival (TFS) (P<0.0001). ROC curves evaluated the prognostic prediction ability of the FPS model. Additionally, the immune cell types and immune-related pathways were correlated with the risk scores in CLL patients. In the validation cohort, the results confirmed that the high-risk group was related to worse OS (P<0.0001), progress-free survival (PFS) (P=0.0140), and TFS (P=0.0072). In the multivariate analysis, only FPS (P=0.011) and CLL-IPI (P=0.010) were independent risk indicators for OS. Furthermore, we established a nomogram including FPS and CLL-IPI that could strongly and reliably predict individual prognosis. CONCLUSION: A novel FPS model can be used in CLL for prognostic prediction. The model index may also facilitate the development of new clinical ferroptosis-targeted therapies in patients with CLL.

18. Absolute quantification and characterization of oxylipins in lupus nephritis and systemic lupus erythematosus.

Front Immunol

2022 Oct 6

He J, Ma C, Tang D

19. Self-reactivity of CD8 T-cell clones determines their differentiation status rather than their responsiveness in infections.

Front Immunol

2022 Oct 6

Paprckova D, Niederlova V, Moudra A

20. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.

Front Immunol

2022 Oct 6

Sancerni T, Renoult O, Luby A

21. Molecular subtypes based on Wnt-signaling gene expression predict prognosis and tumor microenvironment in hepatocellular carcinoma.

Front Immunol

2022 Oct 6

Xu W, Nie C, Lv H

22. Corrigendum: Case report: Persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID.

Front Immunol

2022 Oct 6

Goh D, Lim JCT, Fernaíndez SB

23. Complement C1s as a diagnostic marker and therapeutic target: Progress and propective.

Front Immunol

2022 Oct 6

Ye J, Yang P, Yang Y

24. Inhibition of MRGPRX2 but not FcεRI or MrgprB2-mediated mast cell degranulation by a small molecule inverse receptor agonist.

Front Immunol

2022 Oct 6

Bawazir M, Amponnawarat A, Hui Y

Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) contributes to hypersensitivity reactions to cationic US-Food and Drug Administration (FDA) approved drugs such as the neuromuscular blocking agent, rocuronium. In addition, activation of MRGPRX2 by the neuropeptide substance P (SP) and the pro-adrenomedullin peptide (PAMP-12) is associated with a variety of cutaneous conditions such as neurogenic inflammation, pain, atopic dermatitis, urticaria, and itch. Thus, small molecules aimed at blocking MRGPRX2 constitute potential options for modulating IgE-independent MC-mediated disorders. Two inverse MRGPRX2 agonists, named C9 and C9-6, have recently been identified, which inhibit basal G protein activation and agonist-induced calcium mobilization in transfected HEK293 cells. Substance P serves as a balanced agonist for MRGPRX2 whereby it activates both G protein-mediated degranulation and β-arrestin-mediated receptor internalization. The purpose of this study was to determine if C9 blocks MRGPRX2's G protein and β-arrestin-mediated signaling and to determine its specificity. We found that C9, but not its inactive analog C7, inhibited degranulation in RBL-2H3 cells stably expressing MRGPRX2 in response to SP, PAMP-12 and rocuronium with an IC50 value of ~300 nM. C9 also inhibited degranulation as measured by cell surface expression of CD63, CD107a and β-hexosaminidase release in LAD2 cells and human skin-derived MCs in response to SP but not the anaphylatoxin, C3a or FcϵRI-aggregation. Furthermore, C9 inhibited β-arrestin recruitment and MRGPRX2 internalization in response to SP and PAMP-12. We found that a G protein-coupling defective missense MRGPRX2 variant (V282M) displays constitutive activity for β-arrestin recruitment, and that this response was significantly inhibited by C9. Rocuronium, SP and PAMP-12 caused degranulation in mouse peritoneal MCs and these responses were abolished in the absence of MrgprB2 or cells treated with pertussis toxin but C9 had no effect. These findings suggest that C9 could provide an important framework for developing novel therapeutic approaches for the treatment of IgE-independent MC-mediated drug hypersensitivity and cutaneous disorders.

25. Corrigendum: PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury.

Front Immunol

2022 Oct 6

Zhu CL, Xie J, Zhao ZZ

26. The hexosamine biosynthesis pathway-related gene signature correlates with immune infiltration and predicts prognosis of patients with osteosarcoma.

Front Immunol

2022 Oct 6

Su Z, Wang C, Pan R

OBJECTIVES: Osteosarcoma is a malignant bone tumor with poor outcomes affecting the adolescents and elderly. In this study, we comprehensively assessed the metabolic characteristics of osteosarcoma patients and constructed a hexosamine biosynthesis pathway (HBP)-based risk score model to predict the prognosis and tumor immune infiltration in patients with osteosarcoma. METHODS: Gene expression matrices of osteosarcoma were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. GSVA and univariate Cox regression analysis were performed to screen the metabolic features associated with prognoses. LASSO regression analysis was conducted to construct the metabolism-related risk model. Differentially expressed genes (DEGs) were identified and enrichment analysis was performed based on the risk model. CIBERSORT and ESTIMATE algorithms were executed to evaluate the characteristics of tumor immune infiltration. Comparative analyses for immune checkpoints were performed and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapeutic response. Finally, hub genes with good prognostic value were comprehensive analyzed including drug sensitivity screening and immunohistochemistry (IHC) experiments. RESULTS: Through GSVA and survival analysis, the HBP pathway was identified as the significant prognostic related metabolism feature. Five genes in the HBP pathway including GPI, PGM3, UAP1, OGT and MGEA5 were used to construct the HBP-related risk model. Subsequent DEGs and enrichment analyses showed a strong correlation with immunity. Further, CIBERSORT and ESTIMATE algorithms showed differential immune infiltration characteristics correlated with the HBP-related risk model. TIDE algorithms and immune checkpoint analyses suggested poor immunotherapeutic responses with low expression of immune checkpoints in the high-risk group. Further analysis revealed that the UAP1 gene can predict metastasis. IHC experiments suggested that UAP1 expression correlated significantly with the prognosis and metastasis of osteosarcoma patients. When screening for drug sensitivity, high UAP1 expression was suggestive of great sensitivity to antineoplastic drugs including cobimetinib and selumetinib. CONCLUSION: We constructed an HBP-related gene signature containing five key genes (GPI, PGM3, UAP1, OGT, MGEA5) which showed a remarkable prognostic value for predicting prognosis and can guide immunotherapy and targeted therapy for osteosarcoma.

27. Strategies to overcome DC dysregulation in the tumor microenvironment.

Front Immunol

2022 Oct 6

Mestrallet G, Sone K, Bhardwaj N.

28. The bridge of the gut-joint axis: Gut microbial metabolites in rheumatoid arthritis.

Front Immunol

2022 Oct 6

Xu X, Wang M, Wang Z

29. Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma.

Front Immunol

2022 Oct 6

Maldonado-Pérez N, Tristán-Manzano M, Justicia-Lirio P

30. Integrated machine learning methods identify FNDC3B as a potential prognostic biomarker and correlated with immune infiltrates in glioma.

Front Immunol

2022 Oct 6

Wang X, Huang Y, Li S

BACKGROUND: Recent discoveries have revealed that fibronectin type III domain containing 3B (FNDC3B) acts as an oncogene in various cancers; however, its role in glioma remains unclear. METHODS: In this study, we comprehensively investigated the expression, prognostic value, and immune significance of FNDC3B in glioma using several databases and a variety of machine learning algorithms. RNA expression data and clinical information of 529 patients from the Cancer Genome Atlas (TCGA) and 1319 patients from Chinese Glioma Genome Atlas (CGGA) databases were downloaded for further investigation. To evaluate whether FNDC3B expression can predict clinical prognosis of glioma, we constructed a clinical nomogram to estimate long-term survival probabilities. The predicted nomogram was validated by CGGA cohorts. Differentially expressed genes (DEGs) were detected by the Wilcoxon test based on the TCGA-LGG dataset and the weighted gene co-expression network analysis (WGCNA) was implemented to identify the significant module associated with the expression level of FNDC3B. Furthermore, we investigated the correlation between FNDC3B with cancer immune infiltrates using TISIDB, ESTIMATE, and CIBERSORTx. RESULTS: Higher FNDC3B expression displayed a remarkably worse overall survival and the expression level of FNDC3B was an independent prognostic indicator for patients with glioma. Based on TCGA LGG dataset, a co-expression network was established and the hub genes were identified. FNDC3B expression was positively correlated to the tumor-infiltrating lymphocytes and immune infiltration score, and high FNDC3B expression was accompanied by the increased expression of B7-H3, PD-L1, TIM-3, PD-1, and CTLA-4. Moreover, expression of FNDC3B was significantly associated with infiltrating levels of several types of immune cells and most of their gene markers in glioma. CONCLUSION: This study demonstrated that FNDC3B may be involved in the occurrence and development of glioma and can be regarded as a promising prognostic and immunotherapeutic biomarker for the treatment of glioma.

31. A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report.

Front Immunol

2022 Oct 6

Luo X, Sun Y, Li J

32. The interplay between the airway epithelium and tissue macrophages during the SARS-CoV-2 infection.

Front Immunol

2022 Oct 6

Barreto-Duran E, Szczepański A, Gałuszka-Bulaga A

33. Target tumor microenvironment by innate T cells.

Front Immunol

2022 Oct 6

Li YR, Wilson M, Yang L.

34. On the role of allergen-specific IgG subclasses for blocking human basophil activation.

Front Immunol

2022 Oct 6

Zinkhan S, Thoms F, Augusto G

35. Origin, activation, and targeted therapy of glioma-associated macrophages.

Front Immunol

2022 Oct 6

Xu C, Xiao M, Li X

36. Longitudinal cellular and humoral immune responses after triple BNT162b2 and fourth full-dose mRNA-1273 vaccination in haemodialysis patients.

Front Immunol

2022 Oct 6

Becker M, Cossmann A, Lürken K

Haemodialysis patients respond poorly to vaccination and continue to be at-risk for severe COVID-19. Therefore, dialysis patients were among the first for which a fourth COVID-19 vaccination was recommended. However, targeted information on how to best maintain immune protection after SARS-CoV-2 vaccinations in at-risk groups for severe COVID-19 remains limited. We provide, to the best of our knowledge, for the first time longitudinal vaccination response data in dialysis patients and controls after a triple BNT162b2 vaccination and in the latter after a subsequent fourth full-dose of mRNA-1273. We analysed systemic and mucosal humoral IgG responses against the receptor-binding domain (RBD) and ACE2-binding inhibition towards variants of concern including Omicron and Delta with multiplex-based immunoassays. In addition, we assessed Spike S1-specific T-cell responses by interferon γ release assay. After triple BNT162b2 vaccination, anti-RBD B.1 IgG and ACE2 binding inhibition reached peak levels in dialysis patients, but remained inferior compared to controls. Whilst we detected B.1-specific ACE2 binding inhibition in 84% of dialysis patients after three BNT162b2 doses, binding inhibition towards the Omicron variant was only detectable in 38% of samples and declining to 16% before the fourth vaccination. By using mRNA-1273 as fourth dose, humoral immunity against all SARS-CoV-2 variants tested was strongly augmented with 80% of dialysis patients having Omicron-specific ACE2 binding inhibition. Modest declines in T-cell responses in dialysis patients and controls after the second vaccination were restored by the third BNT162b2 dose and significantly increased by the fourth vaccination. Our data support current advice for a four-dose COVID-19 immunisation scheme for at-risk individuals such as haemodialysis patients. We conclude that administration of a fourth full-dose of mRNA-1273 as part of a mixed mRNA vaccination scheme to boost immunity and to prevent severe COVID-19 could also be beneficial in other immune impaired individuals. Additionally, strategic application of such mixed vaccine regimens may be an immediate response against SARS-CoV-2 variants with increased immune evasion potential.

37. Prospective approaches to enhancing CAR T cell therapy for glioblastoma.

Front Immunol

2022 Oct 6

Choi SI, Yin J.

38. Tumor microenvironment features decipher the outperformance of neoadjuvant immunochemotherapy over chemotherapy in resectable non-small cell lung cancer.

Front Immunol

2022 Oct 6

Cai W, Jing M, Gu Y

39. Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed.

Front Immunol

2022 Oct 6

Hu X, Bian C, Zhao X

40. A retrospective study of the correlation between herpes zoster neuralgia and the serum neuron-specific enolase level in the largest dermatological hospital in Zhejiang province, China.

Front Immunol

2022 Oct 6

Zhong C, Lin D, Liu Y

41. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis.

Front Immunol

2022 Oct 6

Wen JH, Li DY, Liang S

42. Clinical relevance of vitamin B12 level and vitamin B12 metabolic gene variation in pulmonary tuberculosis.

Front Immunol

2022 Oct 6

Zhang TP, Li R, Wang LJ

43. Editorial: Role of lipid rafts in anti-microbial immune response volume II.

Front Immunol

2022 Oct 6

Gagliardi MC, Lai CH, Iwabuchi K.

44. Rare complications of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: Time to nip them in the bud.

Front Immunol

2022 Oct 6

Yang J, Yan B.

45. Gastric alarmin release: A warning signal in the development of gastric mucosal diseases.

Front Immunol

2022 Oct 6

Wu E, Zhu J, Ma Z

46. Costimulators expressed on human endothelial cells modulate antigen-dependent recruitment of circulating T lymphocytes.

Front Immunol

2022 Oct 6

Manes TD, Wang V, Pober JS.

47. Histamine induced high mobility group box-1 release from vascular endothelial cells through H(1) receptor.

Front Immunol

2022 Oct 5

Gao S, Liu K, Ku W

BACKGROUND: Systemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied. METHODS AND RESULTS: EA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H1 receptor antagonist, but not by H2 or H3/4 receptor antagonists. Moreover, an H1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension. CONCLUSION: Histamine induces HMGB1 release from vascular endothelial cells solely through H1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis.

48. System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection.

Front Immunol

2022 Oct 5

Gough M, Singh DK, Singh B

Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Identifying correlates of immune control of infection is important for both vaccine and therapeutics development. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators). We particularly focused on pathways relevant to myeloid origin cells such as macrophages, as these innate immunocytes have an important contribution to the initial control or the lack thereof, following Mtb infection. Using bacterial burden, C-reactive protein (CRP), and other clinical indicators of disease severity as a guide, we were able to establish gene signatures of host disease state and progression. In addition to gene signatures, clustering algorithms were used to differentiate between host disease states and identify relationships between genes. This allowed us to identify clusters of genes which exhibited differential expression profiles between the three groups of macaques: ATB, LTBI and Mtb/SIV. The gene signatures were associated with pathways relevant to apoptosis, ATP production, phagocytosis, cell migration, and Type I interferon (IFN), which are related to macrophage function. Our results suggest novel macrophage functions that may play roles in the control of Mtb infection with and without co-infection with SIV. These results particularly point towards an interplay between Type I IFN signaling and IFN-γ signaling, and the resulting impact on lung macrophages as an important determinant of progression to TB.

49. Severe COVID-19 patients display hyper-activated NK cells and NK cell-platelet aggregates.

Front Immunol

2022 Oct 5

Malengier-Devlies B, Filtjens J, Ahmadzadeh K

COVID-19 is characterised by a broad spectrum of clinical and pathological features. Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we analysed the phenotype and activity of NK cells in the blood of COVID-19 patients using flow cytometry, single-cell RNA-sequencing (scRNA-seq), and a cytotoxic killing assay. In the plasma of patients, we quantified the main cytokines and chemokines. Our cohort comprises COVID-19 patients hospitalised in a low-care ward unit (WARD), patients with severe COVID-19 disease symptoms hospitalised in intensive care units (ICU), and post-COVID-19 patients, who were discharged from hospital six weeks earlier. NK cells from hospitalised COVID-19 patients displayed an activated phenotype with substantial differences between WARD and ICU patients and the timing when samples were taken post-onset of symptoms. While NK cells from COVID-19 patients at an early stage of infection showed increased expression of the cytotoxic molecules perforin and granzyme A and B, NK cells from patients at later stages of COVID-19 presented enhanced levels of IFN-γ and TNF-α which were measured ex vivo in the absence of usual in vitro stimulation. These activated NK cells were phenotyped as CD49a+CD69a+CD107a+ cells, and their emergence in patients correlated to the number of neutrophils, and plasma IL-15, a key cytokine in NK cell activation. Despite lower amounts of cytotoxic molecules in NK cells of patients with severe symptoms, majority of COVID-19 patients displayed a normal cytotoxic killing of Raji tumour target cells. In vitro stimulation of patients blood cells by IL-12+IL-18 revealed a defective IFN-γ production in NK cells of ICU patients only, indicative of an exhausted phenotype. ScRNA-seq revealed, predominantly in patients with severe COVID-19 disease symptoms, the emergence of an NK cell subset with a platelet gene signature that we identified by flow and imaging cytometry as aggregates of NK cells with CD42a+CD62P+ activated platelets. Post-COVID-19 patients show slow recovery of NK cell frequencies and phenotype. Our study points to substantial changes in NK cell phenotype during COVID-19 disease and forms a basis to explore the contribution of platelet-NK cell aggregates to antiviral immunity against SARS-CoV-2 and disease pathology.

50. Immune checkpoint inhibitors as mediators for immunosuppression by cancer-associated fibroblasts: A comprehensive review.

Front Immunol

2022 Oct 5

Eskandari-Malayeri F, Rezaei M.

The tumor microenvironment (TME) is a significant contributor to cancer progression containing complex connections between cellular and chemical components and provides a suitable substrate for tumor growth and development. Growing evidence shows targeting tumor cells while ignoring the surrounding TME is not effective enough to overcome the cancer disease. Fibroblasts are essential sentinels of the stroma that due to certain conditions in TME, such as oxidative stress and local hypoxia, become activated, and play the prominent role in the physical support of tumor cells and the enhancement of tumorigenesis. Activated fibroblasts in TME, defined as cancer-associated fibroblasts (CAFs), play a crucial role in regulating the biological behavior of tumors, such as tumor metastasis and drug resistance. CAFs are highly heterogeneous populations that have different origins and, in addition to their role in supporting stromal cells, have multiple immunosuppressive functions via a membrane and secretory patterns. The secretion of different cytokines/chemokines, interactions that mediate the recruitment of regulatory immune cells and the reprogramming of an immunosuppressive function in immature myeloid cells are just a few examples of how CAFs contribute to the immune escape of tumors through various direct and indirect mechanisms on specific immune cell populations. Moreover, CAFs directly abolish the role of cytotoxic lymphocytes. The activation and overexpression of inhibitory immune checkpoints (iICPs) or their ligands in TME compartments are one of the main regulatory mechanisms that inactivate tumor-infiltrating lymphocytes in cancer lesions. CAFs are also essential players in the induction or expression of iICPs and the suppression of immune response in TME. Based on available studies, CAF subsets could modulate immune cell function in TME through iICPs in two ways; direct expression of iICPs by activated CAFs and indirect induction by production soluble and then upregulation of iICPs in TME. With a focus on CAFs' direct and indirect roles in the induction of iICPs in TME as well as their use in immunotherapy and diagnostics, we present the evolving understanding of the immunosuppressive mechanism of CAFs in TME in this review. Understanding the complete picture of CAFs will help develop new strategies to improve precision cancer therapy.

51. Case Report: Chronic hepatitis E in a hematopoietic stem cell transplant recipient: The first report of hepatitis E virus genotype 4 causing chronic infection in a non-solid organ recipient.

Front Immunol

2022 Oct 5

Chen Z, Wei J, Jiang L

52. Human innate lymphoid cell activation by adenoviruses is modified by host defense proteins and neutralizing antibodies.

Front Immunol

2022 Oct 5

Paris O, Mennechet FJD, Kremer EJ.

53. Stress and cancer: The mechanisms of immune dysregulation and management.

Front Immunol

2022 Oct 5

Liu Y, Tian S, Ning B

54. Spectral flow cytometry cluster analysis of therapeutic donor lymphocyte infusions identifies T cell subsets associated with outcome in patients with AML relapse.

Front Immunol

2022 Oct 5

Odak I, Sikora R, Riemann L

Identification of immune phenotypes linked to durable graft-versus-leukemia (GVL) response following donor lymphocyte infusions (DLI) is of high clinical relevance. In this prospective observational study of 13 AML relapse patients receiving therapeutic DLI, we longitudinally investigated changes in differentiation stages and exhaustion markers of T cell subsets using cluster analysis of 30-color spectral flow cytometry during 24 months follow-up. DLI cell products and patient samples after DLI were analyzed and correlated to the clinical outcome. Analysis of DLI cell products revealed heterogeneity in the proportions of naïve and antigen experienced T cells. Cell products containing lower levels of effector memory (eff/m) cells and higher amounts of naïve CD4+ and CD8+ T cells were associated with long-term remission. Furthermore, investigation of patient blood samples early after DLI showed that patients relapsing during the study period, had higher levels of CD4+ eff/m T cells and expressed a mosaic of surface molecules implying an exhausted functional state. Of note, this observation preceded the clinical diagnosis of relapse by five months. On the other hand, patients with continuous remission retained lower levels of exhausted CD4+ eff/m T cells more than four months post DLI. Moreover, lower frequencies of exhausted CD8+ eff/m T cells as well as higher amounts of CD4+temra CD45RO+ T cells were present in this group. These results imply the formation of functional long-term memory pool of T cells. Finally, unbiased sample analysis showed that DLI cell products with low levels of eff/m cells both in CD4+ and CD8+ T cell subpopulations associate with a lower relapse incidence. Additionally, competing risk analysis of patient samples taken early after DLI revealed that patients with high amounts of exhausted CD4+ eff/m T cells in their blood exhibited significantly higher rates of relapse. In conclusion, differentially activated T cell clusters, both in the DLI product and in patients post infusion, were associated with AML relapse after DLI. Our study suggests that differences in DLI cell product composition might influence GVL. In-depth monitoring of T cell dynamics post DLI might increase safety and efficacy of this immunotherapy, while further studies are needed to assess the functionality of T cells found in the DLI.

55. Comparison of blood and lymph node cells after intramuscular injection with HIV envelope immunogens.

Front Immunol

2022 Oct 5

Day S, Kaur C, Cheeseman HM

BACKGROUND: Harnessing CD4+ T cell help in the lymph nodes through rational antigen design could enhance formation of broadly neutralizing antibodies (bNAbs) during experimental HIV immunization. This process has remained hidden due to difficulty with direct study, with clinical studies instead focusing on responses in the blood as a proxy for the secondary lymphoid tissue. METHODS: To address this, lymph node cells (LNC) were collected using ultrasound guided fine needle aspiration of axillary lymph nodes from 11 HIV negative participants in an experimental HIV immunogen study (European AIDS Vaccine Initiative EAVI2020_01 study, NCT04046978). Cells from lymph node and blood (PBMC), were collected after intramuscular injection with HIV Env Mosaic immunogens based on HIV Envelope glycoprotein and combined with a liposomal toll-like receptor-4 adjuvant; monophosphoryl lipid A. Simultaneously sampled cells from both blood and lymph node in the same donors were compared for phenotype, function, and antigen-specificity. RESULTS: Unsupervised cluster analysis revealed tissue-specific differences in abundance, distribution, and functional response of LNC compared with PBMC. Monocytes were virtually absent from LNC, which were significantly enriched for CD4+ T cells compared with CD8+ T cells. T follicular helper cells with germinal center features were enriched in LNC, which contained specific CD4+ and CD8+ T cell subsets including CD4+ T cells that responded after a single injection with HIV Env Mosaic immunogens combined with adjuvant. Tissue-specific differences in response to an MHC-II dependent superantigen, staphylococcal enterotoxin B, indicated divergence in antigen presentation function between blood and lymph node. CONCLUSIONS: LNC are phenotypically and functionally distinct from PBMC, suggesting that whole blood is only a limited proxy of the T cell lymphatic response to immunization. HIV-specific CD4+ T cells in the lymph node are rapidly inducible upon experimental injection with HIV immunogens. Monitoring evolution of CD4+ T cell memory in LNC with repeated experimental HIV immunization could indicate the strategies most likely to be successful in inducing HIV-specific bNAbs.

56. Targeted nanoparticles modify neutrophil function in vivo.

Front Immunol

2022 Oct 5

Völs S, Kaisar-Iluz N, Shaul ME

57. Tissue resident memory T cells- A new benchmark for the induction of vaccine-induced mucosal immunity.

Front Immunol

2022 Oct 4

Hassert M, Harty JT.

58. Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway.

Front Immunol

2022 Oct 4

Tao YC, Wang YH, Wang ML

BACKGROUND: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due to the shortage of donor organs. Given that both ACLF and ALF are driven by excessive inflammation in the initial stage, molecules targeting inflammation may benefit the two conditions. MicroRNAs (miRNAs) are a group of small endogenous noncoding interfering RNA molecules. Regulation of miRNAs related to inflammation may serve as promising interventions for the treatment of liver failure. AIMS: To explore the role and mechanism of miR-125b-5p in the development of liver failure. METHODS: Six human liver tissues were categorized into HBV-non-ACLF and HBV-ACLF groups. Differentially expressed miRNAs (DE-miRNAs) were screened and identified through high-throughput sequencing analysis. Among these DE-miRNAs, miR-125b-5p was selected for further study of its role and mechanism in lipopolysaccharide (LPS)/D-galactosamine (D-GalN) -challenged Huh7 cells and mice in vitro and in vivo. RESULTS: A total of 75 DE-miRNAs were obtained. Of these DE-miRNAs, miR-125b-5p was the focus of further investigation based on our previous findings and preliminary results. We preliminarily observed that the levels of miR-125b-5p were lower in the HBV-ACLF group than in the HBV-non-ACLF group. Meanwhile, LPS/D-GalN-challenged mice and Huh7 cells both showed decreased miR-125b-5p levels when compared to their untreated control group, suggesting that miR-125b-5p may have a protective role against liver injury, regardless of ACLF or ALF. Subsequent results revealed that miR-125b-5p not only inhibited Huh7 cell apoptosis in vitro but also relieved mouse ALF in vivo with evidence of improved liver histology, decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced tumor necrosis factor-α (TNF-α) and IL-1β levels. Based on the results of a biological prediction website, microRNA.org, Kelch-like ECH-associated protein 1 (Keap1) was predicted to be one of the target genes of miR-125b-5p, which was verified by a dual-luciferase reporter gene assay. Western blot results in vitro and in vivo showed that miR-125b-5p could decrease the expression of Keap1 and cleaved caspase-3 while upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1(HO-1). CONCLUSION: Upregulation of miR-125b-5p can alleviate acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway, and regulation of miR-125b-5p may serve as an alternative intervention for liver failure.

59. Dual immunological and proliferative regulation of immune checkpoint FGL1 in lung adenocarcinoma: The pivotal role of the YY1-FGL1-MYH9 axis.

