生信网-文献期刊

Front Immunol

2022 Mar 9

Liang H, Xu Y, Chen M

2. The Programmed Death-1 Pathway Counter-Regulates Inflammation-Induced Osteoclast Activity in Clinical and Experimental Settings.

Front Immunol

2022 Mar 9

Greisen SR, Kragstrup TW, Thomsen JS

3. Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets.

Front Immunol

2022 Mar 9

Zhang Y, Khan S, Liu Y

4. Heterologous Immune Responses of Serum IgG and Secretory IgA Against the Spike Protein of Endemic Coronaviruses During Severe COVID-19.

Front Immunol

2022 Mar 9

Smit WL, van Tol S, van der Wal S

5. T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C.

Front Immunol

2022 Mar 9

Flickinger JC Jr, Singh J, Yarman Y

6. The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren's Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data.

Front Immunol

2022 Mar 9

Hong X, Wang X, Rang X

OBJECTIVE: This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS). METHODS: MS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein-protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug-Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes. RESULTS: Based on GWAS data, we found 14 hub common susceptibility genes (HLA-DRB1, HLA-DRA, STAT3, JAK1, HLA-B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, TYK2, IL2RA, and MAPK1), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (STAT1, GATA3, PIK3CA) with 3 drugs and 10 common risk pathways with 435 drugs. "JAK-STAT signaling pathway" was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that IL2RA and HLA-DRB1, identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS. CONCLUSION: We observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.

7. Improvement of Lipoplexes With a Sialic Acid Mimetic to Target the C1858T PTPN22 Variant for Immunotherapy in Endocrine Autoimmunity.

Front Immunol

2022 Mar 9

Arena A, Belcastro E, Ceccacci F

8. Machine-Learning Algorithm-Based Prediction of Diagnostic Gene Biomarkers Related to Immune Infiltration in Patients With Chronic Obstructive Pulmonary Disease.

Front Immunol

2022 Mar 8

Zhang Y, Xia R, Lv M

OBJECTIVE: This study aims to identify clinically relevant diagnostic biomarkers in chronic obstructive pulmonary disease (COPD) while exploring how immune cell infiltration contributes towards COPD pathogenesis. METHODS: The GEO database provided two human COPD gene expression datasets (GSE38974 and GSE76925; n=134) along with the relevant controls (n=49) for differentially expressed gene (DEG) analyses. Candidate biomarkers were identified using the support vector machine recursive feature elimination (SVM-RFE) analysis and the LASSO regression model. The discriminatory ability was determined using the area under the receiver operating characteristic curve (AUC) values. These candidate biomarkers were characterized in the GSE106986 dataset (14 COPD patients and 5 controls) in terms of their respective diagnostic values and expression levels. The CIBERSORT program was used to estimate patterns of tissue infiltration of 22 types of immune cells. Furthermore, the in vivo and in vitro model of COPD was established using cigarette smoke extract (CSE) to validated the bioinformatics results. RESULTS: 80 genes were identified via DEG analysis that were primarily involved in cellular amino acid and metabolic processes, regulation of telomerase activity and phagocytosis, antigen processing and MHC class I-mediated peptide antigen presentation, and other biological processes. LASSO and SVM-RFE were used to further characterize the candidate diagnostic markers for COPD, SLC27A3, and STAU1. SLC27A3 and STAU1 were found to be diagnostic markers of COPD in the metadata cohort (AUC=0.734, AUC=0.745). Their relevance in COPD were validated in the GSE106986 dataset (AUC=0.900 AUC=0.971). Subsequent analysis of immune cell infiltration discovered an association between SLC27A3 and STAU1 with resting NK cells, plasma cells, eosinophils, activated mast cells, memory B cells, CD8+, CD4+, and helper follicular T-cells. The expressions of SLC27A3 and STAU1 were upregulated in COPD models both in vivo and in vitro. Immune infiltration activation was observed in COPD models, accompanied by the enhanced expression of SLC27A3 and STAU1. Whereas, the knockdown of SLC27A3 or STAU1 attenuated the effect of CSE on BEAS-2B cells. CONCLUSION: STUA1 and SLC27A3 are valuable diagnostic biomarkers of COPD. COPD pathogenesis is heavily influenced by patterns of immune cell infiltration. This study provides a molecular biology insight into COPD occurrence and in exploring new therapeutic means useful in COPD.

9. Cross-Talk Between m(6)A- and m(5)C-Related lncRNAs to Construct a Novel Signature and Predict the Immune Landscape of Colorectal Cancer Patients.

Front Immunol

2022 Mar 8

Song W, Ren J, Xiang R

BACKGROUND: N6-methyladenosine (m6A) and 5-methylcytosine (m5C) can modify long non-coding RNAs (lncRNAs), thereby affecting tumorigenesis and tumor progression. However, there is a lack of knowledge regarding the potential roles and cross-talk of m6A- and m5C-related lncRNAs in the tumor microenvironment (TME) and their effect on prognosis. METHODS: We systematically evaluated the expression patterns of m6A- and m5C-related lncRNAs in 1358 colorectal cancer (CRC) samples from four datasets. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance, TME, tumor-infiltrating immune cells (TIICs), and immune checkpoints in the different molecular subtypes were analyzed. Finally, we established a m6A- and m5C-related lncRNA signature and a prognostic nomogram. RESULTS: We identified 141 m6A- and m5C-related lncRNAs by co-expression analysis, among which 23 lncRNAs were significantly associated with the overall survival (OS) of CRC patients. Two distinct molecular subtypes (cluster A and cluster B) were identified, and these two distinct molecular subtypes could predict clinicopathological features, prognosis, TME stromal activity, TIICs, immune checkpoints. Next, a m6A- and m5C-related lncRNA signature for predicting OS was constructed, and its predictive capability in CRC patients was validated. We then constructed a highly accurate nomogram for improving the clinical applicability of the signature. Analyses of clinicopathological features, prognosis, TIICs, cancer stem cell (CSC), and drug response revealed significant differences between two risk groups. In addition, we found that patients with a low-risk score exhibited enhanced response to anti-PD-1/L1 immunotherapy. Functional enrichment analysis showed that these lncRNAs related to the high-risk group were involved in the development and progression of CRC. CONCLUSIONS: We conducted a comprehensive analysis of m6A- and m5C-related lncRNAs in CRC and revealed their potential functions in predicting tumor-immune-stromal microenvironment, clinicopathological features, and prognosis, and determined their role in immunotherapy. These findings may improve our understanding of the cross-talk between m6A- and m5C-related lncRNAs in CRC and pave a new road for prognosis assessment and more effective immunotherapy strategies.

10. Reduced NK Cell Cytotoxicity by Papillomatosis-Derived TGF-β Contributing to Low-Risk HPV Persistence in JORRP Patients.

Front Immunol

2022 Mar 8

Wu X, Xiao Y, Guo D

11. RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miRNA-1972 Targeting p53/mTOR Signaling in Vascular Endotheliocyte.

Front Immunol

2022 Mar 8

Chen Y, Dang J, Lin X

12. Human Monocyte-Derived Suppressor Cell Supernatant Induces Immunoregulatory Effects and Mitigates xenoGvHD.

Front Immunol

2022 Mar 8

Gérard C, Thébault M, Lamarthée B

13. GPC2 Is a Potential Diagnostic, Immunological, and Prognostic Biomarker in Pan-Cancer.

Front Immunol

2022 Mar 8

Chen G, Luo D, Zhong N

BACKGROUND: Glypican 2 (GPC2), a member of glypican (GPC) family genes, produces proteoglycan with a glycosylphosphatidylinositol anchor. It has shown its ascending significance in multiple cancers such as neuroblastoma, malignant brain tumor, and small-cell lung cancer. However, no systematic pan-cancer analysis has been conducted to explore its function in diagnosis, prognosis, and immunological prediction. METHODS: By comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression Project (GTEx), cBioPortal, Human Protein Atlas (HPA), UALCAN, StarBase, and Comparative Toxicogenomics Database (CTD), we adopted bioinformatics methods to excavate the potential carcinogenesis of GPC2, including dissecting the correlation between GPC2 and prognosis, gene mutation, immune cell infiltration, and DNA methylation of different tumors, and constructed the competing endogenous RNA (ceRNA) networks of GPC2 as well as explored the interaction of GPC2 with chemicals and genes. RESULTS: The results indicated that GPC2 was highly expressed in most cancers, except in pancreatic adenocarcinoma, which presented at a quite low level. Furthermore, GPC2 showed the early diagnostic value in 16 kinds of tumors and was positively or negatively associated with the prognosis of different tumors. It also verified that GPC2 was a gene associated with most immune-infiltrating cells in pan-cancer, especially in thymoma. Moreover, the correlation with GPC2 expression varied depending on the type of immune-related genes. Additionally, GPC2 gene expression has a correlation with DNA methylation in 20 types of cancers. CONCLUSION: Through pan-cancer analysis, we discovered and verified that GPC2 might be useful in cancer detection for the first time. The expression level of GPC2 in a variety of tumors is significantly different from that of normal tissues. In addition, the performance of GPC2 in tumorigenesis and tumor immunity also confirms our conjecture. At the same time, it has high specificity and sensitivity in the detection of cancers. Therefore, GPC2 can be used as an auxiliary indicator for early tumor diagnosis and a prognostic marker for many types of tumors.

14. Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis.

Front Immunol

2022 Mar 8

Nuñez-Borque E, Fernandez-Bravo S, Yuste-Montalvo A

Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of mediators that give rise to the signs and symptoms of this pathological event. For years, most of the research in anaphylaxis has focused on the contribution of the immune component. However, approaches that shed light on the participation of other cellular and molecular agents are necessary. Among them, the vascular niche receives the various signals (e.g., histamine) that elicit the range of anaphylactic events. Cardiovascular manifestations such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and cardiac alterations are crucial in the pathophysiology of anaphylaxis and are highly involved to the development of the most severe cases. Specifically, the endothelium, vascular smooth muscle cells, and their molecular signaling outcomes play an essential role downstream of the immune reaction. Therefore, in this review, we synthesized the vascular changes observed during anaphylaxis as well as its cellular and molecular components. As the risk of anaphylaxis exists both in clinical procedures and in routine life, increasing our knowledge of the vascular physiology and their molecular mechanism will enable us to improve the clinical management and how to treat or prevent anaphylaxis. KEY MESSAGE: Anaphylaxis, the most severe allergic reaction, involves a variety of immune and non-immune molecular signals that give rise to its pathophysiological manifestations. Importantly, the vascular system is engaged in processes relevant to anaphylactic events such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and decreased cardiac output. The novelty of this review focuses on the fact that new studies will greatly improve the understanding of anaphylaxis when viewed from a vascular molecular angle and specifically from the endothelium. This knowledge will improve therapeutic options to treat or prevent anaphylaxis.

15. Identification of CD101 in Glioma: A Novel Prognostic Indicator Expressed on M2 Macrophages.

Front Immunol

2022 Mar 8

Liu Y, Yao R, Shi Y

16. How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment.

Front Immunol

2022 Mar 8

Nilsson B, Persson B, Eriksson O

Most SARS-CoV-2 infected patients experience influenza-like symptoms of low or moderate severity. But, already in 2020 early during the pandemic it became obvious that many patients had a high incidence of thrombotic complications, which prompted treatment with high doses of low-molecular-weight heparin (LMWH; typically 150-300IU/kg) to prevent thrombosis. In some patients, the disease aggravated after approximately 10 days and turned into a full-blown acute respiratory distress syndrome (ARDS)-like pulmonary inflammation with endothelialitis, thrombosis and vascular angiogenesis, which often lead to intensive care treatment with ventilator support. This stage of the disease is characterized by dysregulation of cytokines and chemokines, in particular with high IL-6 levels, and also by reduced oxygen saturation, high risk of thrombosis, and signs of severe pulmonary damage with ground glass opacities. The direct link between SARS-CoV-2 and the COVID-19-associated lung injury is not clear. Indirect evidence speaks in favor of a thromboinflammatory reaction, which may be initiated by the virus itself and by infected damaged and/or apoptotic cells. We and others have demonstrated that life-threatening COVID-19 ARDS is associated with a strong activation of the intravascular innate immune system (IIIS). In support of this notion is that activation of the complement and kallikrein/kinin (KK) systems predict survival, the necessity for usage of mechanical ventilation, acute kidney injury and, in the case of MBL, also coagulation system activation with thromboembolism. The general properties of the IIIS can easily be translated into mechanisms of COVID-19 pathophysiology. The prognostic value of complement and KKsystem biomarkers demonstrate that pharmaceuticals, which are licensed or have passed the phase I trial stage are promising candidate drugs for treatment of COVID-19. Examples of such compounds include complement inhibitors AMY-101 and eculizumab (targeting C3 and C5, respectively) as well as kallikrein inhibitors ecallantide and lanadelumab and the bradykinin receptor (BKR) 2 antagonist icatibant. In this conceptual review we discuss the activation, crosstalk and the therapeutic options that are available for regulation of the IIIS.

17. Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution.

Front Immunol

2022 Mar 8

Shao MM, Shi M, Du J

18. C5b-9 Membrane Attack Complex Formation and Extracellular Vesicle Shedding in Barrett's Esophagus and Esophageal Adenocarcinoma.

Front Immunol

2022 Mar 8

Kolka CM, Webster J, Lepletier A

The early complement components have emerged as mediators of pro-oncogenic inflammation, classically inferred to cause terminal complement activation, but there are limited data on the activity of terminal complement in cancer. We previously reported elevated serum and tissue C9, the terminal complement component, in esophageal adenocarcinoma (EAC) compared to the precursor condition Barrett's Esophagus (BE) and healthy controls. Here, we investigate the level and cellular fates of the terminal complement complex C5b-9, also known as the membrane attack complex. Punctate C5b-9 staining and diffuse C9 staining was detected in BE and EAC by multiplex immunohistofluorescence without corresponding increase of C9 mRNA transcript. Increased C9 and C5b-9 staining were observed in the sequence normal squamous epithelium, BE, low- and high-grade dysplasia, EAC. C5b-9 positive esophageal cells were morphologically intact, indicative of sublytic or complement-evasion mechanisms. To investigate this at a cellular level, we exposed non-dysplastic BE (BAR-T and CP-A), high-grade dysplastic BE (CP-B and CP-D) and EAC (FLO-1 and OE-33) cell lines to the same sublytic dose of immunopurified human C9 (3 µg/ml) in the presence of C9-depleted human serum. Cellular C5b-9 was visualized by immunofluorescence confocal microscopy. Shed C5b-9 in the form of extracellular vesicles (EV) was measured in collected conditioned medium using recently described microfluidic immunoassay with capture by a mixture of three tetraspanin antibodies (CD9/CD63/CD81) and detection by surface-enhanced Raman scattering (SERS) after EV labelling with C5b-9 or C9 antibody conjugated SERS nanotags. Following C9 exposure, all examined cell lines formed C5b-9, internalized C5b-9, and shed C5b-9+ and C9+ EVs, albeit at varying levels despite receiving the same C9 dose. In conclusion, these results confirm increased esophageal C5b-9 formation during EAC development and demonstrate capability and heterogeneity in C5b-9 formation and shedding in BE and EAC cell lines following sublytic C9 exposure. Future work may explore the molecular mechanisms and pathogenic implications of the shed C5b-9+ EV.

19. Low-Energy Electron Irradiation of Tick-Borne Encephalitis Virus Provides a Protective Inactivated Vaccine.

Front Immunol

2022 Mar 7

Finkensieper J, Issmail L, Fertey J

20. TIGIT Blockade Exerts Synergistic Effects on Microwave Ablation Against Cancer.

Front Immunol

2022 Mar 7

Chen Y, Huang H, Li Y

BACKGROUND: Combination immunotherapy based on immune checkpoint inhibitors (ICIs) has shown great success in the treatment of many types of cancers and has become the mainstream in the comprehensive treatment of cancers. Ablation in combination with immunotherapy has achieved tremendous efficacy in some preclinical and clinical studies. To date, our team proved that ablation in combination with ICIs was a promising antitumor therapeutic strategy for the liver metastasis of colorectal cancer (CRC). Moreover, we found that the expression of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was up-regulated after microwave ablation (MWA), indicating that TIGIT was involved in immunosuppression, and the combination of MWA and TIGIT blockade represented a potential clinical treatment strategy. METHODS: In the present study, we examined the expression of TIGIT using a preclinical mouse model treated with MWA. Moreover, we evaluated the antitumor functions of MWA alone or in combination with TIGIT blockade by monitoring tumor growth and survival of the mice. Besides, we also detected the numbers of tumor-infiltrating lymphocytes (TILs), and effector molecules of CD8+ T cells using flow cytometry. Finally, we analyzed the single-cell RNA sequencing (scRNA-seq) data from the MWA and MWA plus anti-TIGIT groups. RESULTS: The expression of TIGIT in various immune cells was up-regulated after MWA, and the addition of TIGIT blockade to MWA prolonged survival and delayed tumor growth in the MC38 tumor model. Taken together, our findings showed that TIGIT blockade in combination with MWA significantly promoted the expansion and functions of CD8+ TILs and reshaped myeloid cells in the tumor microenvironment (TME) using flow cytometry and scRNA-seq analysis. CONCLUSIONS: TIGIT blockade in combination with MWA was a novel treatment strategy for the liver metastasis of CRC, and this combination therapy could reprogram the TME toward an antitumor environment.

21. Neutralisation Hierarchy of SARS-CoV-2 Variants of Concern Using Standardised, Quantitative Neutralisation Assays Reveals a Correlation With Disease Severity; Towards Deciphering Protective Antibody Thresholds.

Front Immunol

2022 Mar 7

Cantoni D, Mayora-Neto M, Nadesalingam A

22. Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin.

Front Immunol

2022 Mar 7

Sun Y, Zhou J, Jiang Y.

23. Different Multivariable Risk Factors for Rapid Progressive Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis and Anti-Synthetase Syndrome.

Front Immunol

2022 Mar 7

Zuo Y, Ye L, Chen F

BACKGROUND: Interstitial lung disease (ILD) is frequently observed in anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive dermatomyositis (DM) and anti-synthetase syndrome (ASS), where they often develop a rapidly progressive ILD (RP-ILD) leading to poor prognosis. OBJECTIVE: The aim of this study was to construct multivariable prediction risk factors for rapid progressive ILD (RP-ILD) in anti-MDA5 positive DM (MDA5+DM) and ASS. METHODS: 333 idiopathic inflammatory myopathy (IIM) associated ILD patients were studied retrospectively. Risk factors for RP-ILD in MDA5+DM and ASS patients were identified by univariate and multivariable logistic regression analysis. The mortality was assessed using Kaplan-Meier analysis. RESULTS: RP-ILD was more prevalent in MDA5+DM patients than ASS patients. MDA5+DM patients with RP-ILD had significantly lower survival rates than those in ASS patients. The independent risk factors for RP-ILD in MDA5+DM patients were fever (OR 3.67, 95% CI:1.79-7.52), lymphopenia (OR 2.14, 95% CI:1.01-4.53), especially decreased levels of CD3+T cells (OR 2.56, 95% CI:1.17-5.61), decreased levels of CD3+CD4+ T cells (OR 2.80, 95% CI:1.37-5.73), CD3+CD8+T cells (OR 2.18, 95% CI:1.05-4.50), elevated CD5-CD19+ B cells (OR 3.17, 95% CI:1.41-7.13), elevated ALT (OR 2.36, 95% CI:1.15-4.81), high lactate dehydrogenase (LDH) (OR 3.08, 95% CI:1.52-6.27), hyper-ferritin (OR 4.97, 95% CI:1.97-12.50), elevated CEA (OR 2.28, 95% CI:1.13-4.59), and elevated CA153 (OR 3.31, 95% CI:1.50-7.27). While the independent risk factors for RP-ILD in ASS patients were elevated CEA (OR 5.25, 95% CI: 1.73-15.93), CA125 (OR 2.79, 95% CI: 1.10-7.11) and NSE (OR 4.86, 95% CI: 1.44-16.37). Importantly, serum ferritin>2200ng/ml predicted patient's death within half a year in MDA5+DM patients with RP-ILD, but not in ASS patients. CONCLUSIONS: There were significant different mortality and multivariable risk factors for RP-ILD in MDA5+DM patients and ASS patients. Potential clinical benefits of using these different risk factors deserve assessment of severity and prognosis in IIM patients.

24. B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications.

Front Immunol

2022 Mar 7

Ohm B, Jungraithmayr W.

25. Emerging Roles of Mucosal-Associated Invariant T Cells in Rheumatology.

Front Immunol

2022 Mar 4

Li Y, Du J, Wei W.

26. Role of the CXCL13/CXCR5 Axis in Autoimmune Diseases.

Front Immunol

2022 Mar 4

Pan Z, Zhu T, Liu Y

27. Monomeric C-Reactive Protein: Current Perspectives for Utilization and Inclusion as a Prognostic Indicator and Therapeutic Target.

Front Immunol

2022 Mar 4

Slevin M, Heidari N, Azamfirei L.

28. Effect of LncRNA XIST on Immune Cells of Primary Biliary Cholangitis.

Front Immunol

2022 Mar 4

She C, Yang Y, Zang B

29. Coexistence of Anti-p200 Pemphigoid and Psoriasis: A Systematic Review.

Front Immunol

2022 Mar 4

Xie YH, Wang SH, Li SZ

BACKGROUND: A close association between psoriasis and anti-p200 pemphigoid has been demonstrated by numerous studies. However, the clinical characteristics of patients suffering from these two entities have not yet been well-elucidated. OBJECTIVE: This study aimed to review the case reports and case series, summarizing clinical features and therapeutic strategies in patients suffering from anti-p200 pemphigoid and psoriasis. METHODS: A systematic review was conducted by searching PubMed, EMBASE, and Web of Science databases for studies published in English involving patients with psoriasis and anti-p200 pemphigoid on 6 September 2021. All case reports and case series reporting patients diagnosed with anti-p200 pemphigoid and psoriasis were included in this systematic review. RESULTS: A total of 21 eligible studies comprising 26 anti-p200 pemphigoid patients with preceding psoriasis were included in the qualitative synthesis. The average age at blisters eruption was 62.5 years, and the mean duration between the two entities was 15.6 years. Twenty-four percent of patients developed bullous lesions during UV therapy. Clinical manifestation of bullae and/or vesicles was recorded in all patients, and the trunk (94.7%) was most frequently involved, with only 15.8% reporting mucosal involvement. Epitope spreading was detected by immunoblotting in 33.3% of patients. All the patients reached completed remission during the course of disease, with 36.8% experiencing at least one relapse. Monotherapy of prednisolone was the leading therapeutic approach (n=6, 31.6%) required for disease control, but 5 (83.3%) of them suffered from blister recurrence after tapering or ceasing corticosteroid. CONCLUSION: Most of the clinical aspects of patients with anti-p200 pemphigoid and psoriasis were similar to what was demonstrated in previous articles on anti-p200 pemphigoid. Nevertheless, compared with other anti-p200 pemphigoid cases without psoriasis, a clinical manifestation pattern with more frequent involvement of the trunk and less mucosal involvement was illustrated in those with psoriasis. Generally, monotherapy is sufficient for a complete remission for such patients. However, one or more relapses have been recorded in a considerable portion of patients, especially those prescribed with prednisolone. It reminded us to be more cautious during a tapering of medication.

30. Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support.

Front Immunol

2022 Mar 4

Hatami S, Hefler J, Freed DH.

Extracorporeal circulation (ECC) systems, including cardiopulmonary bypass, and extracorporeal membrane oxygenation have been an irreplaceable part of the cardiothoracic surgeries, and treatment of critically ill patients with respiratory and/or cardiac failure for more than half a century. During the recent decades, the concept of extracorporeal circulation has been extended to isolated machine perfusion of the donor organ including thoracic organs (ex-situ organ perfusion, ESOP) as a method for dynamic, semi-physiologic preservation, and potential improvement of the donor organs. The extracorporeal life support systems (ECLS) have been lifesaving and facilitating complex cardiothoracic surgeries, and the ESOP technology has the potential to increase the number of the transplantable donor organs, and to improve the outcomes of transplantation. However, these artificial circulation systems in general have been associated with activation of the inflammatory and oxidative stress responses in patients and/or in the exposed tissues and organs. The activation of these responses can negatively affect patient outcomes in ECLS, and may as well jeopardize the reliability of the organ viability assessment, and the outcomes of thoracic organ preservation and transplantation in ESOP. Both ECLS and ESOP consist of artificial circuit materials and components, which play a key role in the induction of these responses. However, while ECLS can lead to systemic inflammatory and oxidative stress responses negatively affecting various organs/systems of the body, in ESOP, the absence of the organs that play an important role in oxidant scavenging/antioxidative replenishment of the body, such as liver, may make the perfused organ more susceptible to inflammation and oxidative stress during extracorporeal circulation. In the present manuscript, we will review the activation of the inflammatory and oxidative stress responses during ECLP and ESOP, mechanisms involved, clinical implications, and the interventions for attenuating these responses in ECC.

31. Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation.

Front Immunol

2022 Mar 4

Münz C.

32. Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis.