Front Immunol

2022 Oct 4

Tang XY, Xiong YL, Zhao YB

RATIONAL: Lung cancer is the most common tumor worldwide, with the highest mortality rate and second highest incidence. Immunotherapy is one of the most important treatments for lung adenocarcinoma (LUAD); however, it has relatively low response rate and high incidence of adverse events. Herein, we explored the therapeutic potential of fibrinogen-like protein 1 (FGL1) for LUAD. METHODS: Data from GEPIA and ACLBI databases were assessed to explore gene-gene correlations and tumor immune infiltration patterns. A total of 200 patients with LUAD were recruited. FGL1 levels in the serum and cellular supernatant were determined by enzyme-linked immunosorbent assay. In vitro and in vivo experiments were performed to assess the effect FGL1 on the proliferation of LUAD cells. Cocultures were performed to explore the effect of FGL1 knockdown in lung cancer cells on T cells, concerning cytokine secretion and viability. PROMO and hTFtarget databases were used for transcription factor prediction. Quantitative polymerase chain reaction (qPCR), chromatin immunoprecipitation, and dual luciferase reporter assays were performed to validate the identified transcription factor of FGL1. Immunoprecipitation, mass spectrometry and gene ontology analysis were performed to explore the downstream partners of FGL1. RESULTS: FGL1 expression in LUAD was positively associated with PDL1, but not for PD1 expression. Moreover, FGL1 was positively associated with the CD3D expression and negatively associated with FOXP3, S100A9, and TPSB2 within the tumor site. FGL1 promotes the secretion of interleukin-2 by T cells in vitro, simultaneously inducing their apoptosis. Indeed, YY1 is the upstream molecule of FGL1 was found to be transcriptionally regulated by YY1 and to directly by to MYH9 to promote the proliferation of LUAD cells in vitro and in vivo. CONCLUSIONS: FGL1 is involved in the immunological and proliferative regulation of LUAD cells by controlling the secretion of important immune-related cytokines via the YY1-FGL1-MYH9 axis. Hence, targeting FGL1 in LUAD may pave the way for the development of new immunotherapies for tackling this malignancy.

60. A real-world retrospective study of safety, efficacy, compliance and cost of combination treatment with rush immunotherapy plus one dose of pretreatment anti-IgE in Chinese children with respiratory allergies.

Front Immunol

2022 Oct 4

Zhang P, Bian S, Wang X

BACKGROUND: The efficacy of allergen immunotherapy (AIT) in treating pediatric allergy has been clearly demonstrated, however, many patients hesitate to initiate AIT due to weekly hospital visits during the 3-4 months up-dosing phase. Meanwhile, rush immunotherapy (RIT) shortens the duration of the up-dosing phase to 7 days. However, considering that patients receiving RIT are exposed to the allergens during a much shorter period of time and thus may be at a greater risk of systemic reactions, RIT is currently underused, especially in children. This study investigated the utility of combination treatment with RIT plus 1 dose of pretreatment anti-IgE in children with respiratory allergies. METHODS: In this retrospective study, we reviewed records of children with allergic rhinitis (AR) and/or allergic asthma (AA) sensitized to dust mite allergens receiving RIT+1 dose of pretreatment anti-IgE (the RIT group) or conventional immunotherapy (the CIT group) at our hospital from January 2020 to March 2021. Data such as visual analogue scale (VAS) scores, comprehensive symptom and medication score (CSMS), allergy blood test results, adverse reactions, compliance and cost were collected and analyzed. RESULTS: 40 patients in the RIT group and 81 patients in the CIT group were included in this study. Both treatments were well tolerated and patients in the 2 treatment groups had comparable local and systemic reactions. Compared to CIT, RIT + anti-IgE combination led to significantly faster symptomatic improvement as demonstrated by significantly decreased VAS and CSMS starting as early as 1 month after AIT initiation (P<0.05). Nobody dropped out in the RIT group during the 1 year follow-up, while 11 out of 81 patients in the CIT group dropped out (loss rate 13.5%). Thus, the RIT group had a significantly higher compliance rate than the CIT group (P<0.05). Finally, the 2 treatment regimens had comparable cost per patient per injection (P> 0.05). CONCLUSIONS: RIT + 1 dose of pretreatment anti-IgE combination has practical advantages over CIT, including comparable safety, better compliance, and probably a faster onset of clinical efficacy at no additional cost, so it can be an useful regimen for the treatment of Chinese children with respiratory allergies.

61. Possible role of gut microbes and host's immune response in gut-lung homeostasis.

Front Immunol

2022 Oct 4

Rastogi S, Mohanty S, Sharma S

62. Rogue" neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury - studies in human, macaque and rat LPS-inflammation models.

Front Immunol

2022 Oct 4

Carstensen S, Müller M, Tan GLA

BACKGROUND AND OBJECTIVE: The correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models. METHODS: We performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species - human, rhesus macaque, rat - with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats. RESULTS: ChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (P <0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater "intrinsic adhesion to hard-surface" in DEspR+ vs DEspR[-] neutrophils (P <0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (P <0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (P =0.0007) and exhibited brain target engagement and bioeffects. CONCLUSION: Detection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.

63. Editorial: Endothelial cells as innate immune cells.

Front Immunol

2022 Oct 4

Lu Y, Sun Y, Xu K

64. The prognostic impact of the immune signature in head and neck squamous cell carcinoma.

Front Immunol

2022 Oct 4

Baysal H, Siozopoulou V, Zaryouh H

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells; and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come.

65. Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis.

Front Immunol

2022 Oct 4

Irie E, Ishihara R, Mizushima I

66. Uncovering the information immunology journals transmitted for COVID-19: A bibliometric and visualization analysis.

Front Immunol

2022 Oct 31

Zhao J, Zhu J, Huang C

BACKGROUND: Since the global epidemic of the coronavirus disease 2019 (COVID-19), a large number of immunological studies related to COVID-19 have been published in various immunology journals. However, the results from these studies were discrete, and no study summarized the important immunological information about COVID-19 released by these immunology journals. This study aimed to comprehensively summarize the knowledge structure and research hotspots of COVID-19 published in major immunology journals through bibliometrics. METHODS: Publications on COVID-19 in major immunology journals were obtained from the Web of Science Core Collection. CiteSpace, VOSviewer, and R-bibliometrix were comprehensively used for bibliometric and visual analysis. RESULTS: 1,331 and 5,000 publications of 10 journals with high impact factors and 10 journals with the most papers were included, respectively. The USA, China, England, and Italy made the most significant contributions to these papers. University College London, National Institute of Allergy and Infectious Diseases, Harvard Medical School, University California San Diego, and University of Pennsylvania played a central role in international cooperation in the immunology research field of COVID-19. Yuen Kwok Yung was the most important author in terms of the number of publications and citations, and the H-index. CLINICAL INFECTIOUS DISEASES and FRONTIERS IN IMMUNOLOGY were the most essential immunology journals. These immunology journals mostly focused on the following topics: "Delta/Omicron variants", "cytokine storm", "neutralization/neutralizing antibody", "T cell", "BNT162b2", "mRNA vaccine", "vaccine effectiveness/safety", and "long COVID". CONCLUSION: This study systematically uncovered a holistic picture of the current research on COVID-19 published in major immunology journals from the perspective of bibliometrics, which will provide a reference for future research in this field.

67. Editorial: Improvement of melanoma immune checkpoint blockade therapy with potential combinatorial regiments.

Front Immunol

2022 Oct 31

Wang X, Liu X, Hugo W

68. Construction and protective efficacy of a novel Streptococcus pneumoniae fusion protein vaccine NanAT1-TufT1-PlyD4.

Front Immunol

2022 Oct 31

Cui Y, Miao C, Chen W

During the past decades, with the implementation of pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCVs), a dramatic reduction in vaccine type diseases and transmissions has occurred. However, it is necessary to develop a less expensive, serotype-independent pneumococcal vaccine due to the emergence of nonvaccine-type pneumococcal diseases and the limited effect of vaccines on colonization. As next-generation vaccines, conserved proteins, such as neuraminidase A (NanA), elongation factor Tu (Tuf), and pneumolysin (Ply), are promising targets against pneumococcal infections. Here, we designed and constructed a novel fusion protein, NanAT1-TufT1-PlyD4, using the structural and functional domains of full-length NanA, Tuf and Ply proteins with suitable linkers based on bioinformatics analysis and molecular cloning technology. Then, we tested whether the protein protected against focal and lethal pneumococcal infections and examined its potential protective mechanisms. The fusion protein NanAT1-TufT1-PlyD4 consists of 627 amino acids, which exhibits a relatively high level of thermostability, high stability, solubility and a high antigenic index without allergenicity. The purified fusion protein was used to subcutaneously immunize C57BL/6 mice, and NanAT1-TufT1-PlyD4 induced a strong and significant humoral immune response. The anti-NanAT1-TufT1-PlyD4 specific IgG antibody assays increased after the first immunization and reached the highest value at the 35th day. The results from in vitro experiments showed that anti-NanAT1-TufT1-PlyD4 antisera could inhibit the adhesion of Streptococcus pneumoniae (S. pneumoniae) to A549 cells. In addition, immunization with NanAT1-TufT1-PlyD4 significantly reduced S. pneumoniae colonization in the lung and decreased the damage to the lung tissues induced by S. pneumoniae infection. After challenge with a lethal dose of serotype 3 (NC_WCSUH32403), a better protection effect was observed with NanAT1-TufT1-PlyD4-immunized mice than with the separate full-length proteins and the adjuvant control; the survival rate was 50%, which met the standard of the marketed vaccine. Moreover, we showed that the humoral immune response and the Th1, Th2 and Th17-cellular immune pathways are involved in the immune protection of NanAT1-TufT1-PlyD4 to the host. Collectively, our results support that the novel fusion protein NanAT1-TufT1-PlyD4 exhibits extensive immune stimulation and is effective against pneumococcal challenges, and these properties are partially attributed to humoral and cellular-mediated immune responses.

69. Differential regulation of Type 1 and Type 2 mouse eosinophil activation by apoptotic cells.

Front Immunol

2022 Oct 31

Dolitzky A, Hazut I, Avlas S

70. Understanding the role of Toll-like receptors in lung cancer immunity and immunotherapy.

Front Immunol

2022 Oct 31

Hoden B, DeRubeis D, Martinez-Moczygemba M

71. An ambient-temperature stable nanoparticle-based vaccine for nasal application that confers long-lasting immunogenicity to carried antigens.

Front Immunol

2022 Oct 31

Cruz-Resendiz A, Acero G, Sampieri A

72. Humoral and cellular immunogenicity of COVID-19 booster dose vaccination in inflammatory arthritis patients.

Front Immunol

2022 Oct 31

Wroński J, Jaszczyk B, Roszkowski L

73. Chimeric antigen receptor T cells applied to solid tumors.

Front Immunol

2022 Oct 31

Zhou Z, Tao C, Li J

74. A novel oxidative stress- and ferroptosis-related gene prognostic signature for distinguishing cold and hot tumors in colorectal cancer.

Front Immunol

2022 Oct 31

Wang X, Xu Y, Dai L

75. Comparative transcriptomics reveals the immune dynamics during the molting cycle of swimming crab Portunus trituberculatus.

Front Immunol

2022 Oct 31

Liu M, Ni H, Zhang X

Molting is one of the most important biological processes of crustacean species, and a number of molecular mechanisms facilitate this complex procedure. However, the understanding of the immune mechanisms underlying crustacean molting cycle remains very limited. This study performed transcriptome sequencing in hemolymph and hepatopancreas of the swimming crab (Portunus trituberculatus) during the four molting stages: post-molt (AB), inter-molt (C), pre-molt (D), and ecdysis (E). The results showed that there were 78,572 unigenes that were obtained in the hemolymph and hepatopancreas of P. trituberculatus. Further analysis showed that 98 DEGs were involved in immunity response of hemolymph and hepatopancreas, and most of the DEGs participated in the process of signal transduction, pattern recognition proteins/receptors, and antioxidative enzymes system. Specifically, the key genes and pathway involved in signal transduction including the GPCR126, beta-integrin, integrin, three genes in mitogen-activated protein kinase (MAPK) signaling cascade (MAPKKK10, MAPKK4, and p38 MAPK), and four genes in Toll pathway (Toll-like receptor, cactus, pelle-like kinase, and NFIL3). For the pattern recognition proteins/receptors, the lowest expression level of 11 genes was found in the E stage, including C-type lectin receptor, C-type lectin domain family 6 member A and SRB3/C in the hemolymph, and hepatopancreatic lectin 4, C-type lectin, SRB, Down syndrome cell adhesion molecule homolog, Down syndrome cell adhesion molecule isoform, and A2M. Moreover, the expression level of copper/zinc superoxide dismutase isoform 4, glutathione peroxidase, glutathione S-transferase, peroxiredoxin, peroxiredoxin 6, and dual oxidase 2 in stage C or stage D significantly higher than that of stage E or stage AB. These results fill in the gap of the continuous transcriptional changes that are evident during the molting cycle of crab and further provided valuable information for elucidating the molecular mechanisms of immune regulation during the molting cycle of crab.

76. COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation.

Front Immunol

2022 Oct 31

Shi W, Chen Z, Liu H

77. HLA-DR3 restricted environmental epitopes from the bacterium Clostridium tetani have T cell cross-reactivity to the SLE-related autoantigen SmD.

Front Immunol

2022 Oct 31

Zhao Z, Anderson AN, Kannapell CC

78. Nucleic acid-sensing toll-like receptors: Important players in Sjögren's syndrome.

Front Immunol

2022 Oct 31

Alexopoulou L.

79. The efficacy and safety analysis of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma.

Front Immunol

2022 Oct 31

Qian X, Wang Y, Liu F

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive disease without standardized treatment strategies. The efficacy of second-line or beyond immune checkpoint inhibitors (ICIs) has been proven in recent studies, whereas the evidence for first-line immunotherapy for PSC is still limited to case reports and remains poorly understood. MATERIALS AND METHODS: This was a multicenter, retrospective analysis of 21 patients with a histological diagnosis of PSC who received ICI as first-line therapy from January 2019 to March 2022. The expression of PD-L1 was evaluated by immunohistochemistry (IHC) using the monoclonal antibody 22C3. Low and high PD-L1 expressions were defined using the tumor proportion score (TPS), with cutoffs of 1 and 50%, respectively. RESULTS: All eight patients had PD-L1 positivity who underwent PD-L1 expression assessment, and six patients (6/8, 75.0%) had high PD-L1 expression. Among the 21 PSC patients, seven received tislelizumab, six received camrelizumab, four received sintilimab, three received pembrolizumab, and one received durvalumab. Among them, 18 PSCs received combination therapy, whereas another three PSCs received immunotherapy alone. Out of the 21 PSC patients, 12 (57.1%) achieved a partial response (PR), and five patients had stable disease (SD) as the best response, whereas four PSCs experienced dramatic progressive disease (PD). The median progression-free survival (PFS) was 9.2 (95% CI [4.3, 14.1]) months, and the median OS was 22.8 (95% CI [4.0, 41.5]) months. Among the three treatment groups (immunotherapy alone, immunotherapy combined with anlotinib, and chemoimmunotherapy), the median PFS was 8.0, 9.4, and 9.6 months, and the median OS was 19.0, 22.8, and 30.6 months, respectively. There was no difference in PFS and OS between the three treatment regimen groups (P = 0.86 and P = 0.34, respectively) and different immunotherapies (P = 0.10 and P = 0.23, respectively). No serious adverse events (grade ≥ 3) were noted. CONCLUSION: First-line immunotherapy has promising therapeutic potential in the treatment of PSC. More studies are warranted to confirm these findings.

80. A review of spatial profiling technologies for characterizing the tumor microenvironment in immuno-oncology.

Front Immunol

2022 Oct 31

Hu B, Sajid M, Lv R

81. SARS-CoV-2 modulates inflammatory responses of alveolar epithelial type II cells via PI3K/AKT pathway.

Front Immunol

2022 Oct 31

Al-Qahtani AA, Pantazi I, Alhamlan FS

BACKGROUND: SARS-CoV-2 infects through the respiratory route and triggers inflammatory response by affecting multiple cell types including type II alveolar epithelial cells. SARS-CoV-2 triggers signals via its Spike (S) protein, which have been shown to participate in the pathogenesis of COVID19. AIM: Aim of the present study was to investigate the effect of SARS-CoV2 on type II alveolar epithelial cells, focusing on signals initiated by its S protein and their impact on the expression of inflammatory mediators. RESULTS: For this purpose A549 alveolar type II epithelial cells were exposed to SARS CoV2 S recombinant protein and the expression of inflammatory mediators was measured. The results showed that SARS-CoV-2 S protein decreased the expression and secretion of IL8, IL6 and TNFα, 6 hours following stimulation, while it had no effect on IFNα, CXCL5 and PAI-1 expression. We further examined whether SARS-CoV-2 S protein, when combined with TLR2 signals, which are also triggered by SARS-CoV2 and its envelope protein, exerts a different effect in type II alveolar epithelial cells. Simultaneous treatment of A549 cells with SARS-CoV-2 S protein and the TLR2 ligand PAM3csk4 decreased secretion of IL8, IL6 and TNFα, while it significantly increased IFNα, CXCL5 and PAI-1 mRNA expression. To investigate the molecular pathway through which SARS-CoV-2 S protein exerted this immunomodulatory action in alveolar epithelial cells, we measured the induction of MAPK/ERK and PI3K/AKT pathways and found that SARS-CoV-2 S protein induced the activation of the serine threonine kinase AKT. Treatment with the Akt inhibitor MK-2206, abolished the inhibitory effect of SARS-CoV-2 S protein on IL8, IL6 and TNFα expression, suggesting that SARS-CoV-2 S protein mediated its action via AKT kinases. CONCLUSION: The findings of our study, showed that SARS-CoV-2 S protein suppressed inflammatory responses in alveolar epithelial type II cells at early stages of infection through activation of the PI3K/AKT pathway. Thus, our results suggest that at early stages SARS-CoV-2 S protein signals inhibit immune responses to the virus allowing it to propagate the infection while in combination with TLR2 signals enhances PAI-1 expression, potentially affecting the local coagulation cascade.

82. Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies.

Front Immunol

2022 Oct 31

Zou X, Wang L, Xiao L

83. Anti-NMDAR encephalitis in Crohn's disease undergoing long-term infliximab treatment: A case report.

Front Immunol

2022 Oct 31

Oh SJ, Kwon YN, Lee CK

84. Differences of macrophages in the tumor microenvironment as an underlying key factor in glioma patients.

Front Immunol

2022 Oct 31

Wang Y, Liu Y, Zhang C

BACKGROUND: Macrophages, the major immune cells in glioma microenvironment, are closely related to tumor prognosis. Further studies are needed to investigate macrophages, which will be helpful to fully understand the role of it and early achieve clinical translation. METHODS: A total of 1334 glioma cases were enrolled in this study from 3 databases. In our works, the single cell cohorts from GSE89567, GSE84465, and the Chinese Glioma Genome Atlas (CGGA) datasets were used to analyze the key genes of macrophage. The bulk sequencing data from the Cancer Genome Atlas (TCGA) and CGGA datasets were respectively divided into the training set and validation set to test prognostic value of the key genes from single cell analysis. RESULTS: Quantitative and functional differences significantly emerge in macrophage clusters between LGG and GBM. Firstly, we used the Seurat R package to identify 281 genes differentially expressed genes in macrophage clusters between LGG and GBM. Furthermore, based on these genes, we developed a predictive risk model to predict prognosis and reflect the immune microenvironment in glioma. The risk score calculation formula was yielded as follows: Risk score = (0.11 × EXPMACC1) + (-0.31 × EXPOTUD1) + (-0.09 × EXPTCHH) + (0.26 × EXPADPRH) + (-0.40× EXPABCG2) + (0.21 × EXPPLBD1) + (0.12 × EXPANG) + (0.29 × EXPQPCT). The risk score was independently related to prognosis. Further, significant differences existed in immunological characteristics between the low- and high-risk score groups. What is more, mutation analysis found different genomic patterns associated with the risk score. CONCLUSION: This study further confirms that the proportion of macrophage infiltration is not only significantly different, but the function of them is also different. The signature, identified from the differentially expressed macrophage-related genes impacts poor prognosis and short overall survival and may act as therapeutic targets in the future.

85. Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis.

Front Immunol

2022 Oct 31

He X, Shi Y, Zeng Z

86. Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice.

Front Immunol

2022 Oct 31

Chithanathan K, Jürgenson M, Guha M

87. Impact of natural killer cells on outcomes after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

Front Immunol

2022 Oct 3

Mushtaq MU, Shahzad M, Shah AY

BACKGROUND: Natural killer (NK) cells play a vital role in early immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: A literature search was performed on PubMed, Cochrane, and Clinical trials.gov through April 20, 2022. We included 21 studies reporting data on the impact of NK cells on outcomes after HSCT. Data was extracted following the PRISMA guidelines. Pooled analysis was done using the meta-package (Schwarzer et al.). Proportions with 95% confidence intervals (CI) were computed. RESULTS: We included 1785 patients from 21 studies investigating the impact of NK cell reconstitution post-HSCT (8 studies/1455 patients), stem cell graft NK cell content (4 studies/185 patients), therapeutic NK cell infusions post-HSCT (5 studies/74 patients), and pre-emptive/prophylactic NK cell infusions post-HSCT (4 studies/77 patients). Higher NK cell reconstitution was associated with a better 2-year overall survival (OS) (high: 77%, 95%CI 0.73-0.82 vs low: 55%, 95%CI 0.37-0.72; n=899), however, pooled analysis for relapse rate (RR) or graft versus host disease (GVHD) could not be performed due to insufficient data. Higher graft NK cell content demonstrated a trend towards a better pooled OS (high: 65.2%, 95%CI 0.47-0.81 vs low: 46.5%, 95%CI 0.24-0.70; n=157), lower RR (high: 16.9%, 95%CI 0.10-0.25 vs low: 33%, 95%CI 0.04-0.72; n=157), and lower acute GVHD incidence (high: 27.6%, 95%CI 0.20-0.36 vs low: 49.7%, 95%CI 0.26-0.74; n=157). Therapeutic NK or cytokine-induced killer (CIK) cell infusions for hematologic relapse post-HSCT reported an overall response rate (ORR) and complete response (CR) of 48.9% and 11% with CIK cell infusions and 82.8% and 44.8% with NK cell infusions, respectively. RR, acute GVHD, and chronic GVHD were observed in 55.6% and 51.7%, 34.5% and 20%, and 20.7% and 11.1% of patients with CIK and NK cell infusions, respectively. Pre-emptive donor-derived NK cell infusions to prevent relapse post-HSCT had promising outcomes with 1-year OS of 69%, CR rate of 42%, ORR of 77%, RR of 28%, and acute and chronic GVHD rates of 24.9% and 3.7%, respectively. CONCLUSION: NK cells have a favorable impact on outcomes after HSCT. The optimal use of NK cell infusions post-HSCT may be in a pre-emptive fashion to prevent disease relapse.

88. Commentary: Sex-based medicine in psoriatic arthritis: Lessons learned from machine learning-based prediction models.

Front Immunol

2022 Oct 3

Queiro R.

89. Decoupling blood telomere length from age in recipients of allogeneic hematopoietic cell transplant in the BMT-CTN 1202.

Front Immunol

2022 Oct 3

Lai TP, Verhulst S, Dagnall CL

90. Fluorine labelling of therapeutic human tolerogenic dendritic cells for (19)F-magnetic resonance imaging.

Front Immunol

2022 Oct 3

Cooke F, Neal M, Wood MJ

91. PD-1/PD-L1 combined with LAG3 is associated with clinical activity of immune checkpoint inhibitors in metastatic primary pulmonary lymphoepithelioma-like carcinoma.

Front Immunol

2022 Oct 3

Zhong YM, Yin K, Chen Y

92. Live mucosal vaccination stimulates potent protection via varied CD4(+) and CD8(+) T cell subsets against wild-type Brucella melitensis 16M challenge.

Front Immunol

2022 Oct 3

Goodwin ZI, Yang X, Hoffman C

93. IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers.

Front Immunol

2022 Oct 3

Xu L, Li Y, Wu X.

94. Biomarkers and mechanisms of tolerance induction in food allergic patients drive new therapeutic approaches.

Front Immunol

2022 Oct 3

Baloh CH, Huffaker MF, Laidlaw T.

95. A humanized mouse model for in vivo evaluation of invariant Natural Killer T cell responses.

Front Immunol

2022 Oct 3

Saavedra-Avila NA, Dellabona P, Casorati G

96. Dynamic changes in metabolites of the kynurenine pathway in Alzheimer's disease, Parkinson's disease, and Huntington's disease: A systematic Review and meta-analysis.

Front Immunol

2022 Oct 3

Fathi M, Vakili K, Yaghoobpoor S

BACKGROUND: Tryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide adenosine dinucleotide (NAD+), and metabolites of this pathway may have protective or degenerative effects on the nervous system. Thus, the KP may be involved in neurodegenerative diseases. OBJECTIVES: The purpose of this systematic review and meta-analysis is to assess the changes in KP metabolites such as TRP, kynurenine (KYN), kynurenic acid (KYNA), Anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 5-Hydroxyindoleacetic acid (5-HIAA), and 3-Hydroxyanthranilic acid (3-HANA) in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) patients compared to the control group. METHODS: We conducted a literature search using PubMed/Medline, Scopus, Google Scholar, Web of Science, and EMBASE electronic databases to find articles published up to 2022. Studies measuring TRP, KYN, KYNA, AA, 3-HK, 5-HIAA, 3-HANA in AD, PD, or HD patients and controls were identified. Standardized mean differences (SMDs) were used to determine the differences in the levels of the KP metabolites between the two groups. RESULTS: A total of 30 studies compromising 689 patients and 774 controls were included in our meta-analysis. Our results showed that the blood levels of TRP was significantly lower in the AD (SMD=-0.68, 95% CI=-0.97 to -0.40, p=0.000, I2 = 41.8%, k=8, n=382), PD (SMD=-0.77, 95% CI=-1.24 to -0.30, p=0.001, I2 = 74.9%, k=4, n=352), and HD (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) patients compared to the controls. Moreover, the CSF levels of 3-HK in AD patients (p=0.020) and the blood levels of KYN in HD patients (p=0.020) were lower compared with controls. CONCLUSION: Overall, the findings of this meta-analysis support the hypothesis that the alterations in the KP may be involved in the pathogenesis of AD, PD, and HD. However, additional research is needed to show whether other KP metabolites also vary in AD, PD, and HD patients. So, the metabolites of KP can be used for better diagnosing these diseases.

97. MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity.

Front Immunol

2022 Oct 3

Gelzo M, Castaldo A, Giannattasio A

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

98. CD18 controls the development and activation of monocyte-to-macrophage axis during chronic schistosomiasis.

Front Immunol

2022 Oct 3

Souza COS, Elias-Oliveira J, Pastore MR

Schistosomiasis is a neglected tropical disease caused by worms of the genus Schistosoma spp. The progression of disease results in intense tissue fibrosis and high mortality rate. After egg deposition by adult worms, the inflammatory response is characterized by the robust activation of type 2 immunity. Monocytes and macrophages play critical roles during schistosomiasis. Inflammatory Ly6Chigh monocytes are recruited from the blood to the inflammatory foci and differentiate into alternatively activated macrophages (AAMs), which promote tissue repair. The common chain of β2-integrins (CD18) regulates monocytopoiesis and mediates resistance to experimental schistosomiasis. There is still limited knowledge about mechanisms controlled by CD18 that impact monocyte development and effector cells such as macrophages during schistosomiasis. Here, we show that CD18low mice chronically infected with S. mansoni display monocyte progenitors with reduced proliferative capacity, resulting in the accumulation of the progenitor cell denominated proliferating-monocyte (pMo). Consequently, inflammatory Ly6Chigh and patrolling Ly6Clow monocytes are reduced in the bone marrow and blood. Mechanistically, low CD18 expression decreases Irf8 gene expression in pMo progenitor cells, whose encoded transcription factor regulates CSFR1 (CD115) expression on the cell surface. Furthermore, low CD18 expression affects the accumulation of inflammatory Ly6Chigh CD11b+ monocytes in the liver while the adoptive transference of these cells to infected-CD18low mice reduced the inflammatory infiltrate and fibrosis in the liver. Importantly, expression of Il4, Chil3l3 and Arg1 was downregulated, CD206+PD-L2+ AAMs were reduced and there were lower levels of IL-10 in the liver of CD18low mice chronically infected with S. mansoni. Overall, these findings suggest that CD18 controls the IRF8-CD115 axis on pMo progenitor cells, affecting their proliferation and maturation of monocytes. At the same time, CD18 is crucial for the appropriate polarization and function of AAMs and tissue repair during chronic schistosomiasis.