Front Immunol

2022 Mar 4

Farina L, Minnone G, Alivernini S

We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of proNGF on fibroblast-like synoviocytes (FLS), which play a central role in modulating local immune responses and in activating pro-inflammatory pathways. Using single cell RNA sequencing in synovial tissues from active and treatment-naïve rheumatoid arthritis (RA) patients, we demonstrated that p75NTR and sortilin, which form a high affinity receptor complex for proNGF, are highly expressed in PRG4pos lining and THY1posCOL1A1pos sublining fibroblast clusters in RA synovia but decreased in RA patients in sustained clinical remission. In ex vivo experiments we found that FLS from rheumatoid arthritis patients (RA-FLS) retained in vitro a markedly higher expression of p75NTR and sortilin than FLS from osteoarthritis patients (OA-FLS). Inflammatory stimuli further up-regulated p75NTR expression and induced endogenous production of proNGF in RA-FLS, leading to an autocrine activation of the proNGF/p75NTR pathway that results in an increased release of pro-inflammatory cytokines. Our data on the inhibition of p75NTR receptor, which reduced the release of IL-1β, IL-6 and TNF-α, further confirmed the key role of p75NTR activation in regulating inflammatory cytokine production. In a set of ex vivo experiments, we used RA-FLS and cultured them in the presence of synovial fluids obtained from arthritis patients that, as we demonstrated, are characterized by a high concentration of proNGF. Our data show that the high levels of proNGF present in inflamed synovial fluids induced pro-inflammatory cytokine production by RA-FLS. The blocking of NGF binding to p75NTR using specific inhibitors led instead to the disruption of this pro-inflammatory loop, reducing activation of the p38 and JNK intracellular pathways and decreasing inflammatory cytokine production. Overall, our data demonstrate that an active proNGF/p75NTR axis promotes pro-inflammatory responses in synovial fibroblasts, thereby contributing to chronic synovial inflammation, and point to the possible use of p75NTR inhibitors as a novel therapeutic approach in chronic arthritis.

33. Platelets, Thromboinflammation and Neurovascular Disease.

Front Immunol

2022 Mar 4

Sun Y, Langer HF.

34. Molecular Evolution of Transforming Growth Factor-β (TGF-β) Gene Family and the Functional Characterization of Lamprey TGF-β2.

Front Immunol

2022 Mar 4

Liu S, Guo J, Cheng X

The transforming growth factor-βs (TGF-βs) are multifunctional cytokines capable of regulating a wide range of cellular behaviors and play a key role in maintaining the homeostasis of the immune system. The TGF-β subfamily, which is only present in deuterostomes, expands from a single gene in invertebrates to multiple members in jawed vertebrates. However, the evolutionary processes of the TGF-β subfamily in vertebrates still lack sufficient elucidation. In this study, the TGF-β homologs are identified at the genome-wide level in the reissner lamprey (Lethenteron reissneri), the sea lamprey (Petromyzon marinus), and the Japanese lamprey (Lampetra japonica), which are the extant representatives of jawless vertebrates with a history of more than 350 million years. The molecular evolutionary analyses reveal that the lamprey TGF-β subfamily contains two members representing ancestors of TGF-β2 and 3 in vertebrates, respectively, but TGF-β1 is absent. The transcriptional expression patterns show that the lamprey TGF-β2 may play a central regulatory role in the innate immune response of the lamprey since it exhibits a more rapid and significant upregulation of expression than TGF-β3 during lipopolysaccharide stimuli. The incorporation of BrdU assay reveals that the lamprey TGF-β2 recombinant protein exerts the bipolar regulation on the proliferation of the supraneural myeloid body cells (SMB cells) in the quiescent and LPS-activated state, while plays an inhibitory role in the proliferation of quiescent and activated leukocytes in lampreys. Furthermore, caspase-3/7 activity analysis indicates that the lamprey TGF-β2 protects SMB cells from apoptosis after serum deprivation, in contrast to promoting apoptosis of leukocytes. Our composite results offer valuable clues to the origin and evolution of the TGF-β subfamily and imply that TGF-βs are among the most ancestral immune regulators in vertebrates.

35. Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Front Immunol

2022 Mar 4

Bonilla H, Hampton D, Marques de Menezes EG

36. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy.

Front Immunol

2022 Mar 4

Wu R, Fan X, Wang Y

37. A Spontaneous H2-Aa Point Mutation Impairs MHC II Synthesis and CD4(+) T-Cell Development in Mice.

Front Immunol

2022 Mar 4

Zhao Y, Xiong J, Chen HX

38. Tick Intrastadial Feeding and Its Role on IgE Production in the Murine Model of Alpha-gal Syndrome: The Tick "Transmission" Hypothesis.

Front Immunol

2022 Mar 4

Maldonado-Ruiz LP, Boorgula GD, Kim D

Recent studies have provided strong evidence indicating that lone star tick bites are a cause of AGS (alpha-gal syndrome, also known as red meat allergy RMA) in humans. AGS is characterized by an increase in IgE antibody production against galactose-alpha-1,3-galactose (aGal), which is a common glycan found in mammalian tissue, except in Old World monkeys and humans. The main causative factor of AGS, the lone star tick (Amblyomma americanum), is broadly distributed throughout the east and midwest of the United States and is a vector of a wide range of human and animal pathogens. Our earlier glycomics study of the salivary glands of partially fed male and female ticks revealed relatively high levels of aGal epitopes. In this study, we found that partially fed males of A. americanum on bovine blood, which engage in multiple intrastadial feedings, carry a large amount of aGal in the salivary glands. In our current work, we aimed to test whether ticks mediate the transmission of the aGal sensitizer acquired from nonhuman blood to humans in the intrastadial host switch (referred to as the "transmission" hypothesis). To test this hypothesis, we used an alpha-galactosyltransferase knockout mutant mouse (aGT-KO) model system infested with ticks that were unfed or partially fed on bovine blood. Based on the levels of total IgE and specific IgG and IgE antibodies against aGal after tick feedings, aGT-KO mice significantly responded to tick feeding and injection of aGal (Galα1-3Galβ1-4GlcNAc) conjugated to human serum albumin or mouse serum albumin (aGal-HSA or aGal-MSA) by increasing total IgE and aGal-specific IgE levels compared to those in C57BL/6 control mice. All of the treatments of aGT-KO mice involving the feeding of partially fed and unfed ticks functioned as sensitizers that increased the levels of specific IgE against aGal, with large individual variations. The data in this study do not support the "transmission" component of AGS, although they confirmed that aGT-KO mice can be used as a model for RMA studies.

39. Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials.

Front Immunol

2022 Mar 31

Ziemssen T, Arnold DL, Alvarez E

OBJECTIVE: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). BACKGROUND: Previous post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. DESIGN/METHODS: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. RESULTS: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, -0.32% vs. -0.24%, p=0.044, and teriflunomide, -0.43% vs. -0.29%, p=0.002), thalamic volume (-0.56% vs. -0.31%, p=0.047 and -0.94% vs. -0.49%, p<0.001), and WM volume (-0.30% vs. -0.19%, p=0.083 and -0.38% vs. -0.18%, p=0.003) but not of cGM volume (-0.39% vs. -0.32%, p=0.337 and -0.49% vs. -0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. CONCLUSION: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

40. HSV-2-Specific Human Female Reproductive Tract Tissue Resident Memory T Cells Recognize Diverse HSV Antigens.

Front Immunol

2022 Mar 31

Koelle DM, Dong L, Jing L

41. Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia.

Front Immunol

2022 Mar 31

Dijkstra DJ, Lokki AI, Gierman LM

42. The Impact of Alcohol Use Disorder on Tuberculosis: A Review of the Epidemiology and Potential Immunologic Mechanisms.

Front Immunol

2022 Mar 31

Wigger GW, Bouton TC, Jacobson KR

43. Mutation of the Polyproline Sequence in CD3ε Evidences TCR Signaling Requirements for Differentiation and Function of Pro-Inflammatory Tγδ17 Cells.

Front Immunol

2022 Mar 31

Borroto A, Alarcón B, Navarro MN.

44. Early-Life Antibiotic Exposure Associated With Varicella Occurrence and Breakthrough Infections: Evidence From Nationwide Pre-Vaccination and Post-Vaccination Cohorts.

Front Immunol

2022 Mar 31

Lin TL, Fan YH, Chang YL

BACKGROUND: Antibiotic-driven dysbiosis may impair immune function and reduce vaccine-induced antibody titers. OBJECTIVES: This study aims to investigate the impacts of early-life antibiotic exposure on subsequent varicella and breakthrough infections. METHODS: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, we initially enrolled 187,921 children born from 1997 to 2010. Since 2003, the Taiwan government has implemented a one-dose universal varicella vaccination program for children aged 1 year. We identified 82,716 children born during the period 1997 to 2003 (pre-vaccination era) and 48,254 children born from July 1, 2004, to 2009 (vaccination era). In the pre-vaccination era, 4,246 children exposed to antibiotics for at least 7 days within the first 2 years of life (Unvaccinated A-cohort) were compared with reference children not exposed to antibiotics (Unvaccinated R-cohort), with 1:1 matching for gender, propensity score, and non-antibiotic microbiota-altering medications. Using the same process, 9,531 children in the Vaccinated A-cohort and Vaccinated R-cohort were enrolled from the vaccination era and compared. The primary outcome was varicella. In each era, demographic characteristics were compared, and cumulative incidences of varicella were calculated. Cox proportional hazards model was used to examine associations. RESULTS: In the pre-vaccination era, the 5-year cumulative incidence of varicella in the Unvaccinated A-cohort (23.45%, 95% CI 22.20% to 24.70%) was significantly higher than in the Unvaccinated R-cohort (16.72%, 95% CI 15.62% to 17.82%) (p<.001). In the vaccination era, a significantly higher 5-year cumulative incidence of varicella was observed in the Vaccinated A-cohort (1.63%, 95% 1.32% to 1.93%) than in the Vaccinated R-cohort (1.19%, 95% CI 0.90% to 0.45%) (p=0.006). On multivariate analyses, early-life antibiotic exposure was an independent risk factor for varicella occurrence in the pre-vaccination (adjusted hazard ratio [aHR] 1.92, 95% CI 1.74 to 2.12) and vaccination eras (aHR 1.66, 95% CI 1.24 to 2.23). The use of penicillins, cephalosporins, macrolides, or sulfonamides in infancy was all positively associated with childhood varicella regardless of vaccine administration. CONCLUSIONS: Antibiotic exposure in early life is associated with varicella occurrence and breakthrough infections.

45. Adaptation of Imaging Mass Cytometry to Explore the Single Cell Alloimmune Landscape of Liver Transplant Rejection.

Front Immunol

2022 Mar 31

Ung N, Goldbeck C, Man C

46. Neuromyelitis Optica Spectrum Disorder With Anti-Aquaporin-4 Antibody: Outcome Prediction Models.

Front Immunol

2022 Mar 31

Wang L, Du L, Li Q

BACKGROUND: Recognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort. METHODS: Between January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes. RESULTS: Lower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively. CONCLUSION: This study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

47. The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection.

Front Immunol

2022 Mar 31

Zheng K, Zheng X, Yang W.

48. Enhanced Immune Responses in Mice Induced by the c-di-GMP Adjuvanted Inactivated Vaccine for Pseudorabies Virus.

Front Immunol

2022 Mar 31

Hou L, Yu X, Zhang Y

49. Role of Cytokines in Thymic Regulatory T Cell Generation: Overview and Updates.

Front Immunol

2022 Mar 31

Tang M, Jia F, Nan F

50. Biology and Clinical Relevance of HCMV-Associated Adaptive NK Cells.

Front Immunol

2022 Mar 31

Gao F, Zhou Z, Lin Y

51. Interleukin-22 in Renal Protection and Its Pathological Role in Kidney Diseases.

Front Immunol

2022 Mar 31

Ma Q, Luan J, Bai Y

52. Early Blood Transfusion After Kidney Transplantation Does Not Lead to dnDSA Development: The BloodIm Study.

Front Immunol

2022 Mar 31

Jouve T, Noble J, Naciri-Bennani H

Outcomes after kidney transplantation are largely driven by the development of de novo donor-specific antibodies (dnDSA), which may be triggered by blood transfusion. In this single-center study, we investigated the link between early blood transfusion and dnDSA development in a mainly anti-thymocyte globulin (ATG)-induced kidney-transplant cohort. We retrospectively included all recipients of a kidney transplant performed between 2004 and 2015, provided they had >3 months graft survival. DSA screening was evaluated with a Luminex assay (Immucor). Early blood transfusion (EBT) was defined as the transfusion of at least one red blood-cell unit over the first 3 months post-transplantation, with an exhaustive report of transfusion. Patients received either anti-thymocyte globulins (ATG) or basiliximab induction, plus tacrolimus and mycophenolic acid maintenance immunosuppression. A total of 1088 patients received a transplant between 2004 and 2015 in our center, of which 981 satisfied our inclusion criteria. EBT was required for 292 patients (29.7%). Most patients received ATG induction (86.1%); the others received basiliximab induction (13.4%). dnDSA-free graft survival (dnDSA-GS) at 1-year post-transplantation was similar between EBT+ (2.4%) and EBT- (3.0%) patients (chi-squared p=0.73). There was no significant association between EBT and dnDSA-GS (univariate Cox's regression, HR=0.88, p=0.556). In multivariate Cox's regression, adjusting for potential confounders (showing a univariate association with dnDSA development), early transfusion remained not associated with dnDSA-GS (HR 0.76, p=0.449). However, dnDSA-GS was associated with pretransplantation HLA sensitization (HR=2.25, p=0.004), hemoglobin >10 g/dL (HR=0.39, p=0.029) and the number of HLA mismatches (HR=1.26, p=0.05). Recipient's age, tacrolimus and mycophenolic-acid exposures, and graft rank were not associated with dnDSA-GS. Early blood transfusion did not induce dnDSAs in our cohort of ATG-induced patients, but low hemoglobin level was associated with dnDSAs-GS. This suggests a protective effect of ATG induction therapy on preventing dnDSA development at an initial stage post-transplantation.

53. Transcriptional Regulation of Early T-Lymphocyte Development in Thymus.

Front Immunol

2022 Mar 31

Bao X, Qin Y, Lu L

54. A Comprehensive Analysis of METTL1 to Immunity and Stemness in Pan-Cancer.

Front Immunol

2022 Mar 31

Gao Z, Xu J, Zhang Z

BACKGROUND: Previous studies have reported the effect of N7-methylguanosine (m7G) regulator methyltransferase like-1 protein (METTL1) in tumor initiation, metastasis, and chemosensitivity. However, the relationship between METTL1 and cancer immune infiltration is not validated and the prognostic significance of METTL1 in pan-cancer remains unclear. METHODS: Clinical parameters, including gender, age, lifetime, stage, and treatment response were analyzed to evaluate the prognostic significance of METTL1. To evaluate protein level of METTL1, the METTL1 activity was generated by single sample gene set enrichment analysis. The one-class logistic regression algorithm was used to calculate the stemness indices based on transcriptomics and methylation data of pan-cancer and pluripotent stem cells. The relationship between METTL1 expression or activity and tumor immune infiltration were analyzed to explore the significance of METTL1 in tumor immunotherapy. Meanwhile, the correlation between three immunotherapeutic biomarkers and METTL1 was investigated. Finally, to calculate the association between drug sensitivity and METTL1 expression, spearman correlation analysis was performed. RESULTS: METTL1 was not intimately related to gender, age, tumor stage, or treatment outcome of the various cancers, but it displayed potential prognostic significance for evaluating patient survival. High METTL1 expression was related to tumor progression-relevant pathways. Moreover, METTL1 exhibited a distinct correlation with tumor immune microenvironment infiltration and stemness indices. In the anti-PD-L1 cohort, patients in treatment response group exhibited significantly higher METTL1 expression than those in the no/limited response group. Further analysis showed that tumor cell lines with higher METTL1 expression were more sensitive to drugs targeting chromatin histone methylation, ERK-MAPK and WNT signaling pathways. CONCLUSION: This study provides insight into the correlation of METTL1 with tumor immune infiltration and stemness in pan-cancer, revealing the significance of METTL1 for cancer progression and guiding more effective and generalized therapy strategies.

55. Case Report: Multiple Causes of Cardiac Death After the First Infusion of Atezolizumab: Histopathological and Immunohistochemical Findings.

Front Immunol

2022 Mar 31

Kushnareva E, Stepanova M, Artemeva E

56. Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern.

Front Immunol

2022 Mar 31

Shen XT, Xie SZ, Xu J

BACKGROUND: Neutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed. METHODS: We systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups. RESULTS: A gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs. CONCLUSION: NETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.

Front Immunol

2022 Mar 31

Martínez-Sanz J, Ron R, Moreno E

58. Bibliometric Analysis of Chimeric Antigen Receptor-Based Immunotherapy in Cancers From 2001 to 2021.

Front Immunol

2022 Mar 30

Ou Z, Qiu L, Rong H

59. Corrigendum: Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response.

Front Immunol

2022 Mar 30

Ng HP, Wang Y, Jennings S

60. Increased HBV Coinfection and Decreased IFN-γ-Producing HBV-Specific CD8+ T Cell Numbers During HIV Disease Progression.

Front Immunol

2022 Mar 30

Zhu Z, Qin Y, Liang Q

61. Breast Density and Estradiol Are Major Determinants for Soluble TNF-TNF-R Proteins in vivo in Human Breast Tissue.

Front Immunol

2022 Mar 30

Ekstrand J, Zemmler M, Abrahamsson A

High mammographic density and exposure to sex steroids are independent risk factors for breast cancer by yet unknown mechanisms. Inflammation is one hallmark of cancer and the tumor necrosis factor family of proteins (TNFSFs) and receptors (TNFRSFs) are key determinants of tissue inflammation. The relationship between TNFSFs/TNFRSFs and breast tissue density or local breast estradiol levels is unknown. We investigated whether TNFSFs and soluble TNFRSFs (sTNFRSFs) are dysregulated in vivo in human breast cancer and dense breast tissue of postmenopausal women. We explored TNFSF/TNFRSF correlations with breast density and estradiol, both locally in the breast and in abdominal subcutaneous (s.c.) fat as a measure of systemic effects. Microdialysis was used for local sampling of in vivo proteins and estradiol in a total of 73 women; 12 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 healthy premenopausal women. Breast density was determined as lean tissue fraction (LTF) using magnetic resonance imaging. Microdialysis was also performed in estrogen receptor (ER) positive breast cancer in mice treated with the pure anti-estrogen fulvestrant and tumor tissue was subjected to immunohistochemistry. 23 members of the TNFSF/sTNFRSF families were quantified using proximity extension assay.Our data revealed upregulation of TNFSF10, 13 and 13B, TNFRSF6, 6B, 9, 11A, 11B, 13B, 14, and 19, and TNFR-1 and -2 in ER+ breast cancer in women. In dense breast tissue TNFSF10, 13, and 14, TNFRSF3, 6, 9, 10B, 13B, 14, 19, and TNFR-1 and -2 were upregulated. Certain TNFSFs/TNFRSFs were increased in premenopausal breasts relative to postmenopausal breasts. Furthermore, estradiol correlated with most of the TNFSF/sTNFRSF members, though LTF only correlated with some of the proteins. Several of these associations were breast tissue-specific, as very few correlated with estradiol in abdominal s.c. fat. Estrogen dependent regulations of TNFSF2 (TNF-α) and TNF-R2 were corroborated in ER+ breast cancer in mice. Taken together, our data indicate TNFSFs/sTNFRSFs may represent potential targetable pathways for treatment of breast cancer patients and in prevention of breast cancer development in women with dense breasts.

62. Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates.

Front Immunol

2022 Mar 30

Barchi JJ Jr.

63. Alarmin Cytokines as Central Regulators of Cutaneous Immunity.

Front Immunol

2022 Mar 30

Hasegawa T, Oka T, Demehri S.

64. Emerging Strategies in TCR-Engineered T Cells.

Front Immunol

2022 Mar 30

Wei F, Cheng XX, Xue JZ

65. Programmed Cell Death Tunes Tumor Immunity.

Front Immunol

2022 Mar 30

Liu J, Hong M, Li Y

66. Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis.

Front Immunol

2022 Mar 30

Liang Y, Lin H, Dzakah EE

67. Editorial: Extracellular Vesicles as Immunomodulatory Mediators in Inflammatory Processes.

Front Immunol

2022 Mar 3

Donate PB, Lamarre Y, Pino-Lagos K

68. Editorial: The Clinical Application of Neoantigens.

Front Immunol

2022 Mar 3

Zhou JG, Ding Z, Shi H

69. Editorial: The Spectrum of Treg Subsets in Transplantation: Immune Regulation and Tolerance Induction.

Front Immunol

2022 Mar 3

Mohammadnia-Afrouzi M, Mirzakhani M, Shahbazi M

70. DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology.

Front Immunol

2022 Mar 3

Zhao J, Wei K, Chang C

71. Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid.

Front Immunol

2022 Mar 3

Iwamoto Y, Anno T, Koyama K

72. Anti-Microbiota Vaccine Reduces Avian Malaria Infection Within Mosquito Vectors.

Front Immunol

2022 Mar 3

Aželytė J, Wu-Chuang A, Žiegytė R

73. Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.

Front Immunol

2022 Mar 3

Xia Y, Liu X, Mu W

74. Beyond Immunosuppression: The Multifaceted Functions of Tumor-Promoting Myeloid Cells in Breast Cancers.

Front Immunol

2022 Mar 3

Blaye C, Boyer T, Peyraud F

75. Characterization of Macrophage-Like Cells in Retinal Vein Occlusion Using En Face Optical Coherence Tomography.

Front Immunol

2022 Mar 3

Zeng Y, Zhang X, Mi L

76. Corrigendum: Glucagon-Like Peptide-1 Receptor Regulates Macrophage Migration in Monosodium Urate-Induced Peritoneal Inflammation.

Front Immunol

2022 Mar 3

Chen J, Mei A, Liu X

77. The Prognostic Value of Integrated Analysis of Inflammation and Hypoxia-Related Genes in Idiopathic Pulmonary Fibrosis.

Front Immunol

2022 Mar 3

Liu J, Gu L, Li W.

78. Dysregulation of Survivin-Targeting microRNAs in Autoimmune Diseases: New Perspectives for Novel Therapies.

Front Immunol

2022 Mar 3

Shomali N, Suliman Maashi M, Baradaran B

79. IRF4b and IRF8 Negatively Regulate RLR-Mediated NF-κB Signaling by Targeting MITA for Degradation in Teleost Fish.

Front Immunol

2022 Mar 3

Yan X, Zhao X, Zhou M

80. Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation.

Front Immunol

2022 Mar 3

Iwasaki M, Kanda J, Tanaka H

81. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity.

Front Immunol

2022 Mar 3

Duan T, Du Y, Xing C

82. Association of the Microbiota and Pancreatic Cancer: Opportunities and Limitations.

Front Immunol

2022 Mar 3

Chen Z, Zhang S, Dong S

83. Translational Control of COVID-19 and Its Therapeutic Implication.

Front Immunol

2022 Mar 29

Zhang D, Zhu L, Wang Y

84. B-Cell Epitope Mapping of TprC and TprD Variants of Treponema pallidum Subspecies Informs Vaccine Development for Human Treponematoses.

Front Immunol

2022 Mar 29

Molini B, Fernandez MC, Godornes C

85. Therapeutic Effect of Rapamycin-Loaded Small Extracellular Vesicles Derived from Mesenchymal Stem Cells on Experimental Autoimmune Uveitis.

Front Immunol

2022 Mar 29

Li H, Zhang Z, Li Y

86. Cathelicidin-3 Associated With Serum Extracellular Vesicles Enables Early Diagnosis of a Transmissible Cancer.

Front Immunol

2022 Mar 29

Espejo C, Wilson R, Pye RJ

87. Alterations of Urinary Microbial Metabolites and Immune Indexes Linked With COVID-19 Infection and Prognosis.

Front Immunol

2022 Mar 29

Jing Y, Wang J, Zhang H

88. Effects of Immobilized Antimicrobial Peptides on Growth Performance, Serum Biochemical Index, Inflammatory Factors, Intestinal Morphology, and Microbial Community in Weaning Pigs.

Front Immunol

2022 Mar 29

Liu N, Ma X, Jiang X.

This experiment was conducted to investigate the effects of immobilized antimicrobial peptides on growth performance, serum biochemical index, inflammatory factors, intestinal morphology, and microbial community of weaning piglets. A total of 21 weaning piglets [Duroc × (Landrace × Yorkshire)] with initial body weight (7.64 ± 0.65 kg) were randomly allocated to one of three treatments with seven replicates (one pig per replicate) per treatment according to sex and weight in randomized complete block design. Pigs in the three treatments were fed corn-soybean meal-based diet (CON), corn-soybean meal based diet + flavomycin (25 mg/kg) + quinone (50 mg/kg) (AB), and corn-soybean meal based diet + 1,000 mg/kg immobilized antimicrobial peptides (IAMPs), respectively. The experiment lasted for 28 days, including early stage (0-14 days) and late stage (15-28 days). The results showed the following: (1) compared with the CON group, the average daily gain in the whole experimental time (p < 0.05) was significantly increased, and the diarrhea rate of weaning piglets was decreased (p < 0.01) in the IAMPs group; (2) compared with the CON group, the concentrations of serum IgM and superoxide dismutase (SOD) in the IAMPs group were significantly higher than the CON and AB groups (p < 0.01); (3) compared with CON group, the concentrations of serum interleukin (IL)-10 and transforming growth factor (TGF-β) were significantly increased (p < 0.05), and the concentration of IL-12 was significantly decreased (p < 0.05) in the IAMPs group; (4) compared with CON group, the concentrations of serum endotoxin and D-lactate of piglets were significantly reduced (p < 0.05), and the relative expression of ZO-1 and occludin in the jejunum of piglets were significantly increased (p < 0.05) in the IAMPs group; (5) compared with the CON group, the villus height of the duodenum and jejunum of weaning piglets in IAMPs and AB groups was significantly increased (p < 0.05); and (6) compared with CON group, the relative abundance of Escherichia-Shigella in the colon and cecal digesta was decreased. In summary, the addition of 1,000 mg/kg immobilized antimicrobial peptides in the diet effectively relieved weaning stress by showing improved growth performance, antioxidant and immune capacity, intestinal morphology, and microorganisms.