99. Helminth infection and helminth-derived products: A novel therapeutic option for non-alcoholic fatty liver disease.

Front Immunol

2022 Oct 3

Liu X, Jiang Y, Ye J

100. Atopy as an independent predictor for long-term patient and graft survival after kidney transplantation.

Front Immunol

2022 Oct 3

Porret R, Meier RPH, Mikulic J

101. T-cell deficiency and hyperinflammatory monocyte responses associate with Mycobacterium avium complex lung disease.

Front Immunol

2022 Oct 3

Lindestam Arlehamn CS, Benson B, Kuan R

102. Case report: Ruxolitinib as first-line therapy for secondary hemophagocytic lymphohistiocytosis in patients with AIDS.

Front Immunol

2022 Oct 3

Liu X, Zhu X, Zhou X

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a fatal immunological syndrome resulting from excessive production of inflammatory cytokines. The conventional therapies for HLH, which are based on cytotoxic agents, are not always efficacious and safe, especially in patients with severe immunodeficiency. Ruxolitinib, a strong inhibitor of Janus kinase (JAK) 1/2, has already been evaluated as salvage and first-line therapy for HLH. Despite its promising efficacy and tolerability in the treatment of secondary HLH, the efficacy and safety of ruxolitinib in HLH patients with HIV infection remain to be investigated. CASE PRESENTATION: Two men (ages: 45 and 58 years) both presented at our hospital with a high fever. They were found to be HIV-positive with severe immunodeficiency and opportunistic infections. Their laboratory tests showed severe pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and increased levels of inflammatory factors and ferritin. Hemophagocytosis was found in the bone marrow, and abdominal computed tomography or ultrasonography showed splenomegaly. Both patients were diagnosed with infection-induced HLH due to severe immunodeficiency. Given they were both highly immunocompromised, we chose ruxolitinib as a first-line treatment alternative to cytotoxic chemotherapy. Rapid remission of clinical symptoms and normalization of laboratory parameters were achieved after ruxolitinib therapy. Neither patient had any associated adverse drug reactions or other laboratory abnormalities. Both patients were eventually discharged and ruxolitinib was discontinued as their disease alleviated, and they did not show signs of relapse during the 3- and 5-month of follow-up examinations. CONCLUSION: We described two cases of AIDS-related secondary HLH treated with ruxolitinib. Our cases highlight the feasibility of using ruxolitinib as a first-line therapy in patients with HIV infection and secondary HLH. Nevertheless, the safety and efficacy of this novel treatment need to be evaluated in large clinical trials in the future.

103. Distinct responses of newly identified monocyte subsets to advanced gastrointestinal cancer and COVID-19.

Front Immunol

2022 Oct 3

Rigamonti A, Castagna A, Viatore M

Monocytes are critical cells of the immune system but their role as effectors is relatively poorly understood, as they have long been considered only as precursors of tissue macrophages or dendritic cells. Moreover, it is known that this cell type is heterogeneous, but our understanding of this aspect is limited to the broad classification in classical/intermediate/non-classical monocytes, commonly based on their expression of only two markers, i.e. CD14 and CD16. We deeply dissected the heterogeneity of human circulating monocytes in healthy donors by transcriptomic analysis at single-cell level and identified 9 distinct monocyte populations characterized each by a profile suggestive of specialized functions. The classical monocyte subset in fact included five distinct populations, each enriched for transcriptomic gene sets related to either inflammatory, neutrophil-like, interferon-related, and platelet-related pathways. Non-classical monocytes included two distinct populations, one of which marked specifically by elevated expression levels of complement components. Intermediate monocytes were not further divided in our analysis and were characterized by high levels of human leukocyte antigen (HLA) genes. Finally, we identified one cluster included in both classical and non-classical monocytes, characterized by a strong cytotoxic signature. These findings provided the rationale to exploit the relevance of newly identified monocyte populations in disease evolution. A machine learning approach was developed and applied to two single-cell transcriptome public datasets, from gastrointestinal cancer and Coronavirus disease 2019 (COVID-19) patients. The dissection of these datasets through our classification revealed that patients with advanced cancers showed a selective increase in monocytes enriched in platelet-related pathways. Of note, the signature associated with this population correlated with worse prognosis in gastric cancer patients. Conversely, after immunotherapy, the most activated population was composed of interferon-related monocytes, consistent with an upregulation in interferon-related genes in responder patients compared to non-responders. In COVID-19 patients we confirmed a global activated phenotype of the entire monocyte compartment, but our classification revealed that only cytotoxic monocytes are expanded during the disease progression. Collectively, this study unravels an unexpected complexity among human circulating monocytes and highlights the existence of specialized populations differently engaged depending on the pathological context.

104. Probiotics as multifaceted oral vaccines against colon cancer: A review.

Front Immunol

2022 Oct 3

Singh S, Singh M, Gaur S.

105. Maternal, fetal and neonatal outcomes among pregnant women receiving COVID-19 vaccination: The preg-co-vax study.

Front Immunol

2022 Oct 3

Mascolo A, di Mauro G, Fraenza F

INTRODUCTION: Although the European Medicines Agency (EMA) encourage coronavirus disease 2019 (COVID-19) vaccination in pregnant women, the scientific evidence supporting the use of COVID-19 vaccines during pregnancy is still limited. AIM: We aimed to investigate adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy. METHODS: We retrieved Individual Case Safety Reports (ICSRs) related to the use of COVID-19 vaccines during pregnancy from the EudraVigilance database for the year 2021. We analyzed AEFI related to the mother and fetus/newborn. The reporting odds ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between COVID-19 vaccines. RESULTS: During the study period, among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports related to the use in pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. Although the majority (87.82%) of ICSRs concerned serious AEFI, their outcomes were mostly favorable. In this study, 85.0% of total ICSRs referred to pregnant women (n = 2,764), while 7.9% referred to fetuses/newborns (n = 258). We identified 16,569 AEFI. Moreover, 55.16% were AEFI not related to pregnancy (mostly headache, pyrexia, and fatigue), while 17.92% were pregnancy-, newborn-, or fetus-related AEFI. Among pregnancy-related AEFI, the most reported was spontaneous abortion. Messenger RNA (mRNA) vaccines had a lower reporting probability of spontaneous abortion than viral vector-based vaccines (ROR 0.80, 95% CI 0.69-0.93). Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05-1.38 and ROR 1.26, 95% CI 1.08-1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other COVID-19 vaccines (ROR 0.73, 95% CI 0.64-0.84). In addition, 5.8% of ICSRs reported a fatal outcome. CONCLUSIONS: No strong insight of unknown AEFI associated with COVID-19 vaccination in pregnant women was observed. Considering the high risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, our analysis suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks. However, it is important to continue monitoring the safety profile of COVID-19 vaccines in this subpopulation.

106. Regulation of epigenetic modifications in the head and neck tumour microenvironment.

Front Immunol

2022 Oct 28

Liu H, Wang D, Yang Z

107. Corrigendum: Central role of PD-L1 in cardioprotection resulting from P2Y(4) nucleotide receptor loss.

Front Immunol

2022 Oct 28

Horckmans M, Diaz Villamil E, Bianchini M

108. Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation.

Front Immunol

2022 Oct 28

Saas P, Vetter M, Maraux M

Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., "eat-me" signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.

109. Modulation of immune cell function, IDO expression and kynurenine production by the quorum sensor 2-heptyl-3-hydroxy-4-quinolone (PQS).

Front Immunol

2022 Oct 28

Ogbechi J, Huang YS, Clanchy FIL

110. Identification of a novel sepsis prognosis model and analysis of possible drug application prospects: Based on scRNA-seq and RNA-seq data.

Front Immunol

2022 Oct 28

He H, Huang T, Guo S

111. Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus.

Front Immunol

2022 Oct 28

Ohmes J, Comdühr S, Akbarzadeh R

112. Type 1 regulatory T cell-mediated tolerance in health and disease.

Front Immunol

2022 Oct 28

Freeborn RA, Strubbe S, Roncarolo MG.

113. Anti-inflammatory, antioxidant and anti-virulence roles of atractylodin in attenuating Listeria monocytogenes infection.

Front Immunol

2022 Oct 28

Xu L, Zhou Y, Xu J

114. MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I.

Front Immunol

2022 Oct 28

Mendes MFA, de Souza Bragatte M, Vianna P

115. Exploiting the role of T cells in the pathogenesis of Sjögren's syndrome for therapeutic treatment.

Front Immunol

2022 Oct 28

An Q, Zhao J, Zhu X

116. Phage therapy for Clostridioides difficile infection.

Front Immunol

2022 Oct 28

Fujimoto K, Uematsu S.

117. Local cellular immune response plays a key role in protecting chickens against hepatitis-hydropericardium syndrome (HHS) by vaccination with a recombinant fowl adenovirus (FAdV) chimeric fiber protein.

Front Immunol

2022 Oct 28

De Luca C, Schachner A, Heidl S

118. Development of a novel glycolysis-related genes signature for isocitrate dehydrogenase 1-associated glioblastoma multiforme.

Front Immunol

2022 Oct 28

Cai X, Chen Z, Huang C

119. An ion-channel-gene-based prediction model for head and neck squamous cell carcinoma: Prognostic assessment and treatment guidance.

Front Immunol

2022 Oct 28

Han Y, Shi Y, Chen B

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a very diverse malignancy with a poor prognosis. The purpose of this study was to develop a new signature based on 12 ion channel genes to predict the outcome and immune status of HNSCC patients. METHODS: Clinicopathological information and gene sequencing data of HNSCC patients were generated from the Cancer Genome Atlas and Gene Expression Omnibus databases. A set of 323 ion channel genes was obtained from the HUGO Gene Nomenclature Committee database and literature review. Using univariate Cox regression analysis, the ion channel genes related to HNSCC prognosis were identified. A prognostic signature and nomogram were then created using machine learning methods. Kaplan-Meier analysis was used to explore the relevance of the risk scores and overall survival (OS). We also investigated the association between risk scores, tumor immune infiltration, and gene mutational status. Finally, we detected the expression levels of the signature genes by quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: We separated the patients into high- and low-risk groups according to the risk scores computed based on these 12 ion channel genes, and the OS of the low-risk group was significantly longer (p<0.001). The area under the curve for predicting 3-year survival was 0.729. Univariate and multivariate analyses showed that the 12-ion-channel-gene risk model was an independent prognostic factor. We also developed a nomogram model based on risk scores and clinicopathological variables to forecast outcomes. Furthermore, immune cell infiltration, gene mutation status, immunotherapy response, and chemotherapeutic treatment sensitivity were all linked to risk scores. Moreover, high expression levels of ANO1, AQP9, and BEST2 were detected in HNSCC tissues, whereas AQP5, SCNN1G, and SCN4A expression was low in HNSCC tissues, as determined by experiments. CONCLUSION: The 12-ion-channel-gene prognostic signatures have been demonstrated to be highly efficient in predicting the prognosis, immune microenvironment, gene mutation status, immunotherapy response, and chemotherapeutic sensitivity of HNSCC patients.

120. Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease.

Front Immunol

2022 Oct 28

Zhang H, Zhao S, Cao Z.

121. CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways.

Front Immunol

2022 Oct 28

Dicker M, Li Y, Giles DA

Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183, known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18. Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn's disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag-/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag-/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine.

122. Next generations of CAR-T cells - new therapeutic opportunities in hematology?

Front Immunol

2022 Oct 28

Tomasik J, Jasiński M, Basak GW.

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

Front Immunol

2022 Oct 27

Huang Y, Zhu M, Liu Z

124. Exposure to ambient gaseous pollutant and daily hospitalizations for Sjögren's syndrome in Hefei: A time-series study.

Front Immunol

2022 Oct 27

Zhang TP, Wang LJ, Wang S

125. An update on the use of cryoablation and immunotherapy for breast cancer.

Front Immunol

2022 Oct 27

Olagunju A, Forsman T, Ward RC.

126. Effect of the change in antiviral therapy indication on identifying significant liver injury among chronic hepatitis B virus infections in the grey zone.

Front Immunol

2022 Oct 27

Ren S, Wang W, Lu J

OBJECTIVE: In clinical practice, a substantial proportion of chronic hepatitis B virus (HBV) infections that do not fit into any of the usual immune states are considered to be in the "grey zone (GZ)". This study aimed to investigate the effect of the change in antiviral therapy indication on identifying significant hepatic injury among GZ patients. METHODS: Patients with chronic HBV infections and a persistent normal alanine aminotransferase (ALT) level (PNALT) who underwent ultrasonography-guided percutaneous liver biopsy were examined retrospectively. Evidenced hepatic injury (EHI) was defined as an inflammation grade ≥2 (≥G2) and/or fibrosis stage ≥2 (≥F2). Complete clinical data, liver inflammation, and fibrosis grades were collected, and the levels of cytokines were detected by the Luminex technique, all of which were analysed to investigate the immune and histopathology states of the liver. RESULTS: A total of 347 patients with chronic HBV infections and PNALT were categorized into immune tolerant (IT, n = 108), inactive HBV surface antigen (HBsAg) carrier (IHC, n = 61), GZ-1 (HBeAg positive in GZ, n = 92), and GZ-2 (HBeAg negative in GZ, n = 68) phases. Among them, 51.3% were in the GZ phase, and 50.1% presented with EHI. The IL-6 levels were higher in the EHI group than in the non-EHI group (2.77 vs. 1.53 pg/ml, Z = -13.32, p = 0.028). The monocyte chemoattractant protein 1 (MCP-1) level was positively correlated with HBV DNA (R = 0.64, p < 0.001) and HBeAg (R = 0.5, p < 0.001) but negatively correlated with fibrosis grade (R = -0.26, p = 0.048). The ratio of EHI in the GZ phase was 60.55%, which was significantly higher than that in patients in the IT (39.8%) and IHC phases (37.7%) (χ2 = 10.4, p = 0.006). A total of 46.69% of all patients exceeded the new ALT antiviral treatment threshold (30 U/L for men and 19 U/L for women). The EHI values in the IT and IHC phases below the new ALT threshold were 32.6% and 37.8%, respectively, whereas higher EHI values of 67.4% and 68.4% were seen in GZ-1 and GZ-2 patients, respectively, exceeding the new ALT threshold, and the difference was statistically significant (χ2 = 11.13, p < 0.001; χ2 = 14.22, p = 0.002). The median age in our cohort was 38.91 years, and only 21.03% were less than 30 years old. The EHI values in the IT and IHC patients <30 years old were 32.4% and 35.8%, respectively, while the ratio of EHI increased to 43.2% once patients were older than 30 years but still in the IT and IHC stages. CONCLUSION: Setting 30 years old as a cut-off and lowering the ALT threshold could facilitate screening for the presence of significant liver injury, especially for GZ patients. IL-6 was a good indicator of EHI, and MCP-1 was significantly positively correlated with HBV DNA but negatively correlated with liver fibrosis.

127. Bibliometric analysis of tumor necrosis factor in post-stroke neuroinflammation from 2003 to 2021.

Front Immunol

2022 Oct 27

Zhao Y, Zhu Q, Bi C

OBJECTIVE: Tumor necrosis factor (TNF), a crucial cytokine, has important research value in post-stroke neuroinflammation (PSN). We analyzed the studies that have been conducted in this area and used bibliometric methods to predict research hotspots and identify trends regarding TNF in PSN. METHODS: Publications were accessed at the Science Citation Index Expanded 1975-2021 (SCI expanded), Web of Science Core Collection (WoSCC), on May 1, 2022. Additionally, software such as CiteSpace and VOSviewer were utilized for bibliometric analyses. RESULTS: In total, 1391 original articles and reviews on TNF in PSN published from 2003 to 2021 were identified. An upward trend was observed in the number of publications on TNF in PSN. These publications were primarily from 57 countries and 1446 institutions, led by China and the United States with China leading the number of publications (NP) and the US with the number of citations (NC). The League of European Research Universities (LERU) and Journal of Neuroinflammation, respectively were the most prolific branches and journals. Zhang, John H. published the most papers and Finsen, Bente had the most cited papers. One paper by Kettenmann, H. published in 2011 reached the highest level of Global Citation Score (GCS). The keyword co-occurrence and reference co-citation analyses suggest that poststroke therapy and potential mechanistic pathways are important topics related to PSN in recent years. Reference burst detection suggests new burst hotspots after 2015, focusing on pathway modulation and discovery of therapeutic targets, suggesting a substantial development in the study of TNF in PSN research. CONCLUSION: The present bibliometric analysis shows a continuous trend of increasing literature related to TNF in PSN, and shows that TNF plays an important role in PSN involves multiple immune mechanisms and may contribute as a potential target for neuroprotective therapeutics after stroke. Prior to 2011, most of the research was focused on discovering the specific role of TNF in PSN, and in recent years studies have mainly targeted the exploration of the signaling pathways. Future research prospects may lie in finding key therapeutic targets in pathway of TNF in PSN.

128. Distinct immune and inflammatory response patterns contribute to the identification of poor prognosis and advanced clinical characters in bladder cancer patients.

Front Immunol

2022 Oct 27

Chang Z, Li R, Zhang J

Due to the molecular heterogeneity, most bladder cancer (BLCA) patients show no pathological responses to immunotherapy and chemotherapy yet suffer from their toxicity. This study identified and validated three distinct and stable molecular clusters of BLCA in cross-platform databases based on personalized immune and inflammatory characteristics. H&E-stained histopathology images confirmed the distinct infiltration of immune and inflammatory cells among clusters. Cluster-A was characterized by a favorable prognosis and low immune and inflammatory infiltration but showed the highest abundance of prognosis-related favorable immune cell and inflammatory activity. Cluster-B featured the worst prognosis and high immune infiltration, but numerous unfavorable immune cells exist. Cluster-C had a favorable prognosis and the highest immune and inflammatory infiltration. Based on machine learning, a highly precise predictive model (immune and inflammatory responses signature, IIRS), including FN1, IL10, MYC, CD247, and TLR2, was developed and validated to identify the high IIRS-score group that had a poor prognosis and advanced clinical characteristics. Compared to other published models, IIRS showed the highest AUC in 5 years of overall survival (OS) and a favorable predictive value in predicting 1- and 3- year OS. Moreover, IIRS showed an excellent performance in predicting immunotherapy and chemotherapy's response. According to immunohistochemistry and qRT-PCR, IIRS genes were differentially expressed between tumor tissues with corresponding normal or adjacent tissues. Finally, immunohistochemical and H&E-stained analyses were performed on the bladder tissues of 13 BLCA patients to further demonstrate that the IIRS score is a valid substitute for IIR patterns and can contribute to identifying patients with poor clinical and histopathology characteristics. In conclusion, we established a novel IIRS depicting an IIR pattern that could independently predict OS and acts as a highly precise predictive biomarker for advanced clinical characters and the responses to immunotherapy and chemotherapy.

129. The role of gut microbiota in liver regeneration.

Front Immunol

2022 Oct 27

Xu Z, Jiang N, Xiao Y

130. Insulin-regulated aminopeptidase contributes to setting the intensity of FcR-mediated inflammation.

Front Immunol

2022 Oct 27

Bratti M, Vibhushan S, Longé C

131. Early pathogenesis profiles across SARS-CoV-2 variants in K18-hACE2 mice revealed differential triggers of lung damages.

Front Immunol

2022 Oct 27

Aw ZQ, Mok CK, Wong YH

132. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms.

Front Immunol

2022 Oct 27

Giménez-Orenga K, Pierquin J, Brunel J

133. Single-cell RNA sequencing reveals TCR(+) macrophages in HPV-related head and neck squamous cell carcinoma.

Front Immunol

2022 Oct 27

Jiang Y, Zhang S, Tang L

134. Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases.

Front Immunol

2022 Oct 27

Jiao L, Guo S.

135. Haploidentical donor stem cell transplantation had a lower incidence of bronchiolitis obliterans syndrome compared with HLA-matched sibling donor transplantation in patients with hematologic malignancies: Benefit from ATG?

Front Immunol

2022 Oct 27

Weng G, Fan Z, Xue H

BACKGROUND: Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation. METHODS: One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed. RESULTS: The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001). CONCLUSIONS: HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts.

136. A novel asexual blood-stage malaria vaccine candidate: PfRipr5 formulated with human-use adjuvants induces potent growth inhibitory antibodies.

Front Immunol

2022 Oct 27

Takashima E, Nagaoka H, Correia R

137. Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages.

Front Immunol

2022 Oct 27

Zeller T, Lutz S, Münnich IA

138. Case report: Patient specific combination of surgery and immunotherapy in advanced squamous cell carcinoma of the head and neck - a case series and review of literature.

Front Immunol

2022 Oct 27

Olmos M, Lutz R, Büntemeyer TO

BACKGROUND: Prognosis of patients with recurrent or metastatic head and neck cancer is generally poor. Adjuvant immunotherapy (IT) featuring immune checkpoint inhibition (ICI) is standard of care in advanced stage head and neck squamous cell carcinoma (HNSCC) and cutaneous squamous cell carcinoma (CSCC). ICI response rates in CSCC are described as higher than in HNSCC. IT is constantly shifting into earlier disease stages which confronts the surgeon with immunotherapeutically pre-treated patients. It is therefore becoming increasingly difficult to assess which patients with symptomatic tumor disease and a lack of curative surgical option might benefit from salvage surgery. CASE PRESENTATIONS: The following 6 cases describe therapeutic decision-making regarding ICI and (salvage) surgery in patients with advanced stage HNSCC or CSCC. Cases A and B focus on neoadjuvant ICI followed by salvage surgery. In Cases C and D salvage surgery was performed after short-term stabilization with partial response to ICI. The last two cases (Cases E and F) address the surgical approach after failure of ICI. All cases are discussed in the context of the current study landscape and with focus on individual decision-making. For better understanding, a timetable of the clinical course is given for each case. CONCLUSIONS: ICI is rapidly expanding its frontiers into the neoadjuvant setting, frequently confronting the surgeon with heavily pretreated patients. Salvage surgery is a viable therapeutic concept despite the rise of systemic treatment options. Decision-making on surgical intervention in case of a salvage surgery remains an individual choice. For neoadjuvant ICI monitoring regarding pathological tumor response or tumor necrosis rate, we suggest correlation between the initial biopsy and the definite tumor resectate in order to increase its significance as a surrogate marker. Scheduling of neoadjuvant ICI should be further investigated, as recent studies indicate better outcomes with shorter time frames.

139. Low-dose immunogenic chemotherapeutics promotes immune checkpoint blockade in microsatellite stability colon cancer.

Front Immunol

2022 Oct 27

Fang Y, Sun H, Xiao X

140. Monocyte response after colorectal surgery: A prospective cohort study.

Front Immunol

2022 Oct 27

Edomskis PP, Dik WA, Sparreboom CL

141. Establishment and validation of evaluation models for post-inflammatory pigmentation abnormalities.

Front Immunol

2022 Oct 27

Zhang Y, Zeng H, Hu Y

142. Baricitinib is potentially effective in the treatment of refractory livedoid vasculopathy.

Front Immunol

2022 Oct 27

Han Y, Tu P.

143. Cryoablation and immune synergistic effect for lung cancer: A review.

Front Immunol

2022 Oct 27

Tian Y, Qi X, Jiang X

144. CD38-specific nanobodies allow in vivo imaging of multiple myeloma under daratumumab therapy.

Front Immunol

2022 Oct 27

Pape LJ, Hambach J, Gebhardt AJ

145. Editorial: Dissecting the immunological, pathological, and clinical aspects of autoimmune gastritis and its neoplastic complications.

Front Immunol

2022 Oct 27

Lenti MV, Annibale B, Di Sabatino A

146. RNA m(5)C regulator-mediated modification patterns and the cross-talk between tumor microenvironment infiltration in gastric cancer.

Front Immunol

2022 Oct 27

Zhang Q, Sun X, Sun J

147. Developmental defects and behavioral changes in a diet-induced inflammation model of zebrafish.

Front Immunol

2022 Oct 26

Rehman S, Gora AH, Varshney S

148. CD3e-immunotoxin spares CD62L(lo) Tregs and reshapes organ-specific T-cell composition by preferentially depleting CD3e(hi) T cells.

Front Immunol

2022 Oct 26

Kim S, Shukla RK, Yu H

149. IgTreeZ, A Toolkit for Immunoglobulin Gene Lineage Tree-Based Analysis, Reveals CDR3s Are Crucial for Selection Analysis.

Front Immunol

2022 Oct 26

Neuman H, Arrouasse J, Kedmi M

150. New insights into iNKT cells and their roles in liver diseases.

Front Immunol

2022 Oct 26

Gu X, Chu Q, Ma X

151. Identification of a novel role for matrix metalloproteinase-3 in the modulation of B cell responses in multiple sclerosis.

Front Immunol

2022 Oct 26

Chunder R, Schropp V, Jabari S

152. Respiratory tract infections and risk factors for infection in a cohort of 330 patients with axial spondyloarthritis or psoriatic arthritis.

Front Immunol

2022 Oct 26

Frede N, Rieger E, Lorenzetti R

Respiratory tract infections (RTIs) are the most common infections in patients with rheumatic diseases under immunosuppressive treatment and may contribute to morbidity and mortality as well as increased healthcare costs. However, to date only limited data on infection risk in spondyloarthritis (SpA) patients are available. In this study we assessed the occurrence of respiratory tract infections in a monocentric real-world cohort consisting of 330 patients (168 psoriatic arthritis and 162 axial spondyloarthritis patients) and determined factors associated with increased infection risk. Out of 330 SpA patients, 89.3% had suffered from ≥ 1 upper respiratory tract infection (URTI) and 31.1% from ≥ 1 lower respiratory tract infection (LRTI) within the last two years. The most common URTIs were rhinitis and laryngitis/pharyngitis with 87.3% and 36.1%, respectively. Bronchitis constituted the most common LRTI, reported in 29.7% of patients. In a multivariate binomial logistic regression model occurrence of LRTI was associated with chronic lung disease (OR 17.44, p=0.006), glucocorticoid therapy (OR 9.24, p=0.012), previous history of severe airway infections (OR 6.82, p=0.013), and number of previous biological therapies (OR 1.72, p=0.017), whereas HLA B27 positivity was negatively associated (OR 0.29, p=0.025). Female patients reported significantly more LRTIs than male patients (p=0.006) and had a higher rate of antibiotic therapy (p=0.009). There were no significant differences between axSpA and PsA patients regarding infection frequency or antibiotic use. 45.4% of patients had required antibiotics for respiratory tract infections. Antibiotic therapy was associated with smoking (OR 3.40, p=0.008), biological therapy (OR 3.38, p=0.004), sleep quality (OR 1.13, p<0.001) and age (OR 0.96, p=0.030). Hypogammaglobulinemia (IgG<7g/l) was rare (3.4%) in this SpA cohort despite continuous immunomodulatory treatment. Awareness of these risk factors will assist physicians to identify patients with an increased infection risk, who will benefit from additional preventive measures, such as vaccination and smoking cessation or adjustment of DMARD therapy.