89. Differential Expression of miRNAs in Trichloroethene-Mediated Inflammatory/Autoimmune Response and Its Modulation by Sulforaphane: Delineating the Role of miRNA-21 and miRNA-690.

Front Immunol

2022 Mar 29

Banerjee N, Wang H, Wang G

Trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Altered non-coding RNAs, including the expression of microRNAs (miRNAs), can influence target genes, especially related to apoptosis and inflammation, and contribute to ADs. Therefore, the objective of this study was to delineate the contribution of miRNAs in TCE-mediated inflammatory and autoimmune response. To achieve this, we treated female MRL+/+ mice with TCE (10 mmol/kg in corn oil, i.p., every fourth day) with/without antioxidant sulforaphane (SFN; 8 mg/kg in corn oil, i.p., every other day) for 6 weeks. With the use of miRNA microarray, 293 miRNAs were analyzed, which included 35 miRNAs that were relevant to inflammation and ADs. Among those 35 miRNAs, 8 were modulated by TCE and/or TCE+SFN exposure. TCE treatment led to increased expression of 3 miRNAs and also decreased expression of 3 miRNAs. Interestingly, among the 35 differentially expressed miRNAs, antioxidant SFN modulated the expression of 6 miRNAs. Based on the microarray findings, we subsequently focused on two miRNAs (miRNA-21 and miRNA-690), which are known to be involved in inflammation and autoimmune response. The increases in miRNA-21 and miR-690 (observed using miRNA microarray) were further validated by RT-PCR, and the TCE-mediated increases in miR-21 and miR-690 were ameliorated by SFN treatment. Modulating miR-21 and miR-690 by respective inhibitors or mimics suppressed the expression of NF-κB (p65) and IL-12 in RAW 264.7 cells. Our findings suggest a contributory role of miR-21 and miR-690 in TCE-mediated and its metabolite dichloroacetyl chloride (DCAC)-mediated inflammation and autoimmune response and support that antioxidant SFN could be a potential therapeutic candidate for inflammatory responses and ADs.

90. Autophagy May Allow a Cell to Forbear Pyroptosis When Confronted With Cytosol-Invasive Bacteria.

Front Immunol

2022 Mar 29

Harvest CK, Miao EA.

91. Adult Memory T Cell Responses to the Respiratory Syncytial Virus Fusion Protein During a Single RSV Season (2018-2019).

Front Immunol

2022 Mar 29

Blunck BN, Angelo LS, Henke D

Respiratory Syncytial Virus (RSV) is ubiquitous and re-infection with both subtypes (RSV/A and RSV/B) is common. The fusion (F) protein of RSV is antigenically conserved, induces neutralizing antibodies, and is a primary target of vaccine development. Insight into the breadth and durability of RSV-specific adaptive immune response, particularly to the F protein, may shed light on susceptibility to re-infection. We prospectively enrolled healthy adult subjects (n = 19) and collected serum and peripheral blood mononuclear cells (PBMCs) during the 2018-2019 RSV season. Previously, we described their RSV-specific antibody responses and identified three distinct antibody kinetic profiles associated with infection status: uninfected (n = 12), acutely infected (n = 4), and recently infected (n = 3). In this study, we measured the longevity of RSV-specific memory T cell responses to the F protein following natural RSV infection. We stimulated PBMCs with overlapping 15-mer peptide libraries spanning the F protein derived from either RSV/A or RSV/B and found that memory T cell responses mimic the antibody responses for all three groups. The uninfected group had stable, robust memory T cell responses and polyfunctionality. The acutely infected group had reduced polyfunctionality of memory T cell response at enrollment compared to the uninfected group, but these returned to comparable levels by end-of-season. The recently infected group, who were unable to maintain high levels of RSV-specific antibody following infection, similarly had decreased memory T cell responses and polyfunctionality during the RSV season. We observed subtype-specific differences in memory T cell responses and polyfunctionality, with RSV/A stimulating stronger memory T cell responses with higher polyfunctionality even though RSV/B was the dominant subtype in circulation. A subset of individuals demonstrated an overall deficiency in the generation of a durable RSV-specific adaptive immune response. Because memory T cell polyfunctionality may be associated with protection against re-infection, this latter group would likely be at greater risk of re-infection. Overall, these results expand our understanding of the longevity of the adaptive immune response to the RSV fusion protein and should be considered in future vaccine development efforts.

92. Distinct Expression Patterns of Interleukin-22 Receptor 1 on Blood Hematopoietic Cells in SARS-CoV-2 Infection.

Front Immunol

2022 Mar 29

Albayrak N, Orte Cano C, Karimi S

The new pandemic virus SARS-CoV-2 is characterized by uncontrolled hyper-inflammation in severe cases. As the IL-22/IL-22R1 axis was reported to be involved in inflammation during viral infections, we characterized the expression of IL-22 receptor1, IL-22 and IL-22 binding protein in COVID-19 patients. Blood samples were collected from 19 non-severe and 14 severe patients on the day they presented (D0), at D14, and six months later, and from 6 non-infected controls. The IL-22R1 expression was characterized by flow cytometry. Results were related to HLA-DR expression of myeloid cells, to plasma concentrations of different cytokines and chemokines and NK cells and T lymphocytes functions characterized by their IFN-γ, IL-22, IL-17A, granzyme B and perforin content. The numbers of IL-22R1+ classical, intermediate, and non-classical monocytes and the proportions of IL-22R1+ plasmacytoid DC (pDC), myeloid DC1 and DC2 (mDC1, mDC2) were higher in patients than controls at D0. The proportions of IL-22R1+ classical and intermediate monocytes, and pDC and mDC2 remained high for six months. High proportions of IL-22R1+ non-classical monocytes and mDC2 displayed HLA-DRhigh expression and were thus activated. Multivariate analysis for all IL-22R1+ myeloid cells discriminated the severity of the disease (AUC=0.9023). However, correlation analysis between IL-22R1+ cell subsets and plasma chemokine concentrations suggested pro-inflammatory effects of some subsets and protective effects of others. The numbers of IL-22R1+ classical monocytes and pDC were positively correlated with pro-inflammatory chemokines MCP-1 and IP-10 in severe infections, whereas IL-22R1+ intermediate monocytes were negatively correlated with IL-6, IFN-α and CRP in non-severe infections. Moreover, in the absence of in vitro stimulation, NK and CD4+ T cells produced IFN-γ and IL-22, and CD4+ and CD8+ T cells produced IL-17A. CD4+ T lymphocytes also expressed IL-22R1, the density of its expression defining two different functional subsets. In conclusion, we provide the first evidence that SARS-CoV-2 infection is characterized by an abnormal expression of IL22R1 on blood myeloid cells and CD4+ T lymphocytes. Our results suggest that the involvement of the IL-22R1/IL-22 axis could be protective at the beginning of SARS-CoV-2 infection but could shift to a detrimental response over time.

93. A Neurometabolic Pattern of Elevated Myo-Inositol in Children Who Are HIV-Exposed and Uninfected: A South African Birth Cohort Study.

Front Immunol

2022 Mar 28

Bertran-Cobo C, Wedderburn CJ, Robertson FC

INTRODUCTION: Exposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age. METHODS: The South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined. RESULTS: Factor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11-2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 -2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively). DISCUSSION: Increased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful.

94. Schisandrin B Induced ROS-Mediated Autophagy and Th1/Th2 Imbalance via Selenoproteins in Hepa1-6 Cells.

Front Immunol

2022 Mar 28

Tan S, Zheng Z, Liu T

Schisandrin B (Sch B) is well-known for its antitumor effect; however, its underlying mechanism remains confusing. Our study aimed to investigate the role of selenoproteins in Sch B-induced autophagy and Th1/Th2 imbalance in Hepa1-6 cells. Hepa1-6 cells were chosen to explore the antitumor mechanism and were treated with 0, 25, 50, and 100 μM of Sch B for 24 h, respectively. We detected the inhibition rate of proliferation, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, reactive oxygen species (ROS) level and oxidative stress-related indicators, autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein mRNA expression. Moreover, the heat map, principal component analysis (PCA), and correlation analysis were used for further bioinformatics analysis. The results revealed that Sch B exhibited well-inhibited effects on Hepa1-6 cells. Subsequently, under Sch B treatment, typical autophagy characteristics were increasingly apparent, and the level of punctate MDC staining enhanced and regulated the autophagy-related genes. Overall, Sch B induced autophagy in Hepa1-6 cells. In addition, Sch B-promoted ROS accumulation eventually triggered autophagy initiation. Results of Th1 and Th2 cytokine mRNA expression indicated that Th1/Th2 immune imbalance was observed by Sch B treatment in Hepa1-6 cells. Intriguingly, Sch B downregulated the majority of selenoprotein expression. Also, the heat map results observed significant variation of autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein expression in response to Sch B treatment. PCA outcome suggested the key role of Txnrd1, Txnrd3, Selp, GPX2, Dio3, and Selr with its potential interactions in ROS-mediated autophagy and Th1/Th2 imbalance of Hepa1-6 cells. In conclusion, Sch B induced ROS-mediated autophagy and Th1/Th2 imbalance in Hepa1-6 cells. More importantly, the majority of selenoproteins were intimately involved in the process of autophagy and Th1/Th2 imbalance, Txnrd3, Selp, GPX2, Dio3, and Selr had considerable impacts on the process.

95. Corrigendum: Endothelin-A Receptor Antagonist Alleviates Allergic Airway Inflammation via the Inhibition of ILC2 Function.

Front Immunol

2022 Mar 28

Zhang X, Chen Z, Zuo S

96. Leishmania Major Centrin Gene-Deleted Parasites Generate Skin Resident Memory T-Cell Immune Response Analogous to Leishmanization.

Front Immunol

2022 Mar 28

Ismail N, Karmakar S, Bhattacharya P

97. Gill and Liver Transcript Expression Changes Associated With Gill Damage in Atlantic Salmon (Salmo salar).

Front Immunol

2022 Mar 28

Emam M, Caballero-Solares A, Xue X

Gill damage represents a significant challenge in the teleost fish aquaculture industry globally, due to the gill's involvement in several vital functions and direct contact with the surrounding environment. To examine the local and systemic effects accompanying gill damage (which is likely to negatively affect gill function) of Atlantic salmon, we performed a field sampling to collect gill and liver tissue after several environmental insults (e.g., harmful algal blooms). Before sampling, gills were visually inspected and gill damage was scored; gill scores were assigned from pristine [gill score 0 (GS0)] to severely damaged gills (GS3). Using a 44K salmonid microarray platform, we aimed to compare the transcriptomes of pristine and moderately damaged (i.e., GS2) gill tissue. Rank Products analysis (5% percentage of false-positives) identified 254 and 34 upregulated and downregulated probes, respectively, in GS2 compared with GS0. Differentially expressed probes represented genes associated with functions including gill remodeling, wound healing, and stress and immune responses. We performed gill and liver qPCR for all four gill damage scores using microarray-identified and other damage-associated biomarker genes. Transcripts related to wound healing (e.g., neb and klhl41b) were significantly upregulated in GS2 compared with GS0 in the gills. Also, transcripts associated with immune and stress-relevant pathways were dysregulated (e.g., downregulation of snaclec 1-like and upregulation of igkv3) in GS2 compared with GS0 gills. The livers of salmon with moderate gill damage (i.e., GS2) showed significant upregulation of transcripts related to wound healing (i.e., chtop), apoptosis (e.g., bnip3l), blood coagulation (e.g., f2 and serpind1b), transcription regulation (i.e., pparg), and stress-responses (e.g., cyp3a27) compared with livers of GS0 fish. We performed principal component analysis (PCA) using transcript levels for gill and liver separately. The gill PCA showed that PC1 significantly separated GS2 from all other gill scores. The genes contributing most to this separation were pgam2, des, neb, tnnt2, and myom1. The liver PCA showed that PC1 significantly separated GS2 from GS0; levels of hsp70, cyp3a27, pparg, chtop, and serpind1b were the highest contributors to this separation. Also, hepatic acute phase biomarkers (e.g., serpind1b and f2) were positively correlated to each other and to gill damage. Gill damage-responsive biomarker genes and associated qPCR assays arising from this study will be valuable in future research aimed at developing therapeutic diets to improve farmed salmon welfare.