153. Association between the side effect induced by COVID-19 vaccines and the immune regulatory gene polymorphism.

Front Immunol

2022 Oct 26

Chen DP, Wen YH, Lin WT

People often worry about the side effects after vaccination, reducing the willingness to vaccinate. Thus, we tried to find out the risk of single nucleotide polymorphism (SNP) vaccines to improve the willingness and confidence in vaccination. Allergic and inflammatory reactions are the common vaccine side effects caused by immune system overreaction. In addition, a previous study showed significantly higher frequency of febrile reactions to measles vaccines in American Indians than in Caucasian children, indicating that the side effects varied in accordance with genetic polymorphisms in individuals. Thus, SNPs of immune regulatory genes, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily member 4 (TNFSF4) and programmed cell death protein 1 (PDCD1) were included in this study to analyze their association with vaccine side effects. Moreover, 61 healthy participants were asked on the number of doses they received, the brand of the vaccine, and the side effects they suffered. We found that several SNPs were associated with side effects after the first or second dose of mRNA or adenoviral vector vaccines. Furthermore, these SNPs were associated with several autoimmune diseases and cancer types; thus, they played an important role in immune regulation. Moreover, rs3181096 and rs3181098 of CD28, rs733618 and rs3087243 of CTLA, and rs1234314 of TNFSF4 were associated with mild vaccine side effects induced by mRNA and adenoviral vector vaccines, which would play a potential role in vaccine-induced immune responses and may further lead to fatal side effects. These results could serve as a basis for investigating the mechanism of vaccine side effects. Furthermore, it was hoped that these results would address public concerns about the side effects of the COVID-19 vaccination. In clinical application, a rapid screening test can be performed to assess the risk of vaccine side effects before vaccination and provide immediate treatment.

154. Non-criteria antiphospholipid antibodies in antiphospholipid syndrome: Diagnostic value added.

Front Immunol

2022 Oct 26

Liu X, Zhu L, Liu H

155. A network view of human immune system and virus-human interaction.

Front Immunol

2022 Oct 26

Tang K, Tang J, Zeng J

156. Identification of cerebrospinal fluid biomarker candidates for anti-N-methyl-D-aspartate receptor encephalitis: High-throughput proteomic investigation.

Front Immunol

2022 Oct 26

Li Y, Yang K, Zhang F

BACKGROUND: Although the diagnosis is mainly dependent on the detection of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in cerebrospinal fluid (CSF) and/or serum, there was no direct correlations between anti-NMDAR antibody titers in CSF and disease severity and prognosis in anti-NMDAR encephalitis patients. Here, we aimed to extensively identify CSF biomarkers related to the occurrence, development, and prognosis of anti-NMDAR encephalitis using a high-throughput proteomic approach. METHODS: A CSF cytokine antibody array containing 80 cytokines and inflammatory mediators related to immune and inflammatory responses was applied to identify biomarker candidates in individual CSF samples from a well-characterized cohort comprising patients with anti-NMDAR encephalitis (n = 6) and controls (n = 6). Validation and specific detection were performed in an extended cohort consisting of anti-NMDAR encephalitis patients (n = 13), controls (n = 13), and viral encephalitis (n = 13) by enzyme-linked immunosorbent assay (ELISA). Additionally, the levels of some inflammatory proteins in three groups in cohort 2 reported in previous literatures that may be involved in the development of anti-NMDAR encephalitis were also tested by ELISA. Correlations between candidate biomarkers and clinical characteristics of anti-NMDAR encephalitis patients were analyzed. RESULTS: Three differentially expressed cytokines and inflammatory mediators were screened from the 80-cytokine array in cohort 1. Functional enrichment analysis results suggested that these differentially expressed proteins were related to autophagy, immune/inflammatory responses, cell death, and other processes. In cohort 2, the elevations of cellular inhibitor of apoptosis protein-1 (cIAP-1), macrophage colony-stimulating factor (MCSF), CXC chemokine ligand 13 (CXCL13), and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) in anti-NMDAR encephalitis were validated by ELISA. Linear regression revealed that the levels of CSF CXCL13 and cIAP-1 were positively correlated with the highest modified Rankin scale (mRS) score in the acute phase (p < 0.05). The level of cIAP-1 was positively correlated with the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score (p < 0.05). CONCLUSION: These biomarkers show promising functions to evaluate severity or prognosis of anti-NMDAR encephalitis. The biological processes of immune/inflammatory responses, altered levels of autophagy, and the tumor necrosis factor (TNF) signal pathway may be involved in the pathophysiology of anti-NMDAR encephalitis to some extent.

157. Microwave ablation combined with apatinib and camrelizumab in patients with advanced hepatocellular carcinoma: A single-arm, preliminary study.

Front Immunol

2022 Oct 26

Li X, Zhang Q, Lu Q

PURPOSE: The aim of this study was to assess the safety and efficacy of microwave ablation combined with apatinib [vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor] and camrelizumab [anti-programmed death-1 (PD-1) antibody] in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients (age, >18 years) with histologically confirmed HCC and refractory to at least the standard first-line therapy were enrolled from 2 September 2018 to 17 January 2022. They first received ultrasound-guided subtotal microwave ablation. Then, beginning at 7-14 days after ablation, they were given apatinib (250 mg once daily) and camrelizumab (200 mg once every 2 weeks) until unacceptable toxicity or disease progression or death. The coprimary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: Fourteen HCC patients with Barcelona Clinic of Liver Cancer (BCLC) B and C stages were retrospectively enrolled. At data cutoff, follow-up period ranged from 3.8 to 41.3 months (median, 17.4 months), and the median (95% confidence interval) duration of exposure (DE) was 6.4 (4.0-8.9) months. The PFS and OS were 10.8 (0-23.5) months and 19.3 (2.4-36.2) months, respectively. Three (21.4%) patients achieved a confirmed complete response (CR). Confirmed partial response (PR), stable disease (SD), and progression of disease (PD) were achieved in four (28.6%), four (28.6%), and three (21.4%) patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were 50.0% (20.0%-80.0%) and 78.6% (54.0%-100%), respectively. The serious treatment-related adverse events included one (7.1%) case with reactive capillary hemangiomas (grade 4), one (7.1%) with hypertension (grade 3), two (14.3%) with elevated transaminase and bilirubin (grade 4), one (7.1%) with platelet count decrease (grade 4), one (7.1%) with hepatic failure (grade 4), and two (14.3%) with gastrointestinal bleeding (grades 3 and 4). CONCLUSIONS: Microwave ablation combined with apatinib and camrelizumab treatment in advanced HCC patients demonstrated intriguing clinical activity and resulted in durable antitumor responses and significantly improved PFS and OS. The combination therapy is well tolerated, enabling further clinical studies.

158. Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy.

Front Immunol

2022 Oct 25

Kc N, Church LWP, Riyahi P

BACKGROUND: While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. METHODS: Using a standardized enzyme-linked immunosorbent assay, IgG antibodies to the major surface protein on Plasmodium falciparum (Pf) sporozoites (SPZ), the Pf circumsporozoite protein (PfCSP), were measured before and two weeks after administration of a PfSPZ-based malaria vaccine (PfSPZ Vaccine) to 5-month to 61-year-olds in 11 clinical trials in Germany, the US and five countries in Africa, to determine if there were differences in vaccine elicited antibody response between males and females and if these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). RESULTS: Females ≥ 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. CONCLUSION: Immunization with PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. We conclude that the increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver.

159. Fully understanding the efficacy profile of the COVID-19 vaccination and its associated factors in multiple real-world settings.

Front Immunol

2022 Oct 25

Panahi Y, Einollahi B, Beiraghdar F

160. Comparison of pulmonary lesions using lung ultrasound and high-resolution computed tomography in adult patients with primary humoral immunodeficiencies.

Front Immunol

2022 Oct 25

Ziętkiewicz M, Buda N, Więsik-Szewczyk E

Pulmonary involvement is the most common complication in patients with predominantly antibody deficiencies (PADs). Therefore, patients require repeated imaging tests. Unlike high-resolution computed tomography (HRCT), lung ultrasonography (LUS) does not expose patients to X-rays or contrast agents, and can be performed even at the bedside. This study aimed to evaluate lung lesions using simultaneous LUS and HRCT in a group of patients with PADs. Twenty-nine adult patients (13 women and 16 men) diagnosed with PADs according to the ESID criteria (23 Common variable immunodeficiency, 2 X-linked agammaglobulinemia, 2 IgG subclass deficiencies, and 2 Unspecified hypogammaglobulinemia) were included in the study. The mean age was 39.0 ± 11.9 years. The mean time elapsed between the first symptoms of PADs and the examination was 15.4 ± 10.1 years. Lung ultrasonography and high-resolution computed tomography were performed simultaneously according to a defined protocol during the clinic visits. In both examinations, lesions were compared in the same 12 regions: for each lung in the upper, middle, and lower parts, separately, front and back. A total of 435 lesions were described on LUS, whereas 209 lesions were described on HRCT. The frequencies of lesions in the lung regions were similar between LUS and HRCT. In both examinations, lesions in the lower parts of the lungs were most often reported (LUS 60.9% vs. HRCT 55.5%) and least often in the upper parts of the lungs (LUS 12.7% vs. HRCT 12.0%). The most frequently described lesions were LUS consolidations (99; 22.8%) and HRCT fibrosis (74; 16.5%). A statistically significant relationship was found in the detection of fibrosis in 11 of the 12 regions (phi = 0.4-1.0). Maximum values of the phi coefficient for the upper part of the left lung were recorded. Compared with HRCT, LUS is an effective alternative for evaluating and monitoring pulmonary lesions in adult patients with PADs, especially for pulmonary fibrosis.

161. Comprehensive analysis of cuproptosis-related genes in immune infiltration and diagnosis in ulcerative colitis.

Front Immunol

2022 Oct 25

Huang J, Zhang J, Wang F

OBJECTIVES: Cuproptosis is a recently discovered form of programmed cell death; however, its role in ulcerative colitis (UC) remains a void. METHODS: Three gene expression profiles were acquired from the GEO database. Subsequently, the single sample gene set enrichment analysis (ssGSEA) was performed to identify the immune infiltration characteristics of UC. Correlation analysis between cuproptosis and immune infiltration was further conducted, and the cuproptosis-related genes were applied to construct a UC diagnostic model. Subsequently, analysis results of microarray data were experimentally validated by DSS-induced colitis in mice. Finally, therapeutic agents for the cuproptosis-related genes were screened owing to the gaping field of therapeutic agents on cuproptosis. RESULTS: Three gene expression profiles with 343 samples (290 UC and 53 healthy samples) were included. Immune infiltration revealed that UC patients had a higher level of DCs, B cells, CD8+ T cells, iDCs, Macrophages, neutrophils, pDCs, T helper cells, Tfh, Th1 cells, Th2 cells, TIL and Treg than normal subjects. Moreover, almost all cuproptosis-related genes were significantly negatively associated with immune infiltration in UC patients. The risk prediction model based on cuproptosis-related genes showed an excellent discrimination for UC. Animal experiments revealed significant alterations in genes essential for cuproptosis between DSS-induced colitis mice and healthy controls, providing experimental validation for the analysis results of microarray data. Further analysis revealed that latamoxef, vitinoin, clomipramine, chlorzoxazone, glibenclamide, pyruvic acid, clindamycin, medrysone, caspan, and flavin adenine dinucleotide might be the target agents for cuproptosis-related genes. CONCLUSIONS: In conclusion, cuproptosis was significantly associated with immune infiltration in UC, and the cuproptosis-related genes showed an excellent discrimination for UC.

162. Checkpoint inhibitors as immunotherapy for fungal infections: Promises, challenges, and unanswered questions.

Front Immunol

2022 Oct 25

Wurster S, Watowich SS, Kontoyiannis DP.

163. MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil.

Front Immunol

2022 Oct 25

Castelli EC, de Castro MV, Naslavsky MS

BACKGROUND: Although aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome. METHODS: SARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started. RESULTS: We found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins' family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24). CONCLUSION: Since the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.

164. Oral antibiotics relieve allergic asthma in post-weaning mice via reducing iNKT cells and function of ADRB2.

Front Immunol

2022 Oct 25

Li N, Chen J, Xie S

165. Immunosuppressive adenosine-targeted biomaterials for emerging cancer immunotherapy.

Front Immunol

2022 Oct 25

Wei Q, Zhang L, Zhao N

166. Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies.

Front Immunol

2022 Oct 25

Carreón-Talavera R, Santana-Sánchez P, Fuentes-Pananá EM

167. Cancer immunotherapy strategies that target the cGAS-STING pathway.

Front Immunol

2022 Oct 24

Tian Z, Zeng Y, Peng Y

168. A novel risk score based on immune-related genes for hepatocellular carcinoma as a reliable prognostic biomarker and correlated with immune infiltration.

Front Immunol

2022 Oct 24

Long M, Zhou Z, Wei X

169. CEBPB is associated with active tumor immune environment and favorable prognosis of metastatic skin cutaneous melanoma.

Front Immunol

2022 Oct 24

Yang J, Xu Y, Xie K

170. Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B.

Front Immunol

2022 Oct 24

Xie S, Yang L, Bi X

OBJECTIVE: We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV. METHODS: This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg. RESULTS: The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (β=-0.025, t=-2.613, P=0.014; β=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (β=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (β=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (β=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (β=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (β=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (β=-0.137, t=-3.273, P=0.003). CONCLUSIONS: The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.

171. Editorial: Regulatory T lymphocytes in cancer immunity.

Front Immunol

2022 Oct 24

Adeegbe D, Barbi J, Wing J.

172. Short-term safety and immunogenicity of inactivated and peptide-based SARS-CoV-2 vaccines in patients with endocrine-related cancer.

Front Immunol

2022 Oct 24

Song R, Liu L, Pan Q

173. Preclinical and clinical studies of CAR-NK-cell therapies for malignancies.

Front Immunol

2022 Oct 24

Li H, Song W, Li Z

174. Modeling and insights into the structural characteristics of drug-induced autoimmune diseases.

Front Immunol

2022 Oct 24

Guo H, Zhang P, Zhang R

The incidence and complexity of drug-induced autoimmune diseases (DIAD) have been on the rise in recent years, which may lead to serious or fatal consequences. Besides, many environmental and industrial chemicals can also cause DIAD. However, there are few effective approaches to estimate the DIAD potential of drugs and other chemicals currently, and the structural characteristics and mechanism of action of DIAD compounds have not been clarified. In this study, we developed the in silico models for chemical DIAD prediction and investigated the structural characteristics of DIAD chemicals based on the reliable drug data on human autoimmune diseases. We collected 148 medications which were reported can cause DIAD clinically and 450 medications that clearly do not cause DIAD. Several different machine learning algorithms and molecular fingerprints were combined to develop the in silico models. The best performed model provided the good overall accuracy on validation set with 76.26%. The model was made freely available on the website http://diad.sapredictor.cn/. To further investigate the differences in structural characteristics between DIAD chemicals and non-DIAD chemicals, several key physicochemical properties were analyzed. The results showed that AlogP, molecular polar surface area (MPSA), and the number of hydrogen bond donors (nHDon) were significantly different between the DIAD and non-DIAD structures. They may be related to the DIAD toxicity of chemicals. In addition, 14 structural alerts (SA) for DIAD toxicity were detected from predefined substructures. The SAs may be helpful to explain the mechanism of action of drug induced autoimmune disease, and can used to identify the chemicals with potential DIAD toxicity. The structural alerts have been integrated in a structural alert-based web server SApredictor (http://www.sapredictor.cn). We hope the results could provide useful information for the recognition of DIAD chemicals and the insights of structural characteristics for chemical DIAD toxicity.

175. SARS-CoV-2 ORF8: One protein, seemingly one structure, and many functions.

Front Immunol

2022 Oct 24

Vinjamuri S, Li L, Bouvier M.

176. Case report: Long response to PD-1 blockade after failure of trastuzumab plus chemotherapy in advanced Epstein-Barr virus-associated gastric cancer.

Front Immunol

2022 Oct 24

Pan Y, Lu L, Liu H

177. New-onset dermatomyositis following COVID-19: A case report.

Front Immunol

2022 Oct 24

Shimizu H, Matsumoto H, Sasajima T

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most of the infected individuals have recovered without complications, but a few patients develop multiple organ involvements. Previous reports suggest an association between COVID-19 and various inflammatory myopathies, in addition to autoimmune diseases. COVID-19 has been known to exacerbate preexisting autoimmune diseases and trigger various autoantibodies and autoimmune disease occurrence. Here we report a case of complicated COVID-19 with anti-synthetase autoantibodies (ASSs) presenting with skin rash, muscle weakness, and interstitial lung disease (ILD) and subsequently diagnosed with dermatomyositis (DM). A 47-year-old Japanese male patient without any previous history of illness, including autoimmune diseases, presented with a high fever, sore throat, and cough. Oropharyngeal swab for SARS-Cov-2 polymerase chain reaction tested positive. He was isolated at home and did not require hospitalization. However, his respiratory symptoms continued, and he was treated with prednisolone (20 mg/day) for 14 days due to the newly developing interstitial shadows over the lower lobes of both lungs. These pulmonary manifestations remitted within a week. He presented with face edema and myalgia 4 weeks later when he was off corticosteroids. Subsequently, he presented with face erythema, V-neck skin rash, low-grade fever, and exertional dyspnea. High-resolution computed tomography of the chest showed ILD. Biochemical analysis revealed creatine kinase and aldolase elevations, in addition to transaminases. Anti-aminoacyl tRNA synthetase (ARS) was detected using an enzyme-linked immunosorbent assay (170.9 U/mL) (MESACUP™ (Medical & Biological Laboratories, Japan), and the tRNA component was identified as anti-PL-7 and anti-Ro-52 antibodies using an immunoblot assay [EUROLINE Myositis Antigens Profile 3 (IgG), Euroimmun, Lübeck,Germany]. The patient was diagnosed with DM, especially anti- synthase antibody syndrome based on the presence of myositis-specific antibodies, clinical features, and pathological findings. The present case suggests that COVID-19 may have contributed to the production of anti-synthetase antibodies (ASAs) and the development of de novo DM. Our case highlights the importance of the assessment of patients who present with inflammatory myopathy post-COVID-19 and appropriate diagnostic work-up, including ASAs, against the clinical features that mimic DM after post-COVID-19.

178. Biological screening of a unique drug library targeting MRGPRX2.

Front Immunol

2022 Oct 21

Yang F, Limjunyawong N, Peng Q

BACKGROUND: Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets and communicate extracellular signals that initiate cellular responses. Recent evidence shows that GPCR MRGPRX2 is of major importance in IgE-independent pseudo-allergic DHRs based on the suspected interactions between many FDA-approved peptidergic compounds and MRGPRX2. OBJECTIVE: Our aim was to uncover novel MRGPRX2-selective and -potent agonists as drug candidates responsible for clinical features of pseudo-allergic DHRs. METHODS: We conducted a primary high-throughput screening (HTS), coupled with mutagenesis targeting the MRGPRX2 N62S mutation, on a panel of 3,456 library compounds. We discovered pharmacologically active hit compounds as agonists of the MRGPRX2 protein according to high degrees of potency evaluated by the calcium response and validated by the degranulation assay. Using the molecular tool Forge, we also characterized the structure-activity relationship shared by identified hit compounds. RESULTS: The alternative allele of single nucleotide polymorphism rs10833049 (N62S) in MRGPRX2 demonstrated loss-of-function property in response to substance P and antineoplastic agent daunorubicin hydrochloride. We applied a unique assay system targeting the N62S mutation to the HTS and identified 84 MRGPRX2-selective active hit compounds representing diverse classes according to primary drug indications. The top five highly represented groups included fluoroquinolone and non-fluoroquinolone antibiotics; antidepressive/antipsychotic; antihistaminic and antineoplastic agents. We classified hit compounds into 14 clusters representing a variety of chemical and drug classes beyond those reported, such as opioids, neuromuscular blocking agents, and fluoroquinolones. We further demonstrated MRGPRX2-dependent degranulation in the human mast cell line LAD2 cells induced by three novel agonists representing the non-fluoroquinolone antibiotics (bacitracin A), anti-allergic agents (brompheniramine maleate) and tyrosine-kinase inhibitors (imatinib mesylate). CONCLUSION: Our findings could facilitate the development of interventions for personalized prevention and treatment of DHRs, as well as future pharmacogenetic investigations of MRGPRX2 in relevant disease cohorts.

179. Adverse events of immune checkpoint inhibitors for patients with digestive system cancers: A systematic review and meta-analysis.

Front Immunol

2022 Oct 21

Kou L, Wen Q, Xie X

180. Immune defenses of the mammary gland epithelium of dairy ruminants.

Front Immunol

2022 Oct 21

Rainard P, Gilbert FB, Germon P.

181. Humoral and cellular immune responses to CoronaVac up to one year after vaccination.

Front Immunol

2022 Oct 21

Costa PR, Correia CA, Marmorato MP

182. Mining of immunological and prognostic-related biomarker for cervical cancer based on immune cell signatures.

Front Immunol

2022 Oct 21

Wang N, Nanding A, Jia X

BACKGROUND: Immunotherapy has changed the therapeutic landscape of cervical cancer (CC), but has durable anti-tumor activity only in a subset of patients. This study aims to comprehensively analyze the tumor immune microenvironment (TIME) of CC and to mine biomarkers related to immunotherapy and prognosis. METHODS: The Cancer Genome Atlas (TCGA) data was utilized to identify heterogeneous immune subtypes based on survival-related immune cell signatures (ICSs). ICSs prognostic model was constructed by Cox regression analyses, and immunohistochemistry was conducted to verify the gene with the largest weight coefficient in the model. Meanwhile, the tumor immune infiltration landscape was comprehensively characterized by ESTIMATE, CIBERSORT and MCPcounter algorithms. In addition, we also analyzed the differences in immunotherapy-related biomarkers between high and low-risk groups. IMvigor210 and two gynecologic tumor cohorts were used to validate the reliability and scalability of the Risk score. RESULTS: A total of 291 TCGA-CC samples were divided into two ICSs clusters with significant differences in immune infiltration landscape and prognosis. ICSs prognostic model was constructed based on eight immune-related genes (IRGs), which showed higher overall survival (OS) rate in the low-risk group (P< 0.001). In the total population, time-dependent receiver operating characteristic (ROC) curves displayed area under the curve (AUC) of 0.870, 0.785 and 0.774 at 1-, 3- and 5-years. Immunohistochemical results showed that the expression of the oncogene (FKBP10) was negatively correlated with the degree of differentiation and positively correlated with tumor stage, while the expression of tumor suppressor genes (S1PR4) was the opposite. In addition, the low-risk group had more favorable immune activation phenotype and higher enrichment of immunotherapy-related biomarkers. The Imvigor210 and two gynecologic tumor cohorts validated a better survival advantage and immune efficacy in the low-risk group. CONCLUSION: This study comprehensively assessed the TIME of CC and constructed an ICSs prognostic model, which provides an effective tool for predicting patient's prognosis and accurate immunotherapy.

183. Hallucinating structure-conditioned antibody libraries for target-specific binders.

Front Immunol

2022 Oct 21

Mahajan SP, Ruffolo JA, Frick R

184. Establishment and validation of a novel prognostic model for lower-grade glioma based on senescence-related genes.

Front Immunol

2022 Oct 21

Li J, Wang J, Liu D

185. Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages.

Front Immunol

2022 Oct 21

Marrocco A, Ortiz LA.

186. Rheumatoid factor IgM autoantibodies control IgG homeostasis.

Front Immunol

2022 Oct 21

Nicolò A, Amendt T, El Ayoubi O

187. Fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis and intestinal inflammation in multiple sclerosis.

Front Immunol

2022 Oct 21

Yadav SK, Ito N, Mindur JE

Multiple Sclerosis (MS) has been reported to be associated with intestinal inflammation and gut dysbiosis. To elucidate the underlying biology of MS-linked gut inflammation, we investigated gut infiltration of immune cells during the development of spontaneous experimental autoimmune encephalomyelitis (EAE) in humanized transgenic (Tg) mice expressing HLA-DR2a and human T cell receptor (TCR) specific for myelin basic protein peptide (MBP87-99)/HLA-DR2a complexes. Strikingly, we noted the simultaneous development of EAE and colitis, suggesting a link between autoimmune diseases of the central nervous system (CNS) and intestinal inflammation. Examination of the colon in these mice revealed the infiltration of MBP-specific Th17 cells as well as recruitment of neutrophils. Furthermore, we observed that fecal Lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, was significantly elevated and predominantly produced by the gut-infiltrating neutrophils. We then extended our findings to MS patients and demonstrate that their fecal Lcn-2 levels are significantly elevated compared to healthy donors (HDs). The elevation of fecal Lcn-2 levels correlated with reduced bacterial diversity and increased levels of other intestinal inflammation markers including neutrophil elastase and calprotectin. Of interest, bacteria thought to be beneficial for inflammatory bowel disease (IBD) such as Anaerobutyricum, Blautia, and Roseburia, were reduced in fecal Lcn-2-high MS patients. We also observed a decreasing trend in serum acetate (a short-chain fatty acid) levels in MS Lcn-2-high patients compared to HDs. Furthermore, a decrease in the relative abundance of Blautia massiliensis was significantly associated with a reduction of acetate in the serum of MS patients. This study suggests that gut infiltration of Th17 cells and recruitment of neutrophils are associated with the development of gut dysbiosis and intestinal inflammation, and that fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis in multiple sclerosis.

188. Tumor metabolic and secondary lymphoid organ metabolic markers on 18F-fludeoxyglucose positron emission tomography predict prognosis of immune checkpoint inhibitors in advanced lung cancer.

Front Immunol

2022 Oct 21

Jin P, Bai M, Liu J

BACKGROUND: The purpose of this study was to investigate the predictive value of tumor metabolic parameters in combination with secondary lymphoid metabolic parameters on positron emission tomography (PET)/computed tomography (CT) for immune checkpoint inhibitor (ICI) prognosis in advanced lung cancer. METHODS: This study retrospectively included 125 patients who underwent 18F-fludeoxyglucose (FDG) PET/CT before ICI therapy, including 41 patients who underwent a second PET/CT scan during ICI treatment. The measured PET/CT parameters included tumor metabolism parameters [maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV)] and secondary lymphoid organ metabolism parameters [spleen-to-liver SUVmax ratio (SLR) and bone marrow-to-liver SUVmax ratio (BLR)]. The correlation of PET/CT metabolic parameters with early ICI treatment response, progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS: Within a median follow-up of 28.7 months, there were 44 responders and 81 non-responders. The median PFS was 8.6 months (95% confidence interval (CI): 5.872-11.328), and the median OS was 20.4 months (95% CI: 15.526-25.274). Pretreatment tumor metabolic parameters were not associated with early treatment responses. The high bone marrow metabolism (BLR >1.03) was significantly associated with a shorter PFS (p = 0.008). Patients with a high TMTV (>168 mL) and high spleen metabolism (SLR >1.08) had poor OS (p = 0.019 and p = 0.018, respectively). Among the 41 patients who underwent a second PET/CT scan, the ΔSUVmax was significantly lower (p = 0.01) and the SLR was significantly higher (p = 0.0086) in the responders. Populations with low-risk characteristics (low TMTV, low SLR, and ΔSLR > 0) had the longest survival times. CONCLUSION: High pretreatment TMTV and SLR are associated with poor OS, and increased spleen metabolism after ICI therapy predicts treatment benefit. This indicates that the combination of tumor and spleen metabolic parameters is a valuable prognostic strategy.

189. Why do tumor-infiltrating lymphocytes have variable efficacy in the treatment of solid tumors?

Front Immunol

2022 Oct 21

Li B.

190. Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells.

Front Immunol

2022 Oct 21

Mohan N, Wellach K, Özerdem C

191. Bibliometric and visual analysis of neutrophil extracellular traps from 2004 to 2022.

Front Immunol

2022 Oct 21

Wan Y, Shen J, Ouyang J

192. IκBNS expression in B cells is dispensable for IgG responses to T cell-dependent antigens.

Front Immunol

2022 Oct 21

Khoenkhoen S, Ádori M, Solís-Sayago D

193. Bioengineering and computational analysis of programmed cell death ligand-1 monoclonal antibody.

Front Immunol

2022 Oct 21

Kalim M, Ali H, Rehman AU

194. Rhinovirus-induced anti-viral interferon secretion is not deficient and not delayed in sinonasal epithelial cells of patients with chronic rhinosinusitis with nasal polyp.

Front Immunol

2022 Oct 21

Lee SH, Han MS, Lee TH

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 stimulation with poly (I: C) in normal and inflammatory epithelial cells. Inflammatory epithelial cells were obtained from CRS patients with nasal polyps and normal epithelial cells were derived from ethmoid sinus mucosa during endoscopic reduction of blowout fracture or uncinate process mucosa of patients with septal deviation. Cultured cells were infected with RV 16 or treated with poly (I: C) for 24, 48, and 72 h. Cells and media were harvested at each time point and used to evaluate RV16 replication rates, the secretion of IFN-β, -λ1, -λ2, viperin, Mx, and OAS, and the expression levels of TRL3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3. RV replication rates reached peak levels 48 h after inoculation in both normal and inflammatory epithelial cells and showed no difference between both groups of epithelial cells at any time point. The release of IFN-β, -λ1, and -λ2 in normal and inflammatory epithelial cells was also strongly induced 48 h after RV16 inoculation but reached peak levels 24 h after poly (I: C) treatment. The expression levels of viperin, Mx, OAS, TLR3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3 showed similar patterns in both groups of epithelial cells. These results suggest that the production of RV16-induced antiviral interferons is not deficient or delayed in inflammatory epithelial cells from CRS patients with nasal polyps.

195. Immune cells transcriptome-based drug repositioning for multiple sclerosis.

Front Immunol

2022 Oct 20

Yin X, Rang X, Hong X

OBJECTIVE: Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells. MATERIALS AND METHODS: Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: We obtained 50 hub target genes for CD4+ T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19+ B cells and 15 target pathways for CD4+ T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways. CONCLUSION: We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.

196. Helicobacter pylori-infected human neutrophils exhibit impaired chemotaxis and a uropod retraction defect.

Front Immunol

2022 Oct 20

Prichard A, Khuu L, Whitmore LC

197. Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation.

Front Immunol

2022 Oct 20

Matos C, Mamilos A, Shah PN

198. SDF-1 expression and tumor-infiltrating lymphocytes identify clinical subtypes of triple-negative breast cancer with different responses to neoadjuvant chemotherapy and survival.

Front Immunol

2022 Oct 20

Wang RX, Ji P, Gong Y

199. Harmonization and qualification of intracellular cytokine staining to measure influenza-specific CD4(+) T cell immunity within the FLUCOP consortium.

Front Immunol

2022 Oct 20

Begue S, Waerlop G, Salaun B

Despite the knowledge that cell-mediated immunity (CMI) contributes to the reduction of severe influenza infection, transmission, and disease outcome, the correlates of protection for cell-mediated immunity remain still unclear. Therefore, measuring the magnitude and quality of influenza-specific T cell responses in a harmonized way is of utmost importance to improve characterisation of vaccine-induced immunity across different clinical trials. The present study, conducted as part of the FLUCOP project, describes the development of a consensus protocol for the intracellular cytokine staining (ICS) assay, in order to reduce inter-laboratory variability, and its qualification. In order to develop a consensus protocol, the study was divided into different stages. Firstly, two pilot studies evaluated critical parameters in the analytical (read-outs) and post-analytical (gating strategies and data analysis) methods applied by eight different laboratories within the FLUCOP consortium. The methods were then harmonized by fixing the critical parameters and the subsequent consensus protocol was then qualified by one FLUCOP member. The antigen-specific cell population was defined as polypositive CD4+ T cells (i.e. positive for at least two markers among CD40L/IFNγ/IL2/TNFα), which was shown to be the most sensitive and specific read-out. The qualification of this consensus protocol showed that the quantification of polypositive CD4+ T cells was precise, linear and accurate, and sensitive with a lower limit of quantification of 0.0335% antigen-specific polypositive CD4+ T cells. In conclusion, we provide the description of a harmonized ICS assay, which permits quantitative and qualitative evaluation of influenza vaccine-induced T cell responses. Application of this harmonized assay may allow for future comparisons of T cell responses to different influenza vaccines. It may facilitate future assessments of potential correlates of protection with the promise of application across other pathogens.

200. Editorial: The role of neutrophils and its NETosis in autoimmunity and autoinflammation.

Front Immunol

2022 Oct 20

Niyonsaba F.

201. Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms.

Front Immunol

2022 Oct 20

Lima FMS, Toledo-Barros M, Alves VAF

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver-spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver-spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver-spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated β2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.

202. Human placental hematopoietic stem cell-derived natural killer cells (CYNK) recognize and eliminate influenza A virus-infected cells.

Front Immunol

2022 Oct 20

Gunasekaran M, Difiglia A, Fitzgerald J

203. Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology.

Front Immunol

2022 Oct 20

Liu Z, Xiang Y, Zheng Y

204. Comprehensive analysis of cuproptosis-related genes and tumor microenvironment infiltration characterization in breast cancer.

Front Immunol

2022 Oct 20

Song S, Zhang M, Xie P

BACKGROUND: Cuproptosis is a newly discovered programmed cell death dependent on overload copper-induced mitochondrial respiration dysregulation. The positive response to immunotherapy, one of the most important treatments for invasive breast cancer, depends on the dynamic balance between tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). However, cuproptosis-related genes (CRGs) in clinical prognosis, immune cell infiltration, and immunotherapy response remain unclear in breast cancer progression. METHODS: The expression and mutation patterns of 12 cuproptosis-related genes were systematically evaluated in the BRCA training group. Through unsupervised clustering analysis and developing a cuproptosis-related scoring system, we further explored the relationship between cuproptosis and breast cancer progression, prognosis, immune cell infiltration, and immunotherapy. RESULTS: We identified two distinct CuproptosisClusters, which were correlated with the different patterns between clinicopathological features, prognosis, and immune cell infiltration. Moreover, the differences of the three cuproptosis-related gene subtypes were evaluated based on the CuproptosisCluster-related DEGs. Then, a cuproptosis-related gene signature (PGK1, SLC52A2, SEC14L2, RAD23B, SLC16A6, CCL5, and MAL2) and the scoring system were constructed to quantify the cuproptosis pattern of BRCA patients in the training cohort, and the testing cohorts validated them. Specifically, patients from the low-CRG_score group were characterized by higher immune cell infiltration, immune checkpoint expression, immune checkpoint inhibitor (ICI) scores, and greater sensitivity to immunotherapy. Finally, we screened out RAD23B as a favorable target and indicated its expression was associated with breast cancer progression, drug resistance, and poor prognosis in BRCA patients by performing real-time RT-PCR, cell viability, and IC50 assay. CONCLUSIONS: Our results confirmed the essential function of cuproptosis in regulating the progression, prognosis, immune cell infiltration, and response to breast cancer immunotherapy. Quantifying cuproptosis patterns and constructing a CRG_score could help explore the potential molecular mechanisms of cuproptosis regulating BRCA advancement and provide more effective immunotherapy and chemotherapy targets.

205. PET/CT molecular imaging in the era of immune-checkpoint inhibitors therapy.

Front Immunol

2022 Oct 20

Gao Y, Wu C, Chen X

206. Precise strategies for selecting probiotic bacteria in treatment of intestinal bacterial dysfunctional diseases.

Front Immunol

2022 Oct 20

Yang J, Qin S, Zhang H.

Abundant microbiota resides in the organs of the body, which utilize the nutrition and form a reciprocal relationship with the host. The composition of these microbiota changes under different pathological conditions, particularly in response to stress and digestive diseases, making the microbial composition and health of the hosts body interdependent. Probiotics are living microorganisms that have demonstrated beneficial effects on physical health and as such are used as supplements to ameliorate symptoms of various digestive diseases by optimizing microbial composition of the gut and restore digestive balance. However, the supplementary effect does not achieve the expected result. Therefore, a targeted screening strategy on probiotic bacteria is crucial, owing to the presence of several bacterial strains. Core bacteria work effectively in maintaining microbiological homeostasis and stabilization in the gastrointestinal tract. Some of the core bacteria can be inherited and acquired from maternal pregnancy and delivery; others can be acquired from contact with the mother, feces, and the environment. Knowing the genera and functions of the core bacteria could be vital in the isolation and selection of probiotic bacteria for supplementation. In addition, other supporting strains of probiotic bacteria are also needed. A comprehensive strategy for mining both core and supporting bacteria before its clinical use is needed. Using metagenomics or other methods of estimation to discern the typically differentiated strains of bacteria is another important strategy to treat dysbiosis. Hence, these two factors are significant to carry out targeted isolation and selection of the functional strains to compose the resulting probiotic preparation for application in both research and clinical use. In conclusion, precise probiotic supplementation, by screening abundant strains of bacteria and isolating specific probiotic strains, could rapidly establish the core microbiota needed to confer resilience, particularly in bacterial dysfunctional diseases. This approach can help identify distinct bacteria which can be used to improve supplementation therapies.

207. Aging envisage imbalance of the periodontium: A keystone in oral disease and systemic health.

Front Immunol

2022 Oct 20

Villalobos V, Garrido M, Reyes A

208. The lymphatic system and COVID-19 vaccines.

Front Immunol

2022 Oct 20

Miyasaka M.

209. Identification of serum glycobiomarkers for Hepatocellular Carcinoma using lectin microarrays.

Front Immunol

2022 Oct 20

Zhang Y, Zhang S, Liu J

210. Antibody based conditioning for allogeneic hematopoietic stem cell transplantation.

Front Immunol

2022 Oct 20

Saha A, Blazar BR.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.

211. Role of periostin in inflammatory bowel disease development and synergistic effects mediated by the CCL5-CCR5 axis.

Front Immunol

2022 Oct 20

Mukanova S, Borissenko A, Kim A

212. The rectal mucosal immune environment and HIV susceptibility among young men who have sex with men.

Front Immunol

2022 Oct 20

Ackerley CG, Smith SA, Murray PM

213. Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes.

Front Immunol

2022 Oct 20

Torres A, Pedersen B, Guma M.

214. Gut Associated Lymphoid Tissue (GALT) primary cells and stable cell lines as predictive models for intestinal health in rainbow trout (Oncorhynchus mykiss).

Front Immunol

2022 Oct 20

Porter D, Peggs D, McGurk C

215. Impaired intratumoral natural killer cell function in head and neck carcinoma.

Front Immunol

2022 Oct 20

Mele D, Pessino G, Trisolini G

216. Integrated metabolomics and lipidomics study of patients with atopic dermatitis in response to dupilumab.

Front Immunol

2022 Oct 20

Zhang L, Wen X, Hou Y

BACKGROUND: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Dupilumab, a monoclonal antibody that targets the interleukin (IL)-4 and IL-13 receptors, has been widely used in AD because of its efficacy. However, metabolic changes occurring in patients with AD in response to dupilumab remains unknown. In this study, we integrated metabolomics and lipidomics analyses with clinical data to explore potential metabolic alterations associated with dupilumab therapeutic efficacy. In addition, we investigated whether the development of treatment side effects was linked to the dysregulation of metabolic pathways. METHODS: A total of 33 patients with AD were included in the current study, with serum samples collected before and after treatment with dupilumab. Comprehensive metabolomic and lipidomic analyses have previously been developed to identify serum metabolites (including lipids) that vary among treatment groups. An orthogonal partial least squares discriminant analysis model was established to screen for differential metabolites and metabolites with variable importance in projection > 1 and p < 0.05 were considered potential metabolic biomarkers. MetaboAnalyst 5.0 was used to identify related metabolic pathways. Patients were further classified into two groups, well responders (n = 19) and poor responders (n = 14), to identify differential metabolites between the two groups. RESULTS: The results revealed significant changes in serum metabolites before and after 16 weeks of dupilumab treatment. Variations in the metabolic profile were more significant in the well-responder group than in the poor-responder group. Pathway enrichment analysis revealed that differential metabolites derived from the well-responder group were mainly involved in glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis, the citrate cycle, arachidonic acid metabolism, pyrimidine metabolism, and sphingolipid metabolism. CONCLUSION: Serum metabolic profiles of patients with AD varied significantly after treatment with dupilumab. Differential metabolites and their related metabolic pathways may provide clues for understanding the effects of dupilumab on patient metabolism.

217. Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer.

Front Immunol

2022 Oct 20

Liu Y, Li C, Lu Y

Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.

218. Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection.

Front Immunol

2022 Oct 20

Wang Y, Zheng J, Wang X

219. Mycoplasma Bovis adhesins and their target proteins.

Front Immunol

2022 Oct 20

Xu QY, Pan Q, Wu Q

220. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors.

Front Immunol

2022 Oct 20

Rahmy S, Mishra SJ, Murphy S

221. Traumatized triad of complementopathy, endotheliopathy, and coagulopathy - Impact on clinical outcomes in severe polytrauma patients.

Front Immunol

2022 Oct 20

Yang Z, Le TD, Simovic MO

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.

222. Monocyte programming by cancer therapy.

Front Immunol

2022 Oct 20

Patysheva M, Frolova A, Larionova I

223. Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A.

Front Immunol

2022 Oct 20

Kim J, Kim SJ, Jeong HR

224. Standardized in-vitro evaluation of CAR-T cells using acellular artificial target particles.

Front Immunol

2022 Oct 20

Harari-Steinfeld R, Abhinav Ayyadevara VSS, Cuevas L

225. Trends in industrialization and commercialization of IgY technology.

Front Immunol

2022 Oct 20

Yakhkeshi S, Wu R, Chelliappan B

IgY technology refers to the strategic production process involved in generating avian immunoglobulin (IgY) against target antigens in a much more cost-effective manner with broad applications in the fields of diagnostics, prophylaxis, and therapeutics for both human and veterinary medicine. Over the past decade, promising progress in this research area has been evident from the steep increase in the number of registered manufacturing companies involved in the production of IgY products, the number of patents, and the notable number of clinical trials underway. Hence, it is crucial to conduct a prospective analysis of the commercialization and marketing potential of IgY-based commercial products for large-scale applications. This review revealed that the number of IgY patent applications increased steeply after 2010, with the highest of 77 patents filed in 2021. In addition, 73 industries are reportedly involved in marketing IgY products, out of which 27 were promoting biotherapeutics for human and veterinary medicine and 46 were in the diagnostic field. IgY antibodies are being used as primary and secondary antibodies, with approximately 3729 and 846 products, respectively. Biotherapeutic product consumption has notably increased as a food supplement and as a topical application in human and veterinary medicine, which are under different clinical phases of development to reach the market with around 80 and 56 products, respectively. In contrast, the number of IgY products as parenteral administrations and licensed drugs is not well developed given the lack of technical standards established for IgY registration and industrialization, as well as the restriction of the nature of polyclonal antibodies. However, recent ongoing research on functional IgY fragments indicates a promising area for IgY applications in the near future. Therefore, retrospective analysis with speculations is mandatory for IgY technology maturation toward industrialization and commercialization.

226. Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer.

Front Immunol

2022 Oct 20

Wang T, Ba X, Zhang X

227. Molecular profiling of core immune-escape genes highlights LCK as an immune-related prognostic biomarker in melanoma.

Front Immunol

2022 Oct 20

Wang F, Zheng A, Zhang D

228. Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID.

Front Immunol

2022 Oct 20

Kundura L, Cezar R, André S

229. The role of cuproptosis-related gene in the classification and prognosis of melanoma.

Front Immunol

2022 Oct 19

Liu JY, Liu LP, Li Z

BACKGROUND: Melanoma, as one of the most aggressive and malignant cancers, ranks first in the lethality rate of skin cancers. Cuproptosis has been shown to paly a role in tumorigenesis, However, the role of cuproptosis in melanoma metastasis are not clear. Studying the correlation beteen the molecular subtypes of cuproptosis-related genes (CRGs) and metastasis of melanoma may provide some guidance for the prognosis of melanoma. METHODS: We collected 1085 melanoma samples in The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus(GEO) databases, constructed CRGs molecular subtypes and gene subtypes according to clinical characteristics, and investigated the role of CRGs in melanoma metastasis. We randomly divide the samples into train set and validation set according to the ratio of 1:1. A prognostic model was constructed using data from the train set and then validated on the validation set. We performed tumor microenvironment analysis and drug sensitivity analyses for high and low risk groups based on the outcome of the prognostic model risk score. Finally, we established a metastatic model of melanoma. RESULTS: According to the expression levels of 12 cuproptosis-related genes, we obtained three subtypes of A1, B1, and C1. Among them, C1 subtype had the best survival outcome. Based on the differentially expressed genes shared by A1, B1, and C1 genotypes, we obtained the results of three gene subtypes of A2, B2, and C2. Among them, the B2 group had the best survival outcome. Then, we constructed a prognostic model consisting of 6 key variable genes, which could more accurately predict the 1-, 3-, and 5-year overall survival rates of melanoma patients. Besides, 98 drugs were screened out. Finally, we explored the role of cuproptosis-related genes in melanoma metastasis and established a metastasis model using seven key genes. CONCLUSIONS: In conclusion, CRGs play a role in the metastasis and prognosis of melanoma, and also provide new insights into the underlying pathogenesis of melanoma.

230. A novel twelve-gene signature to predict neoadjuvant chemotherapy response and prognosis in breast cancer.

Front Immunol

2022 Oct 19

Wu J, Tian Y, Liu W

BACKGROUND: Accurate evaluation of the response to neoadjuvant chemotherapy (NAC) provides important information about systemic therapies for breast cancer, which implies pharmacological response, prognosis, and guide further therapy. Gene profiles overcome the shortcomings of the relatively limited detection indicators of the classical pathological evaluation criteria and the subjectivity of observation, but are complicated and expensive. Therefore, it is essential to develop a more accurate, repeatable, and economical evaluation approach for neoadjuvant chemotherapy responses. METHODS: We analyzed the transcriptional profiles of chemo-resistant breast cancer cell lines and tumors of chemo-resistant breast cancer patients in the GSE25066 dataset. We preliminarily screened out common significantly differentially expressed genes and constructed a NAC response risk model using LASSO regression and univariate and multivariate analyses. The differences in bioinformatic features of tumor cells, immune characteristics, and prognosis were compared between high and low-risk group. The potential drugs that could reverse chemotherapy resistance in breast cancer were screened by the CMap database. RESULTS: Thirty-six genes were commonly up/down-regulated in both NAC chemo-resistant tumors and cells compared to the sensitive tumors and wild-type cells. Through LASSO regression, we obtained a risk model composed of 12 genes. The risk model divided patients into high and low-risk groups. Univariate and multivariate Cox regression analyses suggested that the risk score is an independent prognostic factor for evaluating NAC response in breast cancer. Tumors in risk groups exhibited significant differences in molecular biological characteristics, tumor-infiltrating lymphocytes, and immunosuppressive molecule expression. Our results suggested that the risk score was also a good prognostic factor for breast cancer. Finally, we screened potential drugs that could reverse chemotherapy resistance in breast cancer. CONCLUSION: A novel 12 gene-signature could be used to predict NAC response and predict prognosis in breast cancer.

231. Conservative oxygen therapy in critically ill and perioperative period of patients with sepsis-associated encephalopathy.

Front Immunol

2022 Oct 19

Li Y, Zhao L, Yu Y

232. A metagenome-wide association study of the gut microbiota in recurrent aphthous ulcer and regulation by thalidomide.

Front Immunol

2022 Oct 19

Wang X, Xiong K, Huang F

233. Differences in inflammatory marker profiles and cognitive functioning between deficit and nondeficit schizophrenia.

Front Immunol

2022 Oct 19

Wang D, Wang Y, Chen Y

Deficit schizophrenia (DS) patient is a homogenous subtype of schizophrenia that includes primary and enduring negative symptoms. This study aimed to compare the differences in cognitive functioning and plasma levels of C-reactive protein (CRP) and inflammatory cytokines among DS patients, nondeficit schizophrenia (NDS) patients, and healthy controls (HCs). A total of 141 schizophrenia patients and 67 HCs were included in this study. The schizophrenia patients were divided into DS (N= 51) and NDS (N=90) groups based on the Proxy for the Deficit Syndrome Scale (PDS). The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were used to evaluate the clinical symptoms and cognitive performances, respectively. The plasma level of CRP, IL-1β, Il-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, and IFN-γ were measured using enzyme-linked immunosorbent assays (ELISAs). Our results showed that DS patients had the worst cognitive performance, especially in the immediate memory, attention, and language dimensions, compared to the NDS and HC groups. Compared to the HCs group, DS patients had higher levels of CRP, IL-1β, IL-6, IL-8, IFN-γ, and total proinflammatory cytokines, and NDS patients had higher levels of IL-1β, IFN-γ, and proinflammatory cytokines. We also found that CRP levels were significantly increased in DS patients compared to NDS patients. Moreover, stepwise logistic regression analysis revealed that CRP is an independent risk factor for DS. Sex stratification analysis showed significant differences in almost all cytokines in female samples but not in male samples. The significant differences in cognitive performance and inflammatory components among groups suggest that deficit syndrome is an independent endophenotype of schizophrenia patients with unique immune-inflammatory features, but may have sex characteristics.

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

Front Immunol

2022 Oct 19

Liu Y, Yuan Y, Zhou Z

235. Transcriptomics and quantitative proteomics reveal changes after second stimulation of bone marrow-derived macrophages from lupus-prone MRL/lpr mice.

Front Immunol

2022 Oct 19

Chen K, Wu T, Wang D

236. Comparative effects of human-equivalent low, moderate, and high dose oral prednisone intake on autoimmunity and glucocorticoid-related toxicity in a murine model of environmental-triggered lupus.

Front Immunol

2022 Oct 19

Heine LK, Benninghoff AD, Ross EA

Autoimmune diseases can be triggered by environmental toxicants such as crystalline silica dust (cSiO2). Here, we characterized the dose-dependent immunomodulation and toxicity of the glucocorticoid (GC) prednisone in a preclinical model that emulates onset and progression of cSiO2-triggered lupus. Two cohorts of 6-wk-old female NZBWF1 mice were fed either control AIN-93G diet or one of three AIN-93G diets containing prednisone at 5, 15, or 50 mg/kg diet which span human equivalent oral doses (HED) currently considered to be low (PL; 5 mg/d HED), moderate (PM; 14 mg/d HED), or high (PH; 46 mg/d HED), respectively. At 8 wk of age, mice were intranasally instilled with either saline vehicle or 1 mg cSiO2 once weekly for 4 wk. The experimental plan was to 1) terminate one cohort of mice (n=8/group) 14 wk after the last cSiO2 instillation for pathology and autoimmunity assessment and 2) to maintain a second cohort (n=9/group) to monitor glomerulonephritis development and survival. Mean blood concentrations of prednisone's principal active metabolite, prednisolone, in mice fed PL, PM, and PH diets were 27, 105, 151 ng/ml, respectively, which are consistent with levels observed in human blood ≤ 12 h after single bolus treatments with equivalent prednisone doses. Results from the first cohort revealed that consumption of PM, but not PL diet, significantly reduced cSiO2-induced pulmonary ectopic lymphoid structure formation, nuclear-specific AAb production, inflammation/autoimmune gene expression in the lung and kidney, splenomegaly, and glomerulonephritis in the kidney. Relative to GC-associated toxicity, PM diet, but not PL diet, elicited muscle wasting, but these diets did not affect bone density or cause glucosuria. Importantly, neither PM nor PL diet improved latency of cSiO2-accelerated death. PH-fed mice in both cohorts displayed robust GC-associated toxicity including body weight loss, reduced muscle mass, and extensive glucosuria 7 wk after the final cSiO2 instillation requiring their early removal from the study. Taken together, our results demonstrate that while moderate doses of prednisone can reduce important pathological endpoints of cSiO2-induced autoimmunity in lupus-prone mice, such as upstream ectopic lymphoid structure formation, these ameliorative effects come with unwanted GC toxicity, and, crucially, none of these three doses extended survival time.

237. DOCK2 and phosphoinositide-3 kinase δ mediate two complementary signaling pathways for CXCR5-dependent B cell migration.

Front Immunol

2022 Oct 19

Wissmann S, Stolp B, Jímenez AM

238. Evaluation of porcine GM-CSF during PRRSV infection in vitro and in vivo indicating a protective role of GM-CSF related with M1 biased activation in alveolar macrophage during PRRSV infection.

Front Immunol

2022 Oct 19

Ji Q, Qu G, Liu B

239. Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation.

Front Immunol

2022 Oct 19

Dabrowska-Leonik N, Pastorczak AK, Bąbol-Pokora K

240. Autoantibodies - enemies, and/or potential allies?

Front Immunol

2022 Oct 19

Ma H, Murphy C, Loscher CE

241. A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression.

Front Immunol

2022 Oct 19

Zhang K, Kang L, Zhang H

242. Evaluation of nanobody-based biologics targeting purinergic checkpoints in tumor models in vivo.

Front Immunol

2022 Oct 19

Demeules M, Scarpitta A, Hardet R

243. The development and improvement of immunodeficient mice and humanized immune system mouse models.

Front Immunol

2022 Oct 19

Chen J, Liao S, Xiao Z

244. Comprehensive analysis of transient receptor potential channels-related signature for prognosis, tumor immune microenvironment, and treatment response of colorectal cancer.