98. Diagnosis and Treatment of a Patient With Severe Combined Immunodeficiency Due to a Novel Homozygous Mutation in the IL-7Rα Chain.

Front Immunol

2022 Mar 28

Mansour R, Bsat YE, Fadel A

99. The Influence of Microenvironment on Survival of Intraportal Transplanted Islets.

Front Immunol

2022 Mar 28

Yan LL, Ye LP, Chen YH

100. Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients.

Front Immunol

2022 Mar 28

Lee SK, Park MJ, Choi JW

101. Antigen Presentation Machinery Signature-Derived CALR Mediates Migration, Polarization of Macrophages in Glioma and Predicts Immunotherapy Response.

Front Immunol

2022 Mar 28

Chen R, Zhang H, Wu W

102. Biomarkers to Predict DMARDs Efficacy and Adverse Effect in Rheumatoid Arthritis.

Front Immunol

2022 Mar 28

Wei K, Jiang P, Zhao J

103. Addressing IGHV Gene Structural Diversity Enhances Immunoglobulin Repertoire Analysis: Lessons From Rhesus Macaque.

Front Immunol

2022 Mar 28

Kaduk M, Corcoran M, Karlsson Hedestam GB.

104. Variation of Immune Cell Responses in Humans Reveals Sex-Specific Coordinated Signaling Across Cell Types.

Front Immunol

2022 Mar 28

Fragiadakis GK, Bjornson-Hooper ZB, Madhireddy D

105. Sex, Age, and Ethnic Background Shape Adaptive Immune Responses Induced by the SARS-CoV-2 mRNA Vaccine.

Front Immunol

2022 Mar 28

Bai J, Chiba A, Murayama G

106. Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders.

Front Immunol

2022 Mar 28

Tastan B, Arioz BI, Genc S.

107. Comprehensive Analysis of Nasal Polyps Reveals a More Pronounced Type 2 Transcriptomic Profile of Epithelial Cells and Mast Cells in Aspirin-Exacerbated Respiratory Disease.

Front Immunol

2022 Mar 28

Bangert C, Villazala-Merino S, Fahrenberger M

108. Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury.

Front Immunol

2022 Mar 28

Huang M, Cai H, Han B

109. Editorial: Immunity to Cytomegalovirus Infections: Challenges and Therapeutic Opportunities.

Front Immunol

2022 Mar 28

Alonso-Arias R, Arens R, Moro-García MA.

110. The Role of the Gut Microbiota in the Development of Ischemic Stroke.

Front Immunol

2022 Mar 28

Wang J, Zhang H, He J

111. Bone Morphogenetic Proteins Shape T(reg) Cells.

Front Immunol

2022 Mar 28

Kraj P.

112. The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies.

Front Immunol

2022 Mar 28

Brom VC, Burger C, Wirtz DC

113. Local Innate Markers and Vaginal Microbiota Composition Are Influenced by Hormonal Cycle Phases.

Front Immunol

2022 Mar 25

Adapen C, Réot L, Nunez N

BACKGROUND: The female reproductive tract (FRT) mucosa is the first line of defense against sexually transmitted infection (STI). FRT environmental factors, including immune-cell composition and the vaginal microbiota, interact with each other to modulate susceptibility to STIs. Moreover, the menstrual cycle induces important modifications within the FRT mucosa. Cynomolgus macaques are used as a model for the pathogenesis and prophylaxis of STIs. In addition, their menstrual cycle and FRT morphology are similar to women. The cynomolgus macaque vaginal microbiota is highly diverse and similar to dysbiotic vaginal microbiota observed in women. However, the impact of the menstrual cycle on immune markers and the vaginal microbiota in female cynomolgus macaques is unknown. We conducted a longitudinal study covering three menstrual cycles in cynomolgus macaques. The evolution of the composition of the vaginal microbiota and inflammation (cytokine/chemokine profile and neutrophil phenotype) in the FRT and blood was determined throughout the menstrual cycle. RESULTS: Cervicovaginal cytokine/chemokine concentrations were affected by the menstrual cycle, with a peak of production during menstruation. We observed three main cervicovaginal neutrophil subpopulations: CD11bhigh CD101+ CD10+ CD32a+, CD11bhigh CD101+ CD10- CD32a+, and CD11blow CD101low CD10- CD32a-, of which the proportion varied during the menstrual cycle. During menstruation, there was an increase in the CD11bhigh CD101+ CD10+ CD32a+ subset of neutrophils, which expressed higher levels of CD62L. Various bacterial taxa in the vaginal microbiota showed differential abundance depending on the phase of the menstrual cycle. Compilation of the factors that vary according to hormonal phase showed the clustering of samples collected during menstruation, characterized by a high concentration of cytokines and an elevated abundance of the CD11bhigh CD101+ CD10+ CD32a+ CD62L+ neutrophil subpopulation. CONCLUSIONS: We show a significant impact of menstruation on the local environment (cytokine production, neutrophil phenotype, and vaginal microbiota composition) in female cynomolgus macaques. Menstruation triggers increased production of cytokines, shift of the vaginal microbiota composition and the recruitment of mature/activated neutrophils from the blood to the FRT. These results support the need to monitor the menstrual cycle and a longitudinal sampling schedule for further studies in female animals and/or women focusing on the mucosal FRT environment.

114. Protein Disulfide-Isomerase A3 Is a Robust Prognostic Biomarker for Cancers and Predicts the Immunotherapy Response Effectively.

Front Immunol

2022 Mar 25

Tu Z, Ouyang Q, Long X

BACKGROUND: Protein disulfide isomerase A3 (PDIA3) is a member of the protein disulfide isomerase (PDI) family that participates in protein folding through its protein disulfide isomerase function. It has been reported to regulate the progression of several cancers, but its function in cancer immunotherapy is unknown. METHODS: The RNA-seq data of cancer and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. The Cbioportal dataset was used to explore the genomic alteration information of PDIA3 in pan-cancer. Human Protein Atlas (HPA) and ComPPI websites were employed to mine the protein information of PDIA3, and western blot assay was performed to monitor the upregulated PDIA3 expression in clinical GBM samples. The univariate Cox regression and the Kaplan-Meier method were utilized to appraise the prognostic role of PDIA3 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was applied to search the associated cancer hallmarks with PDIA3 expression. TIMER2.0 was the main platform to investigate the immune cell infiltrations related to PDIA3 in pan-cancer. The associations between PDIA3 and immunotherapy biomarkers were performed by Spearman correlation analysis. The immunoblot was used to quantify the PDIA3 expression levels, and the proliferative and invasive ability of glioma cells was determined by colony formation and transwell assays. FINDINGS: PDIA3 is overexpressed in most cancer types and exhibits prognosis predictive ability in various cancers, and it is especially expressed in the malignant cells and monocytes/macrophages. In addition, PDIA3 is significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations, and immunoregulators, and the most interesting finding is that PDIA3 could significantly predict anti-PDL1 therapy response. Besides, specific inhibitors that correlated with PDIA3 expression in different cancer types were also screened by using Connectivity Map (CMap). Finally, knockdown of PDIA3 significantly weakened the proliferative and invasive ability of glioma cells. INTERPRETATION: The results revealed that PDIA3 acts as a robust tumor biomarker. Its function in protein disulfide linkage regulation could influence protein synthesis, degradation, and secretion, and then shapes the tumor microenvironment, which might be further applied to develop novel anticancer inhibitors.

115. New Insight on the Immune Modulation and Physical Barrier Protection Caused by Vitamin A in Fish Gills Infected With Flavobacterium columnare.

Front Immunol

2022 Mar 25

Jiang WD, Zhang L, Feng L

In this study, we have investigated the influence of vitamin A on gill barrier function of grass carp (Ctenopharyngodon idella) infected with Flavobacterium columnare. The fish were fed different concentrations of vitamin A diets for 10 weeks and then infected with F. columnare by immersion. We observed that optimal vitamin A significantly prevented gill rot morbidity in fish infected with F. columnare. Further investigations revealed that vitamin A boosted the gill immunity by increasing the contents of complements (C3 and C4), activities of acid phosphatase (ACP) and lysozyme, mRNAs of β-defensin-1, liver-expressed antimicrobial peptide 2A and 2B (LEAP-2A and LEAP-2B), hepcidin, and anti-inflammatory cytokines like transforming growth factor β1 (TGF-β1), TGF-β2, interleukin-10 (IL-10), and IL-11. It also enhanced the levels of various related signaling molecules including inhibitor protein κBα (IκBα), target of rapamycin (TOR), and ribosome protein S6 kinase 1 (S6K1) but downregulated the expression of pro-inflammatory cytokines including IL-1β, IL-8, tumor necrosis factor α (TNF-α), and interferon γ2 (IFN-γ2) and related signaling molecules including nuclear factor κB p65 (NF-κB p65) (rather than NF-κB p52), IκB kinase β (IKKβ), IKKγ (rather than IKKα), eIF4E-binding protein 1 (4E-BP1), and 4E-BP2 mRNA levels in fish gills. In addition, dietary vitamin A markedly lowered the concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl (PC), increased both the activities and mRNAs of copper/zinc superoxide dismutase (Cu/ZnSOD), MnSOD, glutathione transferases (GSTs), glutathione peroxidase (GPx), and glutathione reductase (GR) associated with upregulation of NF-E2-related factor 2 (Nrf2) mRNAs and downregulation of Kelch-like-ECH-associated protein (Keap1a) and Keap1b mRNAs. Moreover, vitamin A decreased the mRNAs of different apoptotic mediators [caspases 8, 9, 3 (rather than 7)] associated with downregulation of signaling molecule p38 mitogen-activated protein kinase (p38MAPK) mRNAs in fish gills. Besides, vitamin A promoted tight junction (TJ) complex mRNAs [including claudin-b, -c, -3, -7, -12, occludin, and zonula occludens-1 (ZO-1)] that have been linked to the downregulation of myosin light chain kinase (MLCK) signaling. Taken together, the current study demonstrated for the first time that vitamin A markedly enhanced gill health associated with immune modulation and physical barrier protection. Based on protecting fish against gill rot morbidity, ACP activity, and against lipid peroxidation, optimum vitamin A concentrations in on-growing grass carp (262-997 g) were found to be 1,991, 2,188, and 2,934 IU/kg diet, respectively.

116. Relationship Between Programmed Death Ligand 1 Expression and Other Clinicopathological Features in a Large Cohort of Gastric Cancer Patients.

Front Immunol

2022 Mar 25

Chen X, Zhang H, Wang M

BACKGROUND: Antibodies against programmed death 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) have recently shown promising results in gastric cancer (GC). However, clinicians still lack predictive biomarkers for the efficacy of anti-PD-1 therapy; thus, we investigated the expression of PD-L1 in GC and further assessed its clinical relevance with other clinicopathological features. METHODS: We retrospectively collected clinical data on 968 consecutive GC cases from Nanfang Hospital between November 2018 and August 2021. Discrepancy in the combined positive score (CPS) of PD-L1 protein expression between gastric mucosa biopsy and postoperative pathology were investigated. Correlations between CPS and clinicopathological parameters were determined using chi-squared test, multiple logistic aggression analysis, and linear regression analysis. RESULTS: Among the 968 consecutive GC patients, 199 who did not receive preoperative chemotherapy or immunotherapy were tested for CPS both in gastric mucosa biopsy and postoperative pathology, and the results showed that the CPS of gastric mucosa biopsy was significantly lower than that of postoperative pathology [mean ± SD: 5.5 ± 9.4 vs. 13.3 ± 17.4; M(IQR): 2(5) vs. 5(12), p<0.001)]. 62.3% of patients (579/930) had CPS≥ 1, 49.2% of patients (458/930) had CPS≥5, and 33.3% of patients (310/930) had CPS≥10. Mismatch repair deficiency (dMMR) status was seen in 6.1% of patients (56 of 919). Positive Epstein-Barr virus (EBV) status was detected in 4.4% of patients (38 of 854). The patients with CPS≥1/CPS≥5/CPS≥10 were significantly independently correlated with age, Lauren classification, Ki-67 index, and EBV status. According to linear regression analysis, PD-L1 expression was correlated with age (p<0.001), Ki-67 index (p<0.001), EBV (p<0.001), and Lauren classification (p=0.002). CONCLUSIONS: Our results confirmed that PD-L1 expression has Intratumoral heterogeneity in GC. Furthermore, the variables of age, Ki-67 index, and Lauren classification, which are common and accessible in most hospitals, are worth exploring as potential biomarkers for anti-PD-1 therapy in GC.