Front Immunol

2022 Oct 18

Wang L, Chen X, Zhang H

BACKGROUND: Transient receptor potential channels (TRPC) play critical regulatory functions in cancer occurrence and progression. However, knowledge on its role in colorectal cancer (CRC) is limited. In addition, neoadjuvant treatment and immune checkpoint inhibitors (ICIs) have increasing roles in CRC management, but not all patients benefit from them. In this study, a TRPC related signature (TRPCRS) was constructed for prognosis, tumor immune microenvironment (TIME), and treatment response of CRC. METHODS: Data on CRC gene expression and clinical features were retrospectively collected from TCGA and GEO databases. Twenty-eight TRPC regulators (TRPCR) were retrieved using gene set enrichment analysis. Different TRPCR expression patterns were identified using non-negative matrix factorization for consensus clustering, and a TRPCRS was established using LASSO. The potential value of TRPCRS was assessed using functional enrichment analysis, tumor immune analysis, tumor somatic mutation analysis, and response to preoperative chemoradiotherapy or ICIs. Moreover, an external validation was conducted using rectal cancer samples that received preoperative chemoradiotherapy at Fujian Cancer Hospital (FJCH) via qRT-PCR. RESULTS: Among 834 CRC samples in the TCGA and meta-GEO cohorts, two TRPCR expression patterns were identified, which were associated with various immune infiltrations. In addition, 266 intersected genes from 5564 differentially expressed genes (DEGs) between two TRPC subtypes, 4605 DEGs between tumor tissue and adjacent non-tumor tissue (all FDR< 0.05, adjusted P< 0.001), and 1329 prognostic related genes (P< 0.05) were identified to establish the TRPCRS, which was confirmed in the TCGA cohort, two cohorts from GEO, and one qRT-PCR cohort from FJCH. According to the current signature, the high-TRPC score group had higher expressions of PD-1, PD-L1, and CTLA4, lower TIDE score, and improved response to anti-PD-1 treatment with better predictive ability. Compared to the high-TRPC score group, the low-TRPC score group comprised an immunosuppressive phenotype with increased infiltration of neutrophils and activated MAPK signaling pathway, but was more sensitive to preoperative chemoradiotherapy and associated with improved prognosis. CONCLUSIONS: The current TRPCRS predicted the prognosis of CRC, evaluated the TIME in CRC, and anticipated the response to immune therapy and neoadjuvant treatment.

245. Prolonged hematological toxicity in patients receiving BCMA/CD19 CAR-T-cell therapy for relapsed or refractory multiple myeloma.

Front Immunol

2022 Oct 18

Li H, Zhao L, Sun Z

246. Photoactivated adenylyl cyclases attenuate sepsis-induced cardiomyopathy by suppressing macrophage-mediated inflammation.

Front Immunol

2022 Oct 18

Xia G, Shi H, Su Y

247. STAT3 signaling modulates the immune response induced after antigen targeting to conventional type 1 dendritic cells through the DEC205 receptor.

Front Immunol

2022 Oct 18

Sulczewski FB, Martino LA, Salles D

248. T-BET drives the conversion of human type 3 innate lymphoid cells into functional NK cells.

Front Immunol

2022 Oct 18

Kiekens L, Wahlen S, Persyn E

249. Pitfalls in complement analysis: A systematic literature review of assessing complement activation.

Front Immunol

2022 Oct 18

Brandwijk RJMGE, Michels MAHM, van Rossum M

BACKGROUND: The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging. OBJECTIVE: We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components. METHODS: A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses. RESULTS: A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used. CONCLUSION: A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis.

250. Editorial: CCR5: A receptor at the center stage in infection.

Front Immunol

2022 Oct 18

Ellwanger JH, Secchi M, Aliberti J

251. Hookworm infection associates with a vaginal Type 1/Type 2 immune signature and increased HPV load.

Front Immunol

2022 Oct 18

Omondi MA, Kamassa EH, Katawa G

252. The IgG glycome of SARS-CoV-2 infected individuals reflects disease course and severity.

Front Immunol

2022 Oct 18

Siekman SL, Pongracz T, Wang W

253. Soluble mediators in the function of the epidermal-immune-neuro unit in the skin.

Front Immunol

2022 Oct 18

Oleszycka E, Kwiecien K, Kwiecinska P

254. Dietary Aflatoxin B1 attenuates immune function of immune organs in grass carp (Ctenopharyngodon idella) by modulating NF-κB and the TOR signaling pathway.

Front Immunol

2022 Oct 18

He XN, Zeng ZZ, Wu P

255. Arginase-1 targeting peptide vaccine in patients with metastatic solid tumors - A phase I trial.

Front Immunol

2022 Oct 17

Lorentzen CL, Martinenaite E, Kjeldsen JW

BACKGROUND: Arginase-1-producing cells inhibit T cell-mediated anti-tumor responses by reducing L-arginine levels in the tumor microenvironment. T cell-facilitated elimination of arginase-1-expressing cells could potentially restore L-arginine levels and improve anti-tumor responses. The activation of arginase-1-specific T cells may convert the immunosuppressive tumor microenvironment and induce or strengthen local Th1 inflammation. In the current clinical study, we examined the safety and immunogenicity of arginase-1-based peptide vaccination. METHODS: In this clinical phase I trial, ten patients with treatment-refractory progressive solid tumors were treated. The patients received an arginase-1 peptide vaccine comprising three 20-mer peptides from the ARG1 immunological "hot spot" region in combination with the adjuvant Montanide ISA-51. The vaccines were administered subcutaneously every third week (maximum 16 vaccines). The primary endpoint was to evaluate safety assessed by Common Terminology Criteria for Adverse Events 4.0 and laboratory monitoring. Vaccine-specific immune responses were evaluated using enzyme-linked immune absorbent spot assays and intracellular cytokine staining on peripheral blood mononuclear cells. Clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: The vaccination was feasible, and no vaccine-related grade 3-4 adverse events were registered. Nine (90%) of ten patients exhibited peptide-specific immune responses in peripheral blood mononuclear cells. Six (86%) of the seven evaluable patients developed a reactive T cell response against at least one of the ARG1 peptides during treatment. A phenotypic classification revealed that arginase-1 vaccine-specific T cells were both CD4+ T cells and CD8+ T cells. Two (20%) of ten patients obtained stable disease for respectively four- and seven months on vaccination treatment. CONCLUSION: The peptide vaccine against arginase-1 was safe. Nine (90%) of ten patients had measurable peptide-specific responses in the periphery blood, and two (20%) of ten patients attained stable disease on protocol treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03689192, identifier NCT03689192.

256. Case report: A rare case of coexisting Waldenstrom Macroglobulinemia and B-cell acute lymphoblastic leukemia with KMT2D and MECOM mutations.

Front Immunol

2022 Oct 17

Wang L, Tang J, Feng J

BACKGROUND: Waldenstrom Macroglobulinemia (WM) is a rare and indolent lymphoma of B-cell origin characterized by elevated monoclonal IgM, with MYD88L265P mutation and CXCR4 mutation as common molecular alterations. B-cell Acute Lymphoblastic Leukemia (B-ALL) is clinically heterogeneous, characterized by abnormal proliferation and aggregation of immature lymphocytes in the bone marrow and lymphoid tissue. WM and ALL are hematologic malignancies of B-cell origin with completely different clinical manifestations and biological features. KMT2D and MECOM mutations are very rare in ALL and usually indicate poor disease prognosis. The coexistence of WM and ALL with KMT2D and MECOM mutations have not been reported. CASE PRESENTATION: A 74-year-old female patient was diagnosed with WM in July 2018 and received four cycles of chemotherapy of bortezomib and dexamethasone. In November 2018, she received immunomodulator thalidomide as maintenance therapy. In November 2020, Bruton's Tyrosine Kinase inhibitors (BTKi) has been introduced into the Chinese market and she took zanubrutinib orally at a dose of 80 mg per day. The disease remained in remission. In December 2021, she presented with multiple enlarged lymph nodes throughout the body. Bone marrow and next-generation sequencing (NGS) suggested the coexistence of WM and B-ALL with KMT2D and MECOM mutations. The patient was treated with zanubrutinib in combination with vincristine and dexamethasone, after which she developed severe myelosuppression and septicemia. The patient finally got remission. Due to the patient's age and poor status, she refused intravenous chemotherapy and is currently treated with zanubrutinib. CONCLUSIONS: The coexistence of WM and B-ALL is very rare and has not been reported. The presence of both KMT2D and MECOM mutations predicts a poor prognosis and the possibility of insensitivity to conventional treatment options. BTKi achieves its anti-tumor effects by inhibiting BTK activation and blocking a series of malignant transformations in B-cell tumors. In addition, it also acts on T-cell immunity and tumor microenvironment. Combination therapy based on BTKi may improve the prognosis of this patient.

257. miRNA profile at diagnosis predicts treatment outcome in patients with B-chronic lymphocytic leukemia: A FILO study.

Front Immunol

2022 Oct 17

Duroux-Richard I, Gagez AL, Alaterre E

During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was the gold standard for first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the treatment of B-CLL patients and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD) in bone marrow (BM), which remains the best predictive factor for survival. MicroRNAs represent a class of molecular biomarkers which expression is altered in B-CLL. Our study aimed at identifying before treatment blood miRNAs that predict treatment outcome in previously untreated B-CLL patients (NCT01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with BM uMRD from 8 patients who did not achieve CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. We identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c relapsed during study follow-up. In contrast, patients with low miR-15b and high miR-412, or with low miR-125b and miR-193b, demonstrated significant low PFS. RNA sequencing of blood at diagnosis identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, MYC target genes, metabolism and translation regulation. Conversely, patients achieving CR with BM uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes. Our results suggest that blood miRNAs are potent predictive biomarkers for FCR treatment efficacy and might be implicated in the FCR efficacy in B-CLL patients, providing new insight into unmet need for the treatment of B-CLL patients and identifying pathways predictive of patients' remission. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01370772.

258. Biological signatures and prediction of an immunosuppressive status-persistent critical illness-among orthopedic trauma patients using machine learning techniques.

Front Immunol

2022 Oct 17

Lei M, Han Z, Wang S

BACKGROUND: Persistent critical illness (PerCI) is an immunosuppressive status. The underlying pathophysiology driving PerCI remains incompletely understood. The objectives of the study were to identify the biological signature of PerCI development, and to construct a reliable prediction model for patients who had suffered orthopedic trauma using machine learning techniques. METHODS: This study enrolled 1257 patients from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Lymphocytes were tracked from ICU admission to more than 20 days following admission to examine the dynamic changes over time. Over 40 possible variables were gathered for investigation. Patients were split 80:20 at random into a training cohort (n=1035) and an internal validation cohort (n=222). Four machine learning algorithms, including random forest, gradient boosting machine, decision tree, and support vector machine, and a logistic regression technique were utilized to train and optimize models using data from the training cohort. Patients in the internal validation cohort were used to validate models, and the optimal one was chosen. Patients from two large teaching hospitals were used for external validation (n=113). The key metrics that used to assess the prediction performance of models mainly included discrimination, calibration, and clinical usefulness. To encourage clinical application based on the optimal machine learning-based model, a web-based calculator was developed. RESULTS: 16.0% (201/1257) of all patients had PerCI in the MIMIC-III database. The means of lymphocytes (%) were consistently below the normal reference range across the time among PerCI patients (around 10.0%), whereas in patients without PerCI, the number of lymphocytes continued to increase and began to be in normal range on day 10 following ICU admission. Subgroup analysis demonstrated that patients with PerCI were in a more serious health condition at admission since those patients had worse nutritional status, more electrolyte imbalance and infection-related comorbidities, and more severe illness scores. Eight variables, including albumin, serum calcium, red cell volume distributing width (RDW), blood pH, heart rate, respiratory failure, pneumonia, and the Sepsis-related Organ Failure Assessment (SOFA) score, were significantly associated with PerCI, according to the least absolute shrinkage and selection operator (LASSO) logistic regression model combined with the 10-fold cross-validation. These variables were all included in the modelling. In comparison to other algorithms, the random forest had the optimal prediction ability with the highest area under receiver operating characteristic (AUROC) (0.823, 95% CI: 0.757-0.889), highest Youden index (1.571), and lowest Brier score (0.107). The AUROC in the external validation cohort was also up to 0.800 (95% CI: 0.688-0.912). Based on the risk stratification system, patients in the high-risk group had a 10.0-time greater chance of developing PerCI than those in the low-risk group. A web-based calculator was available at https://starxueshu-perci-prediction-main-9k8eof.streamlitapp.com/. CONCLUSIONS: Patients with PerCI typically remain in an immunosuppressive status, but those without PerCI gradually regain normal immunity. The dynamic changes of lymphocytes can be a reliable biomarker for PerCI. This work developed a reliable model that may be helpful in improving early diagnosis and targeted intervention of PerCI. Beneficial interventions, such as improving nutritional status and immunity, maintaining electrolyte and acid-base balance, curbing infection, and promoting respiratory recovery, are early warranted to prevent the onset of PerCI, especially among patients in the high-risk group and those with a continuously low level of lymphocytes.

259. Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.

Front Immunol

2022 Oct 17

Xuan FL, Yan L, Li Y

260. Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma.

Front Immunol

2022 Oct 17

Chen X, Ma H, Mo S

Extracellular traps (ETs) and tumor-infiltrating immune cells play crucial roles in tumor progression. However, little is known about the clinical significance of tumor-infiltrating neutrophils and macrophages and the related ETs in pancreatic ductal adenocarcinoma (PDAC). This study investigates the associations between neutrophil or macrophage infiltration or ET formation and the clinicopathological features, molecular characteristics, immune checkpoint molecules, clinical outcomes, and response to adjuvant chemotherapy (ACT) in PDAC. We performed multiplex immunofluorescence staining to detect ET formation by neutrophils or macrophages using tissue microarrays obtained from 205 patients, and analyzed the immunohistochemistry data for PD-L1, PD-L2, B7-H3, and B7-H4. The ET expression rates in macrophages and neutrophils were 23.9% and 45.4%, respectively. Patients with a high density of neutrophils or positive expression of neutrophil ETs exhibited poorer progression-free survival (PFS) and disease-specific survival (DSS), whereas macrophage ETs were not related to PFS and DSS. Neutrophil infiltration and ET formation were identified as independent prognostic predictors of DSS using univariate and multivariate Cox analyses. Patients with PDAC with lower neutrophil infiltration or negative staining for neutrophil ETs are more likely to benefit from ACT. Patients with PDAC were more accurately stratified based on the infiltration of neutrophils and presence of neutrophil ETs, and patients with low neutrophil infiltration and negative staining for neutrophil ETs showed the best survival. Patients with positive neutrophil ETs demonstrated inferior DSS compared to those with negative neutrophil ETs in the PD-L1 tumor proportion score (TPS) < 1% and PD-L1 IC < 1% subgroups. However, the positive expression of neutrophil ETs was not related to DSS in the PD-L1 TPS ≥ 1% or PD-L1 IC ≥ 1% subgroup. Our findings emphasize the potential of neutrophil infiltration and ETs as prognostic markers that could guide the formulation of more effective personalized treatments for PDAC.

261. The role of macrophage scavenger receptor 1 (MSR1) in inflammatory disorders and cancer.

Front Immunol

2022 Oct 17

Gudgeon J, Marín-Rubio JL, Trost M.

262. Immunogenic cell death-related risk signature predicts prognosis and characterizes the tumour microenvironment in lower-grade glioma.

Front Immunol

2022 Oct 17

Cai J, Hu Y, Ye Z

Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite comprehensive traditional treatment. Tumour molecular subtypes and prognostic biomarkers play a crucial role in LGG diagnosis and treatment. Therefore, the identification of novel biomarkers in LGG patients is crucial for predicting the prognosis of glioma. Immunogenic cell death (ICD) is defined as regulated cell death that is sufficient to activate the adaptive immune response of immunocompetent hosts. The combination of ICD and immunotherapy might exert a greater and more persistent antitumour effect in gliomas. In our study, we explored the expression, function, and genetic alterations of 34 ICD-related genes. Using 12 ICD-related genes, including IL17RA, IL1R1, EIF2AK3, CD4, PRF1, CXCR3, CD8A, BAX, PDIA3, CASP8, MYD88, and CASP1, we constructed and validated an ICD-related risk signature via least absolute shrinkage and selection operator (LASSO) Cox regression analysis. All the information was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Our results revealed that ICD-high risk groups have a poor prognosis and might be more sensitive to immune checkpoint blockade (ICB) immunotherapy. In addition, ICD-high risk groups were associated with 1p19q noncodeletion, higher WHO grade, wild type IDH, and an immunosuppressive tumour microenvironment. We verified the prognostic value of 12 ICD-related genes in TCGA and CGGA databases. Immunohistochemistry was performed to verify the expression of several ICD-related genes at the protein level. Our study provides a novel and comprehensive perspective to elucidate the underlying mechanisms of LGG prognosis and direction for future individualized cancer immunotherapy.

263. Autofluorescence identifies highly phagocytic tissue-resident macrophages in mouse and human skin and cutaneous squamous cell carcinoma.

Front Immunol

2022 Oct 17

Bourdely P, Petti L, Khou S

264. High iodine promotes autoimmune thyroid disease by activating hexokinase 3 and inducing polarization of macrophages towards M1.

Front Immunol

2022 Oct 17

Cai T, Du P, Suo L

265. High levels of PF4, VEGF-A, and classical monocytes correlate with the platelets count and inflammation during active tuberculosis.

Front Immunol

2022 Oct 17

Urbán-Solano A, Flores-Gonzalez J, Cruz-Lagunas A

Platelets play a major role in coagulation and hemostasis; evidence supports the hypothesis that they also contribute to immunological processes. Increased platelet counts have been associated with poor prognosis in tuberculosis (TB). Platelet-monocyte aggregates have been reported in patients with TB, but it is still unclear if only one monocyte subpopulation is correlated to the platelet count; moreover, the platelet-monocyte axis has not been studied during latent tuberculosis (LTB). In this study, mononuclear cells and plasma were obtained from patients diagnosed with active drug-sensitive TB (DS-TB, n = 10) and LTB (n = 10); cytokines and growth factors levels associated to platelets were evaluated, and correlations with monocyte subpopulations were performed to identify a relationship between them, as well as an association with the degree of lung damage. Our data showed that, compared to LTB, DS-TB patients had an increased frequency of platelets, monocytes, and neutrophils. Although DS-TB patients showed no significant difference in the frequency of classical and non-classical monocytes, the classical monocytes had increased CD14 intensity of expression and frequency of TLR-2+. Furthermore, the plasma levels of angiogenic factors such as vascular endothelial growth factor (VEGF-A), platelet-derived growth factor (PDGF-BB), and platelet factor-4 (PF4), and pro-inflammatory cytokines like interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and interferon-γ-inducible protein 10 (IP-10) were increased in DS-TB patients. In addition, PF-4 and VEGF-A correlated positively with the frequency of classical monocytes and the platelet count. Using a principal component analysis, we identified four groups of DS-TB patients according to their levels of pro-inflammatory cytokines, angiogenic factors, and degree of lung damage. This study establishes that there is a correlation between VEGF-A and PF4 with platelets and classical monocytes during active TB, suggesting that those cell subpopulations are the major contributors of these molecules, and together, they control the severity of lung damage by amplification of the inflammatory environment.

266. Editorial: Structure, isotypes, targets, and post-translational modifications of immunoglobulins and their role in infection, inflammation and autoimmunity, Volume II.

Front Immunol

2022 Oct 17

Novak J, Berthelot L, Hermouet S.

267. Editorial: The immunology of the male genital tract.

Front Immunol

2022 Oct 17

Tung KSK, Han D, Duan YG.

268. Progress in the application of body fluid and tissue level mRNAs-non-coding RNAs for the early diagnosis and prognostic evaluation of systemic lupus erythematosus.

Front Immunol

2022 Oct 17

Liang J, Xie F, Feng J

269. Not all autoantibodies are clinically relevant. Classic and novel autoantibodies in Sjögren's syndrome: A critical review.

Front Immunol

2022 Oct 17

Vílchez-Oya F, Balastegui Martin H, García-Martínez E

270. Characteristics of cerebral blood flow in an Eastern sample of multiple sclerosis patients: A potential quantitative imaging marker associated with disease severity.

Front Immunol

2022 Oct 17

Zhou Q, Zhang T, Meng H

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is rare in China. At present, there are no widespread quantitative imaging markers associated with disease severity in MS. Despite several previous studies reporting cerebral blood flow (CBF) changes in MS, no consensus has been reached. In this study, we enrolled 30 Eastern MS patients to investigate CBF changes in different brain regions using the arterial spin labeling technique and their relationship with disease severity. The average CBF in MS patients were higher than those in health controls in various brain regions except cerebellum. The results indicated that MS patients with strongly increased CBF showed worse disease severity, including higher Expanded Disability Status Scale (EDSS) scores and serum neurofilament light chain (sNfL) values than those with mildly increased CBF in the parietal lobes, temporal lobes, basal ganglia, and damaged white matter (DWM). From another perspective, MS patients with worse disease severity (higher EDSS score and sNfL values, longer disease duration) showed increased CBF in parietal lobes, temporal lobes, basal ganglia, normal-appearing white matter (NAWM), and DWM. Correlation analysis showed that there was a strong association among CBF, EDSS score and sNfL. MS patients with strongly increased CBF in various brain regions had more ratio in relapsing phase than patients with mildly increased CBF. And relapsing patients showed significantly higher CBF in some regions (temporal lobes, left basal ganglia, right NAWM) compared to remitting patients. In addition, MS patients with cognitive impairment had higher CBF than those without cognitive impairment in the right parietal lobe and NAWM. However, there were no significant differences in CBF between MS patients with and without other neurologic dysfunctions (e.g., motor impairment, visual disturbance, sensory dysfunction). These findings expand our understanding of CBF in MS and imply that CBF could be a potential quantitative imaging marker associated with disease severity.

271. Angioimmunoblastic T-cell lymphoma with predominant CD8+ tumor-infiltrating T-cells is a distinct immune pattern with an immunosuppressive microenvironment.

Front Immunol

2022 Oct 17

Chen Z, Zhu Q, Deng X

272. TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis.

Front Immunol

2022 Oct 17

Komech EA, Koltakova AD, Barinova AA

273. Identification of the immunosuppressive effect of γδ T cells correlated to bone morphogenetic protein 2 in acute myeloid leukemia.

Front Immunol

2022 Oct 17

Liang S, Dong T, Yue K

274. Case report: Reproductive organ preservation and subsequent pregnancy for an infertility patient with lynch syndrome-associated synchronous endometrial cancer and colon cancer after treatment with a PD-1 checkpoint inhibitor.

Front Immunol

2022 Oct 17

Cao D, Gao Y, Zhang RX

275. Salvage high intensity focused ultrasound for residual or recurrent cervical cancer after definitive chemoradiotherapy.

Front Immunol

2022 Oct 17

Zhong Q, Tang F, Ni T

276. Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases.

Front Immunol

2022 Oct 17

Lang R, Li H, Luo X

277. HLA-C dysregulation as a possible mechanism of immune evasion in SARS-CoV-2 and other RNA-virus infections.

Front Immunol

2022 Oct 17

Loi E, Moi L, Cabras P

278. Corrigendum: A comprehensively prognostic and immunological analysis of actin-related protein 2/3 complex subunit 5 in pan-cancer and identification in hepatocellular carcinoma.

Front Immunol

2022 Oct 17

Huang S, Sun L, Hou P

279. β-Carboline dimers inhibit the tumor proliferation by the cell cycle arrest of sarcoma through intercalating to Cyclin-A2.

Front Immunol

2022 Oct 17

Ma H, Yu H, Li Z

β-Carbolines are potentially strong alkaloids with a wide range of bioactivities, and their dimers exhibit stronger antitumor activity other than the monomers. However, the detailed mechanisms of the β-carboline dimers in inhibiting sarcoma (SARC) remain unclear. The results showed that β-carboline-3-carboxylic acid dimers Comp1 and Comp2, which were synthesized in our lab and modified at the N9 position and linked at the C3 position, exhibited effective inhibition activity on MG-63 proliferation (IC50 = 4.6μM). Meanwhile, the large scale transcriptome profiles of SARC from The Cancer Genome Atlas (TCGA) were analyzed, and found that abnormal expression of genes relevant to apoptosis, cell cycle, and signaling pathways of Hedgehog, HIF, Ras involved in the SARC pathogenesis. Interestingly, both dimers could promote the apoptosis and arrest the cell cycle in S phase to inhibit proliferation of MG-63. Moreover, Comp1 and Comp2 inhibited the expression CDK2, CCNA2, DBF4, and PLK1 associated with various immune cells and cell cycle in MG-63. Remarkably, drug-target interaction network analysis showed that numerous proteins involved in cell cycle were the potential targets of Comp1 and Comp2, especially CCNA2. Further molecular docking, isothermal titration calorimetry (ITC) and Cellular Thermal Shift Assay (CETSA) confirmed that both dimers could directly interact with CCNA2, which is significantly correlated with CD4+ T cells, by strong hydrophobic interactions (Kd=5.821 ×106 N). Meanwhile, the levels of CCNA2 and CDK2 were inhibited to decrease in MG-63 by both dimer treatments at transcription and protein levels, implying that Comp1 and Comp2 blocked the interaction between CCNA2 and CDK2 through competitive binding with CCNA2 to arrest the cell cycle of MG-63 cells in the S phase. Additionally, the transcriptome profiles of β-carboline-treated mice from Gene Expression Omnibus (GEO) were obtained, and found that similar antitumor mechanism was shared among β-carboline derivatives. Overall, our results elucidated the antitumor mechanisms of Comp1 and Comp2 through dual-suppressing the function of CCNA2 to profoundly arrest cell cycle of MG-63, then effectively inhibited cell proliferation of MG-63. These results provide new insights into the antitumor mechanism of β-carboline dimers and new routes of various novel cancer-related drug targets for future possible cancer therapy.

280. Galectin-9 protects humanized-ACE2 immunocompetent mice from SARS-CoV-2 infection.

Front Immunol

2022 Oct 17

Yeung ST, Premeaux TA, Du L

281. Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19.

Front Immunol

2022 Oct 14

Schenz J, Rump K, Siegler BH

282. Corrigendum: Susceptibility to infections during acute liver injury depends on transient disruption of liver macrophage niche.

Front Immunol

2022 Oct 14

Lopes ME, Nakagaki BN, Mattos MS

283. Association of dengue infection with anti-alpha-gal antibodies, IgM, IgG, IgG1, and IgG2.

Front Immunol

2022 Oct 14

Olajiga OM, Maldonado-Ruiz LP, Fatehi S

284. Performance of the clinical assessment scale for autoimmune encephalitis in a pediatric autoimmune encephalitis cohort.

Front Immunol

2022 Oct 14

Zhou H, Deng Q, Yang Z

BACKGROUND: The Clinical Assessment Scale for Autoimmune Encephalitis (CASE), a new scale used for rating the severity of autoimmune encephalitis (AE), has demonstrated good validity and reliability in adults with AE, but there is a shortage of data on its performance in children with AE. This study aimed to assess the reliability and validity of the CASE in a cohort of children with AE. METHODS: Forty-seven pediatric inpatients with AE who visited Guizhou Provincial People's Hospital between January 1, 2017, and October 31, 2021, were enrolled in the study. The CASE and mRS scores were obtained through a review of detailed medical records from the Health Information System by two pediatric neurologists. Finally, the performance of the CASE in this pediatric AE cohort was analyzed. RESULTS: The results showed that anti-NMDA receptor encephalitis was the most common (61.70%) type of AE in children. The most common clinical manifestations were language problems (85.1%), psychiatric symptoms (80.9%), and dyskinesia/dystonia (78.7%). The CASE had good item reliability and interevaluator reliability; the Cronbach's alpha value of the total score was 0.825, and the intraclass correlation (ICC) was 0.980. The Cronbach's alpha value by item ranged from 0.16 to 0.406; items 1 and 9 had the lowest and highest Cronbach's alpha values, respectively. The criterion validity between CASE and mRS total scores, as quantified by Pearson correlation, was 0.459, indicating slight to good criterion validity. The area under the curve (AUC) was 0.992 (95% confidence interval: 0.974-1.00). A cutoff value of 14 was selected to determine whether a patient needed admission to the ICU; this cutoff had a sensitivity of 100% and a specificity of 92%. The changes in EEG, MRI, and antibody titers were not related to the severity of AE. A CASE score cutoff of 9 was selected to indicate whether second-line treatment would be needed. CONCLUSION: The CASE has good reliability and validity in children with AE; however, some items of the CASE may not apply to this population. Thus, an in-depth study of the CASE is needed in children with AE.

285. Dysregulation of B7 family and its association with tumor microenvironment in uveal melanoma.

Front Immunol

2022 Oct 14

Chen Y, Zheng A, Zhang Y

BACKGROUND: Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults with a poor prognosis. B7 family is an important modulator of the immune response. However, its dysregulation and underlying molecular mechanism in UVM still remains unclear. METHODS: Data were derived from TCGA and GEO databases. The prognosis was analyzed by Kaplan-Meier curve. The ESTIMATE algorithm, CIBERSORT algorithm, and TIMER database were used to demonstrate the correlation between B7 family and tumor immune microenvironment in UVM. Single-cell RNA sequencing was used to detect the expression levels of the B7 family in different cell types of UVM. UVM was classified into different types by consistent clustering. Enrichment analysis revealed downstream signaling pathways of the B7 family. The interaction between different cell types was visualized by cell chat. RESULTS: The expression level of B7 family in UVM was significantly dysregulated and negatively correlated with methylation level. The expression of B7 family was associated with prognosis and immune infiltration, and B7 family plays an important role in the tumor microenvironment (TME). B7 family members were highly expressed in monocytes/macrophages of UVM compared with other cell types. Immune response and visual perception were the main functions affected by B7 family. The result of cell chat showed that the interaction between photoreceptor cells and immune-related cells was mainly generated by HLA-C-CD8A. CABP4, KCNJ10 and RORB had the strongest correlation with HLA-C-CD8A, and their high expression was significantly correlated with poor prognosis. CABP4 and RORB were specifically expressed in photoreceptor cells. CONCLUSIONS: Dysregulation of the B7 family in UVM is associated with poor prognosis and affects the tumor immune microenvironment. CABP4 and RORB can serve as potential therapeutic targets for UVM, which can be regulated by the B7 family to affect the visual perception and immune response function of the eye, thus influencing the prognosis of UVM.

286. mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model.

Front Immunol

2022 Oct 14

Sittplangkoon C, Alameh MG, Weissman D

287. Gut microbiota composition reflects disease progression, severity and outcome, and dysfunctional immune responses in patients with hypertensive intracerebral hemorrhage.

Front Immunol

2022 Oct 14

Luo J, Chen Y, Tang G

OBJECTIVE: In this study, we aimed to explore the alterations in gut microbiota composition and cytokine responses related to disease progression, severity, and outcomes in patients with hypertensive intracerebral hemorrhage (ICH). METHODS: Fecal microbiota communities of 64 patients with ICH, 46 coronary heart disease controls, and 23 healthy controls were measured by sequencing the V3-V4 region of the 16S ribosomal RNA (16S rRNA) gene. Serum concentrations of a broad spectrum of cytokines were examined by liquid chips and ELISA. Relationships between clinical phenotypes, microbiotas, and cytokine responses were analyzed in the group with ICH and stroke-associated pneumonia (SAP), the major complication of ICH. RESULTS: In comparison with the control groups, the gut microbiota of the patients with ICH had increased microbial richness and diversity, an expanded spectrum of facultative anaerobes and opportunistic pathogens, and depletion of anaerobes. Enterococcus enrichment and Prevotella depletion were more significant in the ICH group and were associated with the severity and functional outcome of ICH. Furthermore, Enterococcus enrichment and Prevotella depletion were also noted in the SAP group in contrast to the non-SAP group. Enterococci were also promising factors in the prognosis of ICH. The onset of ICH induced massive, rapid activation of the peripheral immune system. There were 12 cytokines (Eotaxin, GM-CSF, IL-8, IL-9, IL-10, IL-12p70, IL-15, IL-23, IL-1RA, IP-10, RANTES, and TNF-α) changed significantly with prolongation of ICH, and the Th2 responses correlated with the 90-day outcomes. Cytokines TNF-α, IP-10, IL-1RA, IL-8, IL-18, and MIP-1β in SAP group significantly differed from non-SAP group. Among these cytokines, only IP-10 levels decreased in the SAP group. Enterococcus was positively associated with IL-1RA and negatively associated with IP-10, while Prevotella was inversely associated in both the ICH and SAP groups. CONCLUSION: This study revealed that gut dysbiosis with enriched Enterococcus and depleted Prevotella increased the risk of ICH and subsequently SAP. The altered gut microbiota composition and serum cytokine profiles are potential biomarkers that reflect the inciting physiologic insult/stress involved with ICH.

288. Effects of exogenous taurine supplementation on the growth, antioxidant capacity, intestine immunity, and resistance against Streptococcus agalactiae in juvenile golden pompano (Trachinotus ovatus) fed with a low-fishmeal diet.

Front Immunol

2022 Oct 14

Liu JX, Guo HY, Zhu KC

289. A comprehensive investigation discovered the novel methyltransferase METTL24 as one presumably prognostic gene for kidney renal clear cell carcinoma potentially modulating tumor immune microenvironment.

Front Immunol

2022 Oct 14

Jiang Z, Zhang W, Zeng Z

BACKGROUND: Recently, an increasing number of studies have uncovered the aberrant expression of methyltransferase-like family (METTL) plays an important role in tumorigenesis, such as METTL3 (an m6A writer). In our recent work, we discovered METTL24 expression was highly associated with the hazard ratio (HR) of kidney renal clear cell carcinoma (KIRC) compared to other tumors, implying a special function of METTL24 in KIRC carcinogenesis. Until now, the functions and mechanisms of METTL24 in KIRC have remained mostly unknown. METHODS: The mRNA expression of METTL24 in KIRC was analyzed using the TIMER 2.0, GEPIA, and UALCAN databases. The immunohistochemical assay was performed to validate METTL24 expression in our self-built Chinese cohort (n tumor = 88, n normal = 85). The gene set enrichment analysis (GSEA) was used to investigate the biological processes in which METTL24 might be engaged. The Spearman analysis was used to evaluate the expression correlations between METTL24 and a range of immunological variables, and the effects of METTL24 on the infiltration levels of multiple immune cells were explored using TCGA data. The upstream transcription factors of METTL24 were screened through a multi-omics analysis. RESULTS: METTL24 expression in KIRC tissues was significantly decreased compared to normal adjacent kidney tissues, which was associated with the lower survival rate of KIRC patients. METTL24 potentially participated in the immune-relevant biological processes such as cytokine binding, NF-kappa B binding, MHC protein complex, and interleukin-12 action. Besides, METTL24 expression was linked to a number of immune checkpoints, cytokines, chemokines, and chemokine receptors, and also correlated with the infiltration levels of 10 types of immune cells in KIRC. Meanwhile, METTL24 expression differently affected the overall survival rates (OS) of KIRC patients with high or low levels of immune infiltration. Finally, CTCF and EP300 were discovered to be the probable transcription factors of METTL24 in KIRC. CONCLUSION: This study revealed that METTL24 might serve as a prognostic marker in KIRC and as one immune-relevant target for clinical treatment.

290. Editorial: Immune profile after autologous hematopoietic stem cell transplantation for autoimmune diseases: Where do we stand? Volume II.

Front Immunol

2022 Oct 14

Malmegrim KCR, Toubert A, Farge D

291. Symptomatology during previous SARS-CoV-2 infection and serostatus before vaccination influence the immunogenicity of BNT162b2 COVID-19 mRNA vaccine.

Front Immunol

2022 Oct 14

Nantel S, Bourdin B, Adams K

Public health vaccination recommendations for COVID-19 primary series and boosters in previously infected individuals differ worldwide. As infection with SARS-CoV-2 is often asymptomatic, it remains to be determined if vaccine immunogenicity is comparable in all previously infected subjects. This study presents detailed immunological evidence to clarify the requirements for one- or two-dose primary vaccination series for naturally primed individuals. The main objective was to evaluate the immune response to COVID-19 mRNA vaccination to establish the most appropriate vaccination regimen to induce robust immune responses in individuals with prior SARS-CoV-2 infection. The main outcome measure was a functional immunity score (zero to three) before and after vaccination, based on anti-RBD IgG levels, serum capacity to neutralize live virus and IFN-γ secretion capacity in response to SARS-CoV-2 peptide pools. One point was attributed for each of these three functional assays with response above the positivity threshold. The immunity score was compared based on subjects' symptoms at diagnosis and/or serostatus prior to vaccination. None of the naïve participants (n=14) showed a maximal immunity score of three following one dose of vaccine compared to 84% of the previously infected participants (n=55). All recovered individuals who did not have an immunity score of three were seronegative prior to vaccination, and 67% had not reported symptoms resulting from their initial infection. Following one dose of vaccine, their immune responses were comparable to naïve individuals, with significantly weaker responses than individuals who were symptomatic during infection. These results indicate that the absence of symptoms during initial infection and negative serostatus prior to vaccination predict the strength of immune responses to COVID-19 mRNA vaccine. Altogether, these findings highlight the importance of administering the complete two-dose primary regimen and following boosters of mRNA vaccines to individuals who experienced asymptomatic SARS-CoV-2 infection.

292. An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer.

Front Immunol

2022 Oct 14

Wang KW, Wang MD, Li ZX

OBJECTIVE: The aim of the study was to propose a signature based on genes associated with antigen processing and presentation (APscore) to predict prognosis and response to immune checkpoint inhibitors (ICIs) in advanced gastric cancer (aGC). BACKGROUND: How antigen presentation-related genes affected the immunotherapy response and whether they could predict the clinical outcomes of the immune checkpoint inhibitor (ICI) in aGC remain largely unknown. METHODS: In this study, an aGC cohort (Kim cohort, RNAseq, N=45) treated by ICIs, and 467 aGC patients from seven cohorts were conducted to investigate the value of the APscore predicting the prognosis and response to ICIs. Subsequently, the associations of the APscore with the tumor microenvironment (TME), molecular characteristics, clinical features, and somatic mutation variants in aGC were assessed. The area under the receiver operating characteristic curve (AUROC) of the APscore was analyzed to estimate response to ICIs. Cox regression or Log-rank test was used to estimate the prognosis of aGC patients. RESULTS: The APscore constructed by principal component analysis algorithms was an effective predictive biomarker of the response to ICIs in the Kim cohort and 467 aGC patients (Kim: AUC =0.85, 95% CI: 0.69-1.00; 467 aGC: AUC =0.69, 95% CI: 0.63-0.74). The APscore also was a prognostic biomarker in 467 aGC patients (HR=1.73, 95% CI: 1.21-2.46). Inhibitory immunity, decreased TMB and low stromal scores were observed in the high APscore group, while activation of immunity, increased TMB, and high stromal scores were observed in the low APscore group. Next, we evaluated the value of several central genes in predicting the prognosis and response to ICIs in aGC patients, and verified them using immunogenic, transcriptomic, genomic, and multi-omics methods. Lastly, a predictive model built successfully discriminated patients with vs. without immunotherapy response and predicted the survival of aGC patients. CONCLUSIONS: The APscore was a new biomarker for identifying high-risk aGC patients and patients with responses to ICIs. Exploration of the APscore and hub genes in multi-omics GC data may guide treatment decisions.

293. FOXP3+ regulatory T cells and the immune escape in solid tumours.

Front Immunol

2022 Oct 13

Qiu Y, Ke S, Chen J

294. Innate lymphoid cells type 3 in cancer.

Front Immunol

2022 Oct 13

Castillo-González R, Valle-Noguera A, Gomez-Sánchez MJ

295. Porcine cGAS-STING signaling induced autophagy inhibits STING downstream IFN and apoptosis.

Front Immunol

2022 Oct 13

Xia N, Zheng W, Jiang S

296. Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming.

Front Immunol

2022 Oct 13

Cai Z, Li W, Brenner M

297. Tumor-associated macrophages in tumor progression and the role of traditional Chinese medicine in regulating TAMs to enhance antitumor effects.

Front Immunol

2022 Oct 13

Zhang J, Gao J, Cui J

298. Comprehensive characterization of extracellular matrix-related genes in PAAD identified a novel prognostic panel related to clinical outcomes and immune microenvironment: A silico analysis with in vivo and vitro validation.

Front Immunol

2022 Oct 13

Chen X, Yuan Q, Liu J

The extracellular matrix (ECM) is a vital component of the tumor microenvironment, which interplays with stromal and tumor cells to stimulate the capacity of cancer cells to proliferate, migrate, invade, and undergo angiogenesis. Nevertheless, the crucial functions of ECM-related genes (ECMGs) in pancreatic adenocarcinoma (PAAD) have not been systematically evaluated. Hence, a comprehensive evaluation of the ECMGs is required in pan-cancer, especially in PAAD. First, a pan-cancer overview of ECMGs was explored through the integration of expression profiles, prognostic values, mutation information, methylation levels, and pathway-regulation relationships. Seven ECMGs (i.e. LAMB3, LAMA3, ITGB6, ITGB4, ITGA2, LAMC2, and COL11A1) were identified to be hub genes of PAAD, which were obviously up-regulated in PAAD and considerably linked to tumor stage as well as prognosis. Subsequently, patients with PAAD were divided into 3 clusters premised on ECMG expression and ECM scores. Cluster 2 was the subtype with the best prognosis accompanied by the lowest ECM scores, further verifying ECM's significant contribution to the pathophysiological processes of PAAD. Significant differences were observed for oncogene and tumor suppressor gene expression, immune microenvironment, and chemotherapy sensitivity across three ECM subtypes. After applying a variety of bioinformatics methods, a novel and robust ECM-associated mRNA-lncRNA-based prognostic panel (ECM-APP) was developed and validated for accurately predicting clinical outcomes of patients with PAAD. Patients with PAAD were randomly categorized into the train, internal validation, and external validation cohorts; meanwhile, each patient was allocated into high-risk (unfavorable prognosis) and low-risk (favorable prognosis) populations premised on the expression traits of ECM-related mRNAs and lncRNAs. The discrepancy in the tumor mutation burden and immune microenvironment might be responsible for the difference in prognoses across the high-risk and low-risk populations. Overall, our findings identified and validated seven ECMGs remarkably linked to the onset and progression of PAAD. ECM-based molecular classification and prognostic panel aid in the prognostic assessment and personalized intervention of patients with PAAD.

299. Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis.

Front Immunol

2022 Oct 13

Ascoli C, Schott CA, Huang Y

INTRODUCTION: In sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity. METHODS: Messenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts. RESULTS: We identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion. CONCLUSIONS: Altered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.

300. Therapeutic effects of Fc gamma RIV inhibition are mediated by selectively blocking immune complex-induced neutrophil activation in epidermolysis bullosa acquisita.

Front Immunol

2022 Oct 13

Haeger SC, Kridin K, Pieper M

301. Corrigendum: MicroRNAs as potential regulators of immune response networks in asthma and chronic obstructive pulmonary disease.

Front Immunol

2022 Oct 13

Cañas JA, Rodrigo-Muñoz JM, Sastre B

302. A bibliometric analysis of T cell and atherosclerosis.

Front Immunol

2022 Oct 13

Wei N, Xu Y, Li Y

303. Long-term cellular immune response in immunocompromised unvaccinated COVID-19 patients undergoing monoclonal antibody treatment.

Front Immunol

2022 Oct 13

Thümmler L, Konik M, Lindemann M

304. Evolution of surrogate light chain in tetrapods and the relationship between lengths of CDR H3 and VpreB tails.

Front Immunol

2022 Oct 13

Ott JA, Haakenson JK, Kelly AR

In the mammalian immune system, the surrogate light chain (SLC) shapes the antibody repertoire during B cell development by serving as a checkpoint for production of functional heavy chains (HC). Structural studies indicate that tail regions of VpreB contact and cover the third complementarity-determining region of the HC (CDR H3). However, some species, particularly bovines, have CDR H3 regions that may not be compatible with this HC-SLC interaction model. With immense structural and genetic diversity in antibody repertoires across species, we evaluated the genetic origins and sequence features of surrogate light chain components. We examined tetrapod genomes for evidence of conserved gene synteny to determine the evolutionary origin of VpreB1, VpreB2, and IGLL1, as well as VpreB3 and pre-T cell receptor alpha (PTCRA) genes. We found the genes for the SLC components (VpreB1, VpreB2, and IGLL1) only in eutherian mammals. However, genes for PTCRA occurred in all amniote groups and genes for VpreB3 occurred in all tetrapod groups, and these genes were highly conserved. Additionally, we found evidence of a new VpreB gene in non-mammalian tetrapods that is similar to the VpreB2 gene of eutherian mammals, suggesting VpreB2 may have appeared earlier in tetrapod evolution and may be a precursor to traditional VpreB2 genes in higher vertebrates. Among eutherian mammals, sequence conservation between VpreB1 and VpreB2 was low for all groups except rabbits and rodents, where VpreB2 was nearly identical to VpreB1 and did not share conserved synteny with VpreB2 of other species. VpreB2 of rabbits and rodents likely represents a duplicated variant of VpreB1 and is distinct from the VpreB2 of other mammals. Thus, rabbits and rodents have two variants of VpreB1 (VpreB1-1 and VpreB1-2) but no VpreB2. Sequence analysis of VpreB tail regions indicated differences in sequence content, charge, and length; where repertoire data was available, we observed a significant relationship between VpreB2 tail length and maximum DH length. We posit that SLC components co-evolved with immunoglobulin HC to accommodate the repertoire - particularly CDR H3 length and structure, and perhaps highly unusual HC (like ultralong HC of cattle) may bypass this developmental checkpoint altogether.

305. Human MHC class I molecule, HLA-A2.1, mediates activation of CD8(+) T cell IFN-γ production and the T cell-dependent protection against reactivation of cerebral Toxoplasma infection.

Front Immunol

2022 Oct 13

Mani R, Abdelaziz MH, Michelon A

306. Immunovirotherapy: The role of antibody based therapeutics combination with oncolytic viruses.

Front Immunol

2022 Oct 13

Jafari M, Kadkhodazadeh M, Shapourabadi MB

Despite the fact that the new drugs and targeted therapies have been approved for cancer therapy during the past 30 years, the majority of cancer types are still remain challenging to be treated. Due to the tumor heterogeneity, immune system evasion and the complex interaction between the tumor microenvironment and immune cells, the great majority of malignancies need multimodal therapy. Unfortunately, tumors frequently develop treatment resistance, so it is important to have a variety of therapeutic choices available for the treatment of neoplastic diseases. Immunotherapy has lately shown clinical responses in malignancies with unfavorable outcomes. Oncolytic virus (OV) immunotherapy is a cancer treatment strategy that employs naturally occurring or genetically-modified viruses that multiply preferentially within cancer cells. OVs have the ability to not only induce oncolysis but also activate cells of the immune system, which in turn activates innate and adaptive anticancer responses. Despite the fact that OVs were translated into clinical trials, with T-VECs receiving FDA approval for melanoma, their use in fighting cancer faced some challenges, including off-target side effects, immune system clearance, non-specific uptake, and intratumoral spread of OVs in solid tumors. Although various strategies have been used to overcome the challenges, these strategies have not provided promising outcomes in monotherapy with OVs. In this situation, it is increasingly common to use rational combinations of immunotherapies to improve patient benefit. With the development of other aspects of cancer immunotherapy strategies, combinational therapy has been proposed to improve the anti-tumor activities of OVs. In this regard, OVs were combined with other biotherapeutic platforms, including various forms of antibodies, nanobodies, chimeric antigen receptor (CAR) T cells, and dendritic cells, to reduce the side effects of OVs and enhance their efficacy. This article reviews the promising outcomes of OVs in cancer therapy, the challenges OVs face and solutions, and their combination with other biotherapeutic agents.

307. Donor selection for KIR alloreactivity is associated with superior survival in haploidentical transplant with PTCy.

Front Immunol

2022 Oct 13

Zou J, Kongtim P, Srour SA

308. CXCR2 intrinsically drives the maturation and function of neutrophils in mice.

Front Immunol

2022 Oct 13

Delobel P, Ginter B, Rubio E

309. Distinct CD4+ T cell signature in ANA-positive young adult patients.

Front Immunol

2022 Oct 13

Dei Zotti F, Moriconi C, Qiu A

310. TNF-induced metalloproteinase-9 production is associated with neurological manifestations in HTLV-1-infected individuals.

Front Immunol

2022 Oct 13

Guerra M, Carvalho NB, Santos S

311. IL-6 deletion decreased REV-ERBα protein and influenced autophagy and mitochondrial markers in the skeletal muscle after acute exercise.

Front Immunol

2022 Oct 13

Pinto AP, Muñoz VR, da Rocha AL

Interleukin 6 (IL-6) acts as a pro and anti-inflammatory cytokine, has an intense correlation with exercise intensity, and activates various pathways such as autophagy and mitochondrial unfolded protein response. Also, IL-6 is interconnected to circadian clock-related inflammation and can be suppressed by the nuclear receptor subfamily 1, group D, member 1 (Nr1d1, protein product REV-ERBα). Since IL-6 is linked to physical exercise-modulated metabolic pathways such as autophagy and mitochondrial metabolism, we investigated the relationship of IL-6 with REV-ERBα in the adaptations of these molecular pathways in response to acute intense physical exercise in skeletal muscle. The present study was divided into three experiments. In the first one, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were divided into three groups: Basal time (Basal; sacrificed before the acute exercise), 1 hour (1hr post-Ex; sacrificed 1 hour after the acute exercise), and 3 hours (3hr post-Ex; sacrificed 3 hours after the acute exercise). In the second experiment, C2C12 cells received IL-6 physiological concentrations or REV-ERBα agonist, SR9009. In the last experiment, WT mice received SR9009 injections. After the protocols, the gastrocnemius muscle or the cells were collected for reverse transcription-quantitative polymerase chain reaction (RTq-PCR) and immunoblotting techniques. In summary, the downregulation of REV-ERBα, autophagic flux, and most mitochondrial genes was verified in the IL-6 KO mice independent of exercise. The WT and IL-6 KO treated with SR9009 showed an upregulation of autophagic genes. C2C12 cells receiving IL-6 did not modulate the Nr1d1 mRNA levels but upregulated the expression of some mitochondrial genes. However, when treated with SR9009, IL-6 and mitochondrial gene expression were upregulated in C2C12 cells. The autophagic flux in C2C12 suggest the participation of REV-ERBα protein in the IL-6-induced autophagy. In conclusion, the present study verified that the adaptations required through physical exercise (increases in mitochondrial content and improvement of autophagy machinery) might be intermediated by an interaction between IL-6 and REVERBα.

312. Analysis on heterogeneity of hepatocellular carcinoma immune cells and a molecular risk model by integration of scRNA-seq and bulk RNA-seq.

Front Immunol

2022 Oct 13

Liu X, Li J, Wang Q

313. The role of radiotherapy-related autophagy genes in the prognosis and immune infiltration in lung adenocarcinoma.

Front Immunol

2022 Oct 13

Gao J, Lu F, Yan J

BACKGROUND: There is a close relationship between radiotherapy and autophagy in tumors, but the prognostic role of radiotherapy-related autophagy genes (RRAGs) in lung adenocarcinoma (LUAD) remains unclear. METHODS: Data used in the current study were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted gene co-expression network analysis (WGCNA) was executed to recognize module genes associated with radiotherapy. The differentially expressed genes (DEGs) between different radiotherapy response groups were filtered via edgeR package. The differentially expressed radiotherapy-related autophagy genes (DERRAGs) were obtained by overlapping the module genes, DEGs, and autophagy genes (ATGs). Then, prognostic autophagy genes were selected by Cox analyses, and a risk model and nomogram were subsequently built. Gene Set Enrichment Analysis (GSEA) and single-sample Gene Set Enrichment Analysis (ssGSEA) were performed to investigate potential mechanisms through which prognostic autophagy signatures regulate LUAD. Radiotherapy-resistant cell lines (A549IR and PC9IR) were established after exposure to hypo-fractionated irradiation. Ultimately, mRNA expression was validated by quantitative real-time PCR (qRT-PCR), and relative protein levels were measured in different cell lines by western blot. RESULTS: A total of 11 DERRAGs were identified in LUAD. After Cox analyses, SHC1, NAPSA, and AURKA were filtered as prognostic signatures in LUAD. Then, the risk score model was constructed using the prognostic signatures, which had a good performance in predicting the prognosis, as evidenced by receiver operating characteristics curves. Furthermore, Cox regression analyses demonstrated that risk score was deemed as an independent prognostic factor in LUAD. Moreover, GSEA and ssGSEA results revealed that prognostic RRAGs may regulate LUAD by modulating the immune microenvironment and affecting cell proliferation. The colony formation assay showed that the radiosensitivity of radiation-resistant cell lines was lower than that of primary cells. The western blot assay found that the levels of autophagy were elevated in the radiotherapy-resistant cell lines. Moreover, the expression of DERRAGs (SHC1, AURKA) was higher in the radiotherapy-resistant cells than in primary cells. CONCLUSION: Our study explored the role of RRAGs in the prognosis of LUAD and identified three biomarkers. The findings enhanced the understanding of the relationship between radiotherapy, autophagy, and prognosis in LUAD and provided potential therapeutic targets for LUAD patients.

314. Case Report: Anlotinib combined with PD-1 inhibitor and sequential GA regimen or FOLFIRINOX Chemotherapy in treatment of KRAS G12V mutated pancreatic ductal adenocarcinoma with liver metastasis: A case and literature review.

Front Immunol

2022 Oct 13

Wang Y, Wang B, Xiang L

315. The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus.

Front Immunol

2022 Oct 13

Qiu W, Yu T, Deng GM.

316. Bibliometric and visualization analysis of mesenchymal stem cells and rheumatoid arthritis (from 2012 to 2021).

Front Immunol

2022 Oct 13

Liu J, Gao J, Niu Q

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint deformity and loss of function. Recent studies have shown great progress in the research of mesenchymal stem cells (MSCs) in RA. However, thus far, there have been no bibliometric or visualization analyses in this field. This bibliometric analysis provides a comprehensive overview of the general information and research hotspots of MSCs and RA. METHODS: Articles relevant to MSCs and RA, published between 2012 and 2021, were searched using the Web of Science Core Collection database. Irrelevant publications were excluded from the analysis. Bibliometric and visualization analyses were conducted using VOSviewer, CiteSpace, and Scimago Graphica. RESULTS: A total of 577 articles were analyzed. The annual number of publications increased from 2012 to 2017 and plateaued from 2017 to 2021. China and the USA had the largest number of publications. Collaboration among different organizations mainly occurs between institutes of the same country. Stem Cell Research and Therapy and Frontiers in Immunology were the most popular journals in this field. All the top 20 co-cited authors had a positive co-citation relationship. The top references indicate that MSCs can contribute to RA research and treatment mainly via immunomodulation. From 2012 to 2021, "collagen-induced arthritis," "immunomodulation," and "therapy" were some of the keywords associated with MSCs and RA, while "extracellular vesicles" showed a strong keyword burst from 2019 to 2021. CONCLUSION: MSCs and RA have been widely studied in different countries and institutions and by different authors over the last ten years. China and the USA had the largest number of publications. Different types of journals provide admirable sources for researchers. Some keywords, including immunomodulation and extracellular vesicles, may be hot spots in the near future. There will be more basic research and clinical translation of MSCs and RA, and substantial new treatments for RA will soon be developed.