117. Immunological Memory and Affinity Maturation After Vaccination in Patients With Propionic Acidemia.

Front Immunol

2022 Mar 25

Zlamy M, Zöggeler T, Bachmann M

118. Swine Interferon-Inducible Transmembrane Proteins Potently Inhibit African Swine Fever Virus Replication.

Front Immunol

2022 Mar 25

Cai S, Zheng Z, Cheng J

119. Anti-GAD65 Antibody-Associated Autoimmune Encephalitis With Predominant Cerebellar Involvement Following Toripalimab Treatment: A Case Report of a Novel irAE of Toripalimab.

Front Immunol

2022 Mar 25

Zhou H, Xie X, Zhang T

120. Placental Inflammasome mRNA Levels Differ by Mode of Delivery and Fetal Sex.

Front Immunol

2022 Mar 25

Arthurs AL, Smith MD, Hintural MD

Parturition signals the end of immune tolerance in pregnancy. Term labour is usually a sterile inflammatory process triggered by damage associated molecular patterns (DAMPs) as a consequence of functional progesterone withdrawal. Activation of DAMPs recruits leukocytes and inflammatory cytokine responses in the myometrium, decidua, cervix and fetal membranes. Emerging evidence shows components of the inflammasome are detectable in both maternal decidua and placenta. However, the activation of the placental inflammasome with respect to mode of delivery has not been profiled. Placental chorionic villus samples from women delivering at term via unassisted vaginal (UV) birth, labouring lower segment caesarean section (LLSCS, emergency caesarean section) and prelabour lower segment caesarean section (PLSCS, elective caesarean section) underwent high throughput RNA sequencing (NextSeq Illumina) and bioinformatic analyses to identify differentially expressed inflammatory (DE) genes. DE genes (IL1RL1, STAT1, STAT2, IL2RB, IL17RE, IL18BP, TNFAIP2, TNFSF10 and TNFRSF8), as well as common inflammasome genes (IL1B, IL1R1, IL1R2, IL6, IL18, IL18R1, IL18R1, IL10, and IL33), were targets for further qPCR analyses and Western blotting to quantify protein expression. There was no specific sensor molecule-activated inflammasome which dominated expression when stratified by mode of delivery, implying that multiple inflammasomes may function synergistically during parturition. Whilst placentae from women who had UV births overall expressed pro-inflammatory mediators, placentae from LLSCS births demonstrated a much greater pro-inflammatory response, with additional interplay of pro- and anti-inflammatory mediators. As expected, inflammasome activation was very low in placentae from women who had PLSCS births. Sex-specific differences were also detected. Placentae from male-bearing pregnancies displayed higher inflammasome activation in LLSCS compared with PLSCS, and placentae from female-bearing pregnancies displayed higher inflammasome activation in LLSCS compared with UV. In conclusion, placental inflammasome activation differs with respect to mode of delivery and neonatal sex. Its assessment may identify babies who have been exposed to aberrant inflammation at birth that may compromise their development and long-term health and wellbeing.

121. Leukemia's Next Top Model? Syngeneic Models to Advance Adoptive Cellular Therapy.

Front Immunol

2022 Mar 25

Zoine JT, Moore SE, Velasquez MP.

122. Sirolimus Monotherapy for Thrombocytopenia in Primary Antiphospholipid Syndrome: A Pilot Study From a Tertiary Referral Center.

Front Immunol

2022 Mar 25

Xie W, Ji L, Zhang Z.

BACKGROUND: Thrombocytopenia (TP) is considered as a warning sign of high-risk antiphospholipid syndrome (APS) and sometimes a paradoxical sign of anti-thrombosis treatment. Currently, there is an extreme paucity of effective and safe drugs for long-term management of TP in primary APS patients; therefore, we explored the efficacy and safety of sirolimus monotherapy. METHODS: In this real-world study, we included 7 consecutive patients with primary APS who received sirolimus monotherapy for TP. Oral sirolimus was initiated at a dose of 1-2 mg once daily and then adjusted primarily based on clinical efficacy and tolerance, with consideration of the sirolimus trough concentration of ≤15 ng/ml. RESULTS: Of included patients, the median age was 58 years with a median disease course of 1.5 years and 4 patients were treatment-naïve. All patients completed 6 months of sirolimus therapy with a median follow-up of 6 months (range: 6-15). All patients received sirolimus monotherapy for TP during the entire follow-up, without any additional agents. Overall, the platelet count exhibited a substantially increasing trend after sirolimus administration during the first 6 months (p < 0.001) and stability later. Specifically, the median platelet count was significantly increased from 59 × 109/l before sirolimus to 90 × 109/l at month 1 (p = 0.028), 131 × 109/l at 3 months (p = 0.028), and 178 × 109/l at 6 months (p = 0.018). Overall and complete responses were respectively achieved in 6 (85.7%) and 5 (71.4%) patients at month 6. Importantly, overall response was achieved in all 4 treatment-naïve patients. Additionally, there were different extents of decline in the titers of antiphospholipid antibodies after sirolimus treatment. Regarding safety, only one patient experienced an elevated cholesterol level with recovery after atorvastatin treatment. CONCLUSION: Sirolimus monotherapy confers good efficacy and tolerance for TP in primary APS patients and therefore may be considered as a first-line therapy.

123. MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis.

Front Immunol

2022 Mar 24

Chang C, Xu L, Zhang R

124. Exploring Macrophage-Dependent Wound Regeneration During Mycobacterial Infection in Zebrafish.

Front Immunol

2022 Mar 24

Bohaud C, Johansen MD, Varga B

125. Single-Cell Profiling Reveals Heterogeneity of Primary and Lymph Node Metastatic Tumors and Immune Cell Populations and Discovers Important Prognostic Significance of CCDC43 in Oral Squamous Cell Carcinoma.

Front Immunol

2022 Mar 24

Wang Z, Zhang H, Zhai Y

126. BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis.

Front Immunol

2022 Mar 24

Hoffner O'Connor M, Berglind A, Kennedy Ng MM

127. An Oral Microencapsulated Vaccine Loaded by Sodium Alginate Effectively Enhances Protection Against GCRV Infection in Grass Carp (Ctenopharyngodon idella).

Front Immunol

2022 Mar 24

Xu C, Qiao M, Huo X

Grass carp reovirus (GCRV) is highly infectious and lethal to grass carp, causing huge economic losses to the aquaculture industry annually. Currently, vaccination is the most effective method against viral infections. Among the various vaccination methods, the oral vaccination is an ideal way in aquaculture. However, low protective efficiency is the major problem for oral vaccination owing to some reasons, such as antigen degradation and low immunogenicity. In our study, we screened the antigenic epitopes of GCRV-II and prepared an oral microencapsulated vaccine using sodium alginate (SA) as a carrier and flagellin B (FlaB) as an adjuvant, and evaluated its protective effects against GCRV-II infection in grass carp. The full length and three potential antigenic epitope regions of GCRV-II VP56 gene were expressed in Escherichia coli and purified by glutathione affinity column respectively. The optimal antigen (VP56-3) was screened by enzyme-linked immunosorbent assay (ELISA). Adjuvant FlaB was also expressed in E. coli and purified by Ni2+ affinity column. Subsequently, we prepared the oral vaccines using sodium alginate as a carrier. The vaccine (SA-VP56-3/FlaB) forms microsphere (1.24 ± 0.22 μm), examined by transmission electron microscopy, scanning electron microscopy, and dynamic light scattering assay. SA-VP56-3/FlaB vaccine has excellent stability, slow-release, and low toxicity by dynamic light scattering assay, release dynamic assay, in vivo fluorescence imaging system, hemolytic activity and cytotoxicity. Then we vaccinated grass carp orally with SA-VP56-3/FlaB and measured immune-related parameters (serum neutralizing antibody titer, serum enzyme activity (TSOD, LZM, C3), immune-related genes ((IgM, IFN1, MHC-II, CD8 in head kidney and spleen), IgZ in hindgut)). The results showed that SA-VP56-3/FlaB significantly induced strong immune responses, compared to other groups. The highest survival rate achieved in SA-VP56-3/FlaB microencapsulated vaccine (56%) in 2 weeks post GCRV challenge, while 10% for the control group. Meanwhile, the tissue virus load in survival grass carp is lowest in SA-VP56-3/FlaB group. These results indicated that SA-VP56-3/FlaB could be a candidate oral vaccine against GCRV-II infection in aquaculture.

128. TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model.

Front Immunol

2022 Mar 24

Lima C, Maleski ALA, Bernardo JTG

TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.

129. Antibiotic Exposure Aggravates Bacteroides-Linked Uremic Toxicity in the Gut-Kidney Axis.

Front Immunol

2022 Mar 24

Ray N, Jeong H, Kwon D

130. Mechanistic Insights Into the Immune Pathophysiology of COVID-19; An In-Depth Review.

Front Immunol

2022 Mar 24

Shafqat A, Shafqat S, Salameh SA

131. MiRAGDB: A Knowledgebase of RAG Regulators.

Front Immunol

2022 Mar 24

Desai SS, Whadgar S, Raghavan SC

132. Case Report: Concurrence of Dermatomyositis and Autoimmune Blistering Diseases: Two Case Reports and a Literature Review.

Front Immunol

2022 Mar 24

Wu H, Diao L, Xue K

133. Improving Access to HLA-Matched Kidney Transplants for African American Patients.

Front Immunol

2022 Mar 24

Bekbolsynov D, Mierzejewska B, Khuder S

INTRODUCTION: Kidney transplants fail more often in Black than in non-Black (White, non-Black Hispanic, and Asian) recipients. We used the estimated physicochemical immunogenicity for polymorphic amino acids of donor/recipient HLAs to select weakly immunogenic kidney transplants for Black vs. White or non-Black patients. METHODS: OPTN data for 65,040 donor/recipient pairs over a 20-year period were used to calculate the individual physicochemical immunogenicity by hydrophobic, electrostatic and amino acid mismatch scores (HMS, EMS, AMS) and graft-survival outcomes for Black vs. White or vs. non-Black recipients, using Kaplan-Meier survival and Cox regression analyses. Simulations for re-matching recipients with donors were based on race-adjusted HMS thresholds with clinically achievable allocations. RESULTS: The retrospective median kidney graft survival was 12.0 years in Black vs. 18.6 years in White (6.6-year difference; p>0.001) and 18.4 years in non-Black (6.4-year difference; p>0.01) recipients. Only 0.7% of Blacks received transplants matched at HLA-A/B/DR/DQ (HMS=0) vs. 8.1% in Whites (p<0.001). Among fully matched Blacks (HMS=0), graft survival was 16.1-years and in well-matched Blacks (HMS ≤ 3.0) it was 14.0-years. Whites had 21.6-years survival at HMS ≤ 3.0 and 18.7-years at HMS ≤ 7.0 whereas non-Blacks had 22.0-year at HMS ≤ 3.0 and 18.7-year at HMS ≤ 7.0, confirming that higher HMS thresholds produced excellent survival. Simulation of ABO-compatible donor-recipient pairs using race-adjusted HMS thresholds identified weakly immunogenic matches at HMS=0 for 6.1% Blacks and 18.0% at HMS ≤ 3.0. Despite prioritizing Black patients, non-Black patients could be matched at the same level as in current allocation (47.0% vs 56.5%, at HMS ≤ 7.0). CONCLUSIONS: Race-adjusted HMS (EMS, AMS)-based allocation increased the number of weakly immunogenic donors for Black patients, while still providing excellent options for non-Black recipients.

134. A Novel m1A-Score Model Correlated With the Immune Microenvironment Predicts Prognosis in Hepatocellular Carcinoma.

Front Immunol

2022 Mar 24

Zhao M, Shen S, Xue C.

135. Cell-Crossing Functional Network Driven by microRNA-125a Regulates Endothelial Permeability and Monocyte Trafficking in Acute Inflammation.

Front Immunol

2022 Mar 24

Müller MB, Hübner M, Li L

136. Characterising the Intestinal Bacterial and Fungal Microbiome Associated With Different Cytokine Profiles in Two Bifidobacterium strains Pre-Treated Rats With D-Galactosamine-Induced Liver Injury.