317. H-TEX-mediated signaling between hepatocellular carcinoma cells and macrophages and exosome-targeted therapy for hepatocellular carcinoma.

Front Immunol

2022 Oct 13

Yu S, Zhou L, Fu J

318. Clinical characteristics of hepatitis flares during pregnancy and postpartum in Chinese chronic hepatitis B virus carriers-a prospective cohort study of 417 cases.

Front Immunol

2022 Oct 13

Wang X, Song A, Lin X

BACKGROUND: In China, it is common for pregnant women with a high load of hepatitis B virus (HBV) to take nucleos(t)ide analogue (NA) to prevent maternal-to-child transmission of HBV. However, the impact of NA intervention on virological and biochemical parameters in pregnant and postpartum women and the safety of drug cessation remain unclear. A prospective observational cohort was established in this study to analyze the clinical characteristics of hepatitis flares in pregnant and postpartum chronic HBV carriers, with or without NA intervention. METHODS: Pregnant women who were chronic HBV carriers were enrolled in this study and divided into an NA intervention group and a non-intervention group according to their preferences. Liver function, HBV DNA level, and HBV serological markers were regularly measured during pregnancy and at approximately 6 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks postpartum. RESULTS: A total of 417 patients were enrolled, including 303 in the NA intervention group and 114 in the non-intervention group. The incidence rates of postpartum hepatitis flares in both groups were higher than that of during pregnancy (45.7% vs 10.9%, p < 0.001; 41.2% vs 17.7%, p < 0.001). The second trimester was the peak of the incidence of flares during pregnancy and the incidence peak of postpartum flares was about 6 weeks postpartum. A total of 98% (145/148) of postpartum flares occurred within 24 weeks postpartum. After drug cessation, the incidence rate of flares was 34.1% (44/129). CONCLUSION: In pregnant chronic HBV carriers, a certain proportion of hepatitis flares occurred during pregnancy and postpartum regardless of whether NA intervention was used, and the incidence of postpartum flares (44.6%) was significantly higher than that (12.8%) of during pregnancy. The flare incidence peaked at approximately 6 weeks postpartum, which may be the time period suitable for treatment. Since 98% of postpartum flares occurred within 24 weeks postpartum, the follow-up after drug cessation should be at least 24 weeks postpartum.

319. African swine fever virus infection activates inflammatory responses through downregulation of the anti-inflammatory molecule C1QTNF3.

Front Immunol

2022 Oct 12

Lv C, Zhang Q, Zhao L

320. Diagnostic accuracy of the European League against rheumatism/American College of Rheumatology-2019 versus the Systemic Lupus International Collaborating Clinics-2012 versus the ACR-1997 classification criteria in adult systemic lupus erythematosus: A systematic review and meta-analysis.

Front Immunol

2022 Oct 12

Lu W, Tian F, Ma J

AIM: To evaluate the diagnostic performance of the American College of Rheumatology (ACR)-1997, the Systemic Lupus International Collaborating Clinics (SLICC)-2012, and the European League against Rheumatism (EULAR)/ACR-2019 classification criteria in adult patients with systemic lupus erythematosus (SLE). METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were searched for literature comparing the three classification criteria of ACR-1997, SLICC-2012 and EULAR/ACR-2019, which took clinical diagnosis as reference. Meta-analysis was used to evaluate and compare the sensitivity, specificity and diagnostic odds ratio of ACR-1997, SLICC-2012 and EULAR/ACR-2019. To assess the early diagnosis capability of the classification criteria, subgroups of patients with disease duration < 3 years and < 1 year were selected for comparison of sensitivity and specificity based on the inclusion of the original study. The sensitivity and specificity of each item in three sets of classification criteria were evaluated. In addition, the clinical and immunological characteristics of patients who did not meet the three classification criteria were compared. RESULTS: Nine original studies were included in the analysis, including 6404 SLE patients and 3996 controls. Results showed that the diagnostic odds ratios (95% confidence interval) of the SLICC-2012 [136.35 (114.94, 161.75)] and EULAR/ACR-2019 [187.47 (158.00, 222.42)] were higher than those of the ACR-1997 [67.53 (58.75, 77.63)]. Compared with ACR-1997[(0.86 (0.82, 0.89)], SLICC-2012[(0.96 (0.93, 0.97)] and EULAR/ACR-2019[(0.95 (0.92, 0.97)] had higher sensitivity. The specificity of the three classification criteria was similar: ACR-1997, SLICC-2012, and EULAR/ACR-2019 were 0.93 (0.89, 0.95), 0.86 (0.79, 0.91), and 0.91 (0.85, 0.95), respectively. The sensitivity of SLICC-2012 and EULAR/ACR-2019 were higher than that of ACR-1997 in early-course subgroups. Patients who did not meet ACR-1997 had more hypocomplementemia, patients who did not meet SLICC-2012 had more cutaneous lupus and photosensitivity, and patients who did not meet EULAR/ACR-2019 had more cutaneous lupus and leucopenia. CONCLUSIONS: SLICC-2012 and EULAR/ACR-2019 have better diagnostic ability than the ACR-1997, and the sensitivity of the former two criteria is also higher than that of the latter; Moreover, the SLICC-2012 and EULAR/ACR-2019 for patients in the early stages of disease performed equally excellent.

321. Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

Front Immunol

2022 Oct 12

Buonocore SM, van der Most RG.

In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine Pandemrix (GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4+ T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a "two-hit" hypothesis. The collective in silico, in vitro, and preclinical in vivo data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.

322. Correlation between serologic parameters and disease activity of IgG4-related disease: Differences between patients with normal and elevated serum IgG4 concentrations.

Front Immunol

2022 Oct 12

Kwon OC, Park MC, Kim YG.

323. SARS-CoV-2 specific antibody trajectories in mothers and infants over two months following maternal infection.

Front Immunol

2022 Oct 12

Martin MA, Keith M, Pace RM

324. Corrigendum: Orange-derived and dexamethasone-encapsulated extracellular vesicles reduced proteinuria and alleviated pathological lesions in IgA nephropathy by targeting intestinal lymphocytes.

Front Immunol

2022 Oct 12

Zhang W, Yuan Y, Li X

325. Significance of macrophage infiltration in the prognosis of lung adenocarcinoma patients evaluated by scRNA and bulkRNA analysis.

Front Immunol

2022 Oct 12

Zhu H, Zheng C, Liu H

326. The association of cervicovaginal Langerhans cells with clearance of human papillomavirus.

Front Immunol

2022 Oct 12

Dai W, Gui L, Du H

327. Development and validation of nomogram prediction model for severe kidney disease in children with Henoch-Schönlein purpura: A prospective analysis of two independent cohorts-forecast severe kidney disease outcome in 2,480 hospitalized Henoch-Schönlein purpura children.

Front Immunol

2022 Oct 12

Wang K, Sun X, Jing S

328. Advances in immunotherapy for glioblastoma multiforme.

Front Immunol

2022 Oct 12

Mahmoud AB, Ajina R, Aref S

329. Mucin-degrading gut commensals isolated from healthy faecal donor suppress intestinal epithelial inflammation and regulate tight junction barrier function.

Front Immunol

2022 Oct 12

Pan M, Barua N, Ip M.

The intestinal epithelium surface is covered by a layer of mucus that harbors a complex and dynamic population of bacteria termed gut microbiota. In particular, some gut bacteria have the ability to degrade the mucin glycan for nutritional sources. However, the bacterial diversity of mucin-degrading bacteria in human gut microbiota and their role in the gut remains unclear. In this study, we characterized the diversity of mucin-degrading bacteria in the human gut microbiota by an established cultivation-based molecular profiling method. The results showed the gut commensals having the mucin degrading ability were widely distributed in the gut microbiota and were more abundant than previously thought. In addition, many previously uncharacterized mucin degraders were isolated from faecals samples, suggesting the mucin-degrading gut commensals were underappreciated. To gain a better understanding of the interaction between these mucin-degrading gut commensals and the host, the effect of the commensals on intestinal epithelial cells were examined, and the results revealed that the commensals (8 Bacteroides spp., 2 Parabacteroides spp, Akkermanisa muciniphila and Bifidobacterial dentium) incited low level of inflammatory response (IL-8 and TNF-α) but suppressed the inflammatory response induced by E. coli through downregulating the NF-κB pathway. The presence of gut commensals also showed potential in enhancing the epithelial tight junction (TJ) barrier function through regulating the mRNA expression of TJ protein genes such as Zo-1, Occludin, Claudin-1 and E-cadherin. Furthermore, the presence of commensal bacteria P. distasonis, B. thetaiotaomicron and A. muciniphila completely or partly restored the pro-inflammatory cytokine IL-1β induced TJ barrier disruption. In conclusion, these findings indicate that mucin-degrading gut commensals were widely distributed in the gut microbiota and showed anti-inflammatory effect against pathogen infection and potential in modulating the epithelial barrier function.

330. Factors influencing the SARS-CoV-2 infection and vaccination induced immune response in rheumatoid arthritis.

Front Immunol

2022 Oct 12

Nemeth D, Vago H, Tothfalusi L

BACKGROUND: To investigate the factors that have significant impact on the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and vaccination induced immune response in rheumatoid arthritis (RA). METHODS: Serological response was measured by quantifying anti-SARS-CoV-2 specific antibodies, while the cell-mediated response was measured by a whole-blood test quantifying the interferon (IFN)-γ response to different SARS-CoV-2-specific domains. RESULTS: We prospectively enrolled 109 RA patients and 43 healthy controls. The median time (IQR) between the confirmed infection or the last vaccination dose and the day when samples were taken ("sampling interval") was 3.67 (2.03, 5.50) months in the RA group. Anti-Spike (anti-S) specific antibodies were detected in 94% of RA patients. Among the investigated patient related variables, age (p<0.004), sampling interval (p<0.001), the brand of the vaccine (p<0.001) and targeted RA therapy (TNF-inhibitor, IL-6 inhibitor, anti-CD20 therapy) had significant effect on the anti-S levels. After covariate adjustment TNF-inhibitor therapy decreased the anti-S antibody concentrations by 80% (p<0.001). The same figures for IL-6 inhibitor and anti-CD20 therapy were 74% (p=0.049) and 97% (p=0.002), respectively. Compared to subjects who were infected but were not vaccinated, the RNA COVID-19 vaccines increased the anti-S antibody levels to 71.1 (mRNA-1273) and 36.0 (BNT162b2) fold (p<0.001). The corresponding figure for the ChAdOx1s vaccine is 18.1(p=0.037). Anti-CCP (anti-cyclic citrullinated peptides) positive patients had 6.28 times (p= 0.00165) higher anti-S levels, than the anti-CCP negative patients. Positive T-cell response was observed in 87% of the healthy volunteer group and in 52% of the RA patient group. Following vaccination or infection it declined significantly (p= 0.044) but more slowly than that of anti-S titer (6%/month versus 25%). Specific T-cell responses were decreased by 65% in patients treated with anti-CD20 therapy (p=0.055). CONCLUSION: Our study showed that the SARS-CoV-2-specific antibody levels were substantially reduced in RA patients treated with TNF-α-inhibitors (N=51) and IL-6-inhibitor (N=15). In addition, anti-CD20 therapy (N=4) inhibited both SARS-CoV-2-induced humoral and cellular immune responses. Furthermore, the magnitude of humoral and cellular immune response was dependent on the age and decreased over time. The RNA vaccines and ChAdOx1s vaccine effectively increased the level of anti-S antibodies.

331. Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms.

Front Immunol

2022 Oct 12

Guo H, Yang J, Wang H

332. Exploring metabolism in scleroderma reveals opportunities for pharmacological intervention for therapy in fibrosis.

Front Immunol

2022 Oct 11

Cantanhede IG, Liu H, Liu H

BACKGROUND: Recent evidence has indicated that alterations in energy metabolism play a critical role in the pathogenesis of fibrotic diseases. Studies have suggested that 'metabolic reprogramming' involving the glycolysis and oxidative phosphorylation (OXPHOS) in cells lead to an enhanced generation of energy and biosynthesis. The aim of this study was to assess the molecular basis of changes in fibrotic metabolism in systemic sclerosis (Scleroderma; SSc) and highlight the most appropriate targets for anti-fibrotic therapies. MATERIALS AND METHODS: Dermal fibroblasts were isolated from five SSc patients and five healthy donors. Cells were cultured in medium with/without TGF-β1 and with/without ALK5, pan-PIM or ATM kinase inhibitors. Extracellular flux analyses were performed to evaluate glycolytic and mitochondrial respiratory function. The mitochondrial network in TMRM-stained cells was visualized by confocal laser-scanning microscopy, followed by semi-automatic analysis on the ImageJ platform. Protein expression of ECM and fibroblast components, glycolytic enzymes, subunits of the five OXPHOS complexes, and dynamin-related GTPases and receptors involved in mitochondrial fission/fusion were assessed by western blotting. RESULTS: Enhanced mitochondrial respiration coupled to ATP production was observed in SSc fibroblasts at the expense of spare respiratory capacity. Although no difference was found in glycolysis when comparing SSc with healthy control fibroblasts, levels of phophofructokinase-1 isoform PFKM were significantly lower in SSc fibroblasts (P<0.05). Our results suggest that the number of respirasomes is decreased in the SSc mitochondria; however, the organelles formed a hyperfused network, which is thought to increase mitochondrial ATP production through complementation. The increased mitochondrial fusion correlated with a change in expression levels of regulators of mitochondrial morphology, including decreased levels of DRP1, increased levels of MIEF2 and changes in OPA1 isoform ratios. TGF-β1 treatment strongly stimulated glycolysis and mitochondrial respiration and induced the expression of fibrotic markers. The pan-PIM kinase inhibitor had no effect, whereas both ALK5 and ATM kinase inhibition abrogated TGF-β1-mediated fibroblast activation, and upregulation of glycolysis and respiration. CONCLUSIONS: Our data provide evidence for a novel mechanism(s) by which SSc fibroblasts exhibit altered metabolic programs and highlight changes in respiration and dysregulated mitochondrial morphology and function, which can be selectively targeted by small molecule kinase inhibitors.

333. Remodeling the bladder tumor immune microenvironment by mycobacterial species with changes in their cell envelope composition.

Front Immunol

2022 Oct 11

Senserrich J, Guallar-Garrido S, Gomez-Mora E

Intravesical BCG instillation after bladder tumor resection is the standard treatment for non-muscle invasive bladder cancer; however, it is not always effective and frequently has undesirable side effects. Therefore, new strategies that improve the clinical management of patients are urgently needed. This study aimed to comprehensively evaluate the bladder tumor immune microenvironment profile after intravesical treatment with a panel of mycobacteria with variation in their cell envelope composition and its impact on survival using an orthotopic murine model to identify more effective and safer therapeutic strategies. tumor-bearing mice were intravesically treated with a panel of BCG and M. brumae cultured under different conditions. Untreated tumor-bearing mice and healthy mice were also included as controls. After mycobacterial treatments, the infiltrating immune cell populations in the bladder were analysed by flow cytometry. We provide evidence that mycobacterial treatment triggered a strong immune infiltration into the bladder, with BCG inducing higher global absolute infiltration than M. brumae. The induced global immune microenvironment was strikingly different between the two mycobacterial species, affecting both innate and adaptive immunity. Compared with M. brumae, BCG treated mice exhibited a more robust infiltration of CD4+ and CD8+ T-cells skewed toward an effector memory phenotype, with higher frequencies of NKT cells, neutrophils/gMDSCs and monocytes, especially the inflammatory subset, and higher CD4+ TEM/CD4+ Treg and CD8+ TEM/CD4+ Treg ratios. Conversely, M. brumae treatment triggered higher proportions of total activated immune cells and activated CD4+ and CD8+ TEM cells and lower ratios of CD4+ TEM cells/CD4+ Tregs, CD8+ TEM cells/CD4+ Tregs and inflammatory/reparative monocytes. Notably, the mycobacterial cell envelope composition in M. brumae had a strong impact on the immune microenvironment, shaping the B and myeloid cell compartment and T-cell maturation profile and thus improving survival. Overall, we demonstrate that the bladder immune microenvironment induced by mycobacterial treatment is species specific and shaped by mycobacterial cell envelope composition. Therefore, the global bladder immune microenvironment can be remodelled, improving the quality of infiltrating immune cells, the balance between inflammatory and regulatory/suppressive responses and increasing survival.

334. Development and validation of four ferroptosis-related gene signatures and their correlations with immune implication in hepatocellular carcinoma.

Front Immunol

2022 Oct 11

Zhang Y, Ren H, Zhang C

335. Editorial: Osteoarticular-immunological interplay in response to disease and therapy.

Front Immunol

2022 Oct 11

Deloch L, Filkova M, Tomcik M.

336. Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis.

Front Immunol

2022 Oct 11

Zhao-Fleming HH, Zahid A, Lu T

337. Identification and verification of the prognostic value of CUL7 in colon adenocarcinoma.

Front Immunol

2022 Oct 11

Wang C, Zhao Z, Zhang Y

CUL7, a gene composed of 26 exons associated with cullin 7 protein, is also an E3 ligase that is closely related to cell senescence, apoptosis, and cell transformation and also plays an important role in human cancer. However, there is no systematic pan-cancer analysis has been performed to explore its role in prognosis and immune prediction. In this study, the expression of CUL7 in colon adenocarcinoma (COAD) was investigated to determine its prognosis value. First, based on the Cancer Genome Atlas (TCGA), Genotypic-Tissue Expression Project(GTEx), Cancer Cell Line Encyclopedias(CCLE), and TISIDB database, the potential role of CUL7 in different tumors was explored. Subsequently, the expression of CUL7 in COAD was explored and verified by Immunohistochemistry (IHC). Furthermore, the mutation frequency of CUL7 in COAD was analyzed, and the prognostic value of CUL7 in COAD was discussed. In addition, the nomogram was constructed, and its prognostic value was verified by follow-up data from Jiangmen Central Hospital. Finally, PPI network analysis explored the potential biological function of CUL7 in COAD. The results show that CUL7 is upregulated in most tumors, which is significantly associated with poor survival. At the same time, CUL7 is correlated with the clinical stage and immune landscape of various tumors. In colorectal cancer, CUL7 was overexpressed in tumor tissues by IHC with a mutation frequency of about 4%. CUL7 is an independent prognostic factor for colorectal cancer. The nomogram constructed has effective predictive performance, and external databases proved the prognostic value of CUL7. In addition, PPI network analysis showed that CUL7 was closely related to FBXW8, and further pathway enrichment analysis showed that CUL7 was mainly involved in ubiquitin-mediated proteolysis. Therefore, our study provides a comprehensive understanding of the potential role of CUL7 in different tumors, and CUL7 might be a prognostic marker for COAD.

338. Clinical cancer immunotherapy: Current progress and prospects.

Front Immunol

2022 Oct 11

Liu C, Yang M, Zhang D

339. The prognostic value and therapeutic targeting of myeloid-derived suppressor cells in hematological cancers.

Front Immunol

2022 Oct 11

Fan R, De Beule N, Maes A

340. Pembrolizumab in Chinese patients with advanced melanoma: 3-year follow-up of the KEYNOTE-151 study.

Front Immunol

2022 Oct 11

Si L, Zhang X, Shu Y

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT02821000.

341. Impact of the host response and osteoblast lineage cells on periodontal disease.

Front Immunol

2022 Oct 11

Zhou M, Graves DT.

Periodontitis involves the loss of connective tissue attachment and alveolar bone. Single cell RNA-seq experiments have provided new insight into how resident cells and infiltrating immune cells function in response to bacterial challenge in periodontal tissues. Periodontal disease is induced by a combined innate and adaptive immune response to bacterial dysbiosis that is initiated by resident cells including epithelial cells and fibroblasts, which recruit immune cells. Chemokines and cytokines stimulate recruitment of osteoclast precursors and osteoclastogenesis in response to TNF, IL-1β, IL-6, IL-17, RANKL and other factors. Inflammation also suppresses coupled bone formation to limit repair of osteolytic lesions. Bone lining cells, osteocytes and periodontal ligament cells play a key role in both processes. The periodontal ligament contains cells that exhibit similarities to tendon cells, osteoblast-lineage cells and mesenchymal stem cells. Bone lining cells consisting of mesenchymal stem cells, osteoprogenitors and osteoblasts are influenced by osteocytes and stimulate formation of osteoclast precursors through MCSF and RANKL, which directly induce osteoclastogenesis. Following bone resorption, factors are released from resorbed bone matrix and by osteoclasts and osteal macrophages that recruit osteoblast precursors to the resorbed bone surface. Osteoblast differentiation and coupled bone formation are regulated by multiple signaling pathways including Wnt, Notch, FGF, IGF-1, BMP, and Hedgehog pathways. Diabetes, cigarette smoking and aging enhance the pathologic processes to increase bone resorption and inhibit coupled bone formation to accelerate bone loss. Other bone pathologies such as rheumatoid arthritis, post-menopausal osteoporosis and bone unloading/disuse also affect osteoblast lineage cells and participate in formation of osteolytic lesions by promoting bone resorption and inhibiting coupled bone formation. Thus, periodontitis involves the activation of an inflammatory response that involves a large number of cells to stimulate bone resorption and limit osseous repair processes.

342. Identification of N7-methylguanosine related subtypes and construction of prognostic model in gastric cancer.

Front Immunol

2022 Oct 10

Li X, Dong H, Chen L

BACKGROUND: N7-methylguanosine (m7G), one of the most common post-transcriptional modifications, can be present in tRNA, mRNA, and miRNA to mediate the progression of various tumors. However, the possible role of m7G in gastric cancer (GC) is still unknown. MATERIALS AND METHODS: In this study, SNVs (single nucleotide variations), CNVs (copy number variations), and methylation of m7G-related genes (m7GRGs) were analyzed. The relationship between them and the expression of m7GRGs and prognosis of GC patients was explored. Based on 13 prognostic-related m7GRGs, 567 GC samples were classified into three subtypes using the ConsensusClusterPlus package. we compared survival status, clinical traits, immune cell infiltration, immune checkpoints, tumor microenvironment (TME), tumor immune dysfunction and exclusion (TIDE), and potential biological pathways among the three subtypes. Then, patients were again grouped into different genetic subtypes based on the DEGs among the three subtypes. In addition, a prognostic m7GRG_Score was constructed using five risk genes applicable to patients of any age, gender and stage. We also assessed tumor mutational burden (TMB), microsatellite instability (MSI), cancer stem cell (CSC) index, sensitivity of antineoplastic drugs, efficacy of anti-PD-1 and anti-CTLA4 immunotherapy between high and low m7GRG_Score groups. Finally, we established a nomogram based on m7GRG_Score and tumor stage to enhance the clinical application of the model. miRNAs and lncRNAs that could regulate expression of risk genes were searched. RESULTS: SNVs, CNVs, and methylation of m7GRGs were associated with m7GRGs expression. However, they did not significantly affect the survival of GC patients. Our results also confirmed that patients in subtypes B and C and low m7GRG_Score groups had longer survival time, better clinical stage, more immune cell infiltration, fewer immune escape and dysfunction compared to subtype A and high m7GRG_Score groups. A low m7GRG_score was featured with increased microsatellite instability-high (MSI-H), TMB, and efficacy of immunotherapy. CONCLUSION: The m7GRG_Score model may become a beneficial tool for predicting prognosis and guiding personalized treatment in GC patients. These findings will improve our knowledge of m7G in GC and provide new methods for more effective treatment strategies.

343. Efficacy and safety profile of phosphodiesterase 4 inhibitor in the treatment of psoriasis: A systematic review and meta-analysis of randomized controlled trials.

Front Immunol

2022 Oct 10

Kang Q, Chen JS, Yang H.

344. Cumulative evidence for associations between genetic variants in interleukin 17 family gene and risk of human diseases.

Front Immunol

2022 Oct 10

Liu T, Yang L, Lv X

345. ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance.

Front Immunol

2022 Oct 10

Ge L, Wang T, Shi D

346. Improved diagnostic performance of CASPAR criteria with integration of ultrasound.

Front Immunol

2022 Oct 10

Geng Y, Song Z, Zhang X

BACKGROUND: The difficulty in determining synovitis, tenosynovitis, or enthesitis by physical examination (PE) has limited the diagnostic capability of CASPAR for psoriatic arthritis (PsA). Therefore, we aimed to evaluate the diagnostic utility of CASPAR with the integration of ultrasound (US). METHODS: Patients with a hint of PsA were enrolled. Besides routine PE for tender or swollen joints, enthesitis, and dactylitis, US was performed to evaluate peripheral joints, entheses, and tendons. The additional value of the US to the CASPAR criteria was analyzed. RESULTS: A total of 326 consecutive patients with 164 PsA and 162 non-PsA were enrolled. A total of 162 non-PsA patients consisted of 58 cases of psoriasis (PsO), 27 osteoarthritis with PsO/family history of PsO, five fibromyalgia with PsO, 69 sero-negative rheumatoid arthritis, and three undifferentiated arthritis. Significantly higher frequencies of tenosynovitis and enthesitis on US and new bone formation on X-rays were found in PsA vs. non-PsA patients (59.1% vs. 13.0%; 63.4% vs. 14.2%; 62.2% vs. 8.0%, p <0.01 for all). Logistic regression analysis showed that dactylitis (OR = 12.0, p <0.01), family history of PsO/PsA (OR = 3.1, p <0.05), nail involvement (OR = 3.5, p = 0.01), new bone formation on X-ray (OR = 14.8, p <0.01), tenosynovitis on US (OR = 21.3, p <0.01), and enthesitis on US (OR = 21.7, p <0.01) were independent risk factors for PsA. By combining US tenosynovitis and/or enthesitis, the diagnostic utility of CASPAR criteria was improved, with superior specificity (91.4% vs. 84.0%) and similar sensitivity (95.7% vs. 94.5%). Replacing X-ray by US or adding US, the CASPAR criteria showed comparable sensitivity and specificity for PsA diagnosis. The diagnostic accuracy was 89.3% for CASPAR criteria based on PE, 93.6% for CASPAR added with US, and 93.3% for CASPAR with US replacing X-ray. CONCLUSION: The diagnostic utility of the CASPAR was improved by integrating tenosynovitis and/or enthesitis when using US. US provides additional value for PsA recognition.

347. Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis.

Front Immunol

2022 Oct 10

Lopez-Santalla M, Conde C, Rodriguez-Trillo A

348. The clinical value of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and D-dimer-to-fibrinogen ratio for predicting pneumonia and poor outcomes in patients with acute intracerebral hemorrhage.

Front Immunol

2022 Oct 10

Luo S, Yang WS, Shen YQ

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Newmer生物