Front Immunol

2022 Mar 24

Zha H, Li Q, Chang K

Multiple probiotics have protective effects against different types of liver injury. Different intestinal microbes could be beneficial to the protective effects of the probiotics on the treated cohorts in different aspects. The current study was designed to determine the intestinal bacterial and fungal microbiome associated with different cytokine profiles in the Bifidobacterium pseudocatenulatum LI09 and Bifidobacterium catenulatum LI10 pretreated rats with D-galactosamine-induced liver injury. In this study, partition around medoids clustering analysis determined two distinct cytokine profiles (i.e., CP1 and CP2) comprising the same 11 cytokines but with different levels among the LI09, LI10, positive control (PC), and negative control (NC) cohorts. All rats in PC and NC cohorts were determined with CP1 and CP2, respectively, while the rats with CP1 in LI09 and LI10 cohorts had more severe liver injury than those with CP2, suggesting that CP2 represented better immune status and was the "better cytokine profile" in this study. PERMANOVA analyses showed that the compositions of both bacterial and fungal microbiome were different in the LI10 cohorts with different cytokine profiles, while the same compositions were similar between LI09 cohorts with different cytokine profiles. The phylotype abundances of both bacteria and fungi were different in the rats with different cytokine profiles in LI09 or LI10 cohorts according to similarity percentage (SIMPER) analyses results. At the composition level, multiple microbes were associated with different cytokine profiles in LI09 or LI10 cohorts, among which Flavonifractor and Penicillium were the bacterium and fungus most associated with LI09 cohort with CP2, while Parabacteroides and Aspergillus were the bacterium and fungus most associated with LI10 cohort with CP2. These microbes were determined to influence the cytokine profiles of the corresponding cohorts. At the structure level, Corynebacterium and Cephalotrichiella were determined as the two most powerful gatekeepers in the microbiome networks of LI09 cohort CP2, while Pseudoflavonifractor was the most powerful gatekeeper in LI10 cohort with CP2. These identified intestinal microbes were likely to be beneficial to the effect of probiotic Bifidobacterium on the immunity improvement of the treated cohorts, and they could be potential microbial biomarkers assisting with the evaluation of immune status of probiotics-treated cohorts.

137. Flagella at the Host-Microbe Interface: Key Functions Intersect With Redundant Responses.

Front Immunol

2022 Mar 24

Akahoshi DT, Bevins CL.

138. Cannabidiol and SARS-CoV-2 Infection.

Front Immunol

2022 Mar 24

Vallée A.

139. Zebrafish as a Vertebrate Model for Studying Nodavirus Infections.

Front Immunol

2022 Mar 24

Lama R, Pereiro P, Figueras A

Nervous necrosis virus (NNV) is a neurotropic pathogenic virus affecting a multitude of marine and freshwater fish species that has a high economic impact on aquaculture farms worldwide. Therefore, the development of new tools and strategies aimed at reducing the mortality caused by this virus is a pivotal need. Although zebrafish is not considered a natural host for NNV, the numerous experimental advantages of this species make zebrafish an attractive model for studying different aspects of the disease caused by NNV, viral encephalopathy and retinopathy (VER). In this work, we established the best way and age to infect zebrafish larvae with NNV, obtaining significant mortalities in 3-day-postfertilization larvae when the virus was inoculated directly into the brain or by intramuscular microinjection. As occurs in naturally susceptible fish species, we confirmed that after intramuscular injection the virus was able to migrate to the central nervous system (CNS). As expected, due to the severe damage that this virus causes to the CNS, alterations in the swimming behavior of the zebrafish larvae were also observed. Taking advantage of the existence of transgenic fluorescent zebrafish lines, we were able to track the migration of different innate immune cells, mainly neutrophils, to the site of infection with NNV via the brain. However, we did not observe colocalization between the viral particles and neutrophils. RNA-Seq analysis of NNV-infected and uninfected larvae at 1, 3 and 5 days postinfection (dpi) revealed a powerful modulation of the antiviral immune response, especially at 5 dpi. We found that this response was dominated by, though not restricted to, the type I interferon system, the major defence mechanism in the innate immune response against viral pathogens. Therefore, as zebrafish larvae are able to develop the main characteristic of NNV infection and respond with an efficient immune arsenal, we confirmed the suitability of zebrafish larvae for modelling VER disease and studying different aspects of NNV pathogenesis, immune response and screening of antiviral drugs.

140. Negative Immune Checkpoint Protein, VISTA, Regulates the CD4(+) T(reg) Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival.

Front Immunol

2022 Mar 24

Gray CC, Biron-Girard B, Wakeley ME

Sepsis is a systemic immune response to infection that is responsible for ~35% of in-hospital deaths and over 24 billion dollars in annual treatment costs. Strategic targeting of non-redundant negative immune checkpoint protein pathways can cater therapeutics to the individual septic patient and improve prognosis. B7-CD28 superfamily member V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (Treg), in response to septic challenge, thus playing a protective role/reducing septic morbidity/mortality. Further, we investigated if changes in morbidity/mortality are due to a Treg-mediated effect during the acute response to septic challenge. To test this, we used the cecal ligation and puncture model as a proxy for polymicrobial sepsis and assessed the phenotype of CD4+ Tregs in VISTA-gene deficient (VISTA-/-) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA-/- and wild-type mice. We found that in wild-type mice, CD4+ Tregs exhibit a significant upregulation of VISTA which correlates with higher Treg abundance in the spleen and small intestine following septic insult. However, VISTA-/- mice have reduced Treg abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA-/- mice also have a significant survival deficit, higher levels of soluble indicators of liver injury (i.e., ALT, AST, bilirubin), and increased circulating proinflammatory cytokines (i.e., IL-6, IL-10, TNFα, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of Tregs in VISTA-/- sepsis mortality, we adoptively transferred VISTA-expressing Tregs into VISTA-/- mice. This adoptive transfer rescued VISTA-/- survival to wild-type levels. Taken together, we propose a protective Treg-mediated role for VISTA by which inflammation-induced tissue injury is suppressed and improves survival in early-stage murine sepsis. Thus, enhancing VISTA expression or adoptively transferring VISTA+ Tregs in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.

141. Epigenetic Regulation in the Pathogenesis of Rheumatoid Arthritis.

Front Immunol

2022 Mar 24

Yang C, Li D, Teng D

142. Interacting Effects of Sea Louse (Lepeophtheirus salmonis) Infection and Formalin-Killed Aeromonas salmonicida on Atlantic Salmon Skin Transcriptome.

Front Immunol

2022 Mar 24

Caballero-Solares A, Umasuthan N, Xue X

Lepeophtheirus salmonis (sea lice) and bacterial co-infection threatens wild and farmed Atlantic salmon performance and welfare. In the present study, pre-adult L. salmonis-infected and non-infected salmon were intraperitoneally injected with either formalin-killed Aeromonas salmonicida bacterin (ASAL) or phosphate-buffered saline (PBS). Dorsal skin samples from each injection/infection group (PBS/no lice, PBS/lice, ASAL/no lice, and ASAL/lice) were collected at 24 h post-injection and used for transcriptome profiling using a 44K salmonid microarray platform. Microarray results showed no clear inflammation gene expression signatures and revealed extensive gene repression effects by pre-adult lice (2,189 down and 345 up-regulated probes) in the PBS-injected salmon (PBS/lice vs. PBS/no lice), which involved basic cellular (e.g., RNA and protein metabolism) processes. Lice repressive effects were not observed within the group of ASAL-injected salmon (ASAL/lice vs. ASAL/no lice); on the contrary, the observed skin transcriptome changes -albeit of lesser magnitude (82 up and 1 down-regulated probes)- suggested the activation in key immune and wound healing processes (e.g., neutrophil degranulation, keratinocyte differentiation). The molecular skin response to ASAL was more intense in the lice-infected (ASAL/lice vs. PBS/lice; 272 up and 11 down-regulated probes) than in the non-infected fish (ASAL/no lice vs. PBS/no lice; 27 up-regulated probes). Regardless of lice infection, the skin's response to ASAL was characterized by the putative activation of both antibacterial and wound healing pathways. The transcriptomic changes prompted by ASAL+lice co-stimulation (ASAL/lice vs. PBS/no lice; 1878 up and 3120 down-regulated probes) confirmed partial mitigation of lice repressive effects on fundamental cellular processes and the activation of pathways involved in innate (e.g., neutrophil degranulation) and adaptive immunity (e.g., antibody formation), as well as endothelial cell migration. The qPCR analyses evidenced immune-relevant genes co-stimulated by ASAL and lice in an additive (e.g., mbl2b, bcl6) and synergistic (e.g., hampa, il4r) manner. These results provided insight on the physiological response of the skin of L. salmonis-infected salmon 24 h after ASAL stimulation, which revealed immunostimulatory properties by the bacterin with potential applications in anti-lice treatments for aquaculture. As a simulated co-infection model, the present study also serves as a source of candidate gene biomarkers for sea lice and bacterial co-infection.

143. Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia.

Front Immunol

2022 Mar 24

Veiga DFT, Tremblay M, Gerby B

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

144. Cardiovascular Dysfunction in COVID-19: Association Between Endothelial Cell Injury and Lactate.

Front Immunol

2022 Mar 23

Yang K, Holt M, Fan M

145. YAP Transcriptional Activity Dictates Cell Response to TNF In Vitro.

Front Immunol

2022 Mar 23

Caire R, Dalix E, Chafchafi M

146. Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity.

Front Immunol

2022 Mar 23

Tuomela K, Ambrose AR, Davis DM.

147. Development and Validation of an Immune-Based Prognostic Risk Score for Patients With Resected Non-Small Cell Lung Cancer.

Front Immunol

2022 Mar 23

He L, Huang Y, Chen X

BACKGROUND: Despite the well-known role of immunoscore, as a prognostic tool, that appeared to be superior to tumor-node-metastasis (TNM) staging system, no prognostic scoring system based on immunohistochemistry (IHC) staining digital image analysis has been established in non-small cell lung cancer (NSCLC). Hence, we aimed to develop and validate an immune-based prognostic risk score (IMPRS) that could markedly improve individualized prediction of postsurgical survival in patients with resected NSCLC. METHODS: In this retrospective study, complete resection of NSCLC (stage I-IIIA) was performed for two independent patient cohorts (discovery cohort, n=168; validation cohort, n=115). Initially, paraffin-embedded resected specimens were stained by immunohistochemistry (IHC) of three immune cell types (CD3+, CD4+, and CD8+ T cells), and a total of 5,580 IHC-immune features were extracted from IHC digital images for each patient by using fully automated pipeline. Then, an IHC-immune signature was constructed with selected features using the LASSO Cox analysis, and the association of signature with patients' overall survival (OS) was analyzed by Kaplan-Meier method. Finally, IMPRS was established by incorporating IHC-immune signature and independent clinicopathological variables in multivariable Cox regression analysis. Furthermore, an external validation cohort was included to validate this prognostic risk score. RESULTS: Eight key IHC-immune features were selected for the construction of IHC-immune signature, which showed significant associations with OS in all cohorts [discovery: hazard ratio (HR)=11.518, 95%CI, 5.444-24.368; validation: HR=2.664, 95%CI, 1.029-6.896]. Multivariate analyses revealed IHC-immune signature as an independent prognostic factor, and age, T stage, and N stage were also identified and entered into IMPRS (all p<0.001). IMPRS had good discrimination ability for predicting OS (C-index, 0.869; 95%CI, 0.861-0.877), confirmed using external validation cohort (0.731, 0.717-0.745). Interestingly, IMPRS had better prognostic value than clinicopathological-based model and TNM staging system termed as C-index (clinicopathological-based model: 0.674; TNM staging: 0.646, all p<0.05). More importantly, decision curve analysis showed that IMPRS had adequate performance for predicting OS in resected NSCLC patients. CONCLUSIONS: Our findings indicate that the IMPRS that we constructed can provide more accurate prognosis for individual prediction of OS for patients with resected NSCLC, which can help in guiding personalized therapy and improving outcomes for patients.

148. Development of Potent Cellular and Humoral Immune Responses in Long-Term Hemodialysis Patients After 1273-mRNA SARS-CoV-2 Vaccination.

Front Immunol

2022 Mar 23

Gonzalez-Perez M, Montes-Casado M, Conde P

149. Enhanced Migratory Ability of Neutrophils Toward Epidermis Contributes to the Development of Psoriasis via Crosstalk With Keratinocytes by Releasing IL-17A.

Front Immunol

2022 Mar 23

Liu XT, Shi ZR, Lu SY

150. Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus.

Front Immunol

2022 Mar 23

Ghanem MH, Shih AJ, Khalili H

151. ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19.

Front Immunol

2022 Mar 23

Maza MDC, Úbeda M, Delgado P

152. Identification of a Novel Antimicrobial Peptide From the Ancient Marine Arthropod Chinese Horseshoe Crab, Tachypleus tridentatus.

Front Immunol

2022 Mar 23

Wang WF, Xie XY, Huang Y

153. Age-Associated Seroprevalence of Coronavirus Antibodies: Population-Based Serosurveys in 2013 and 2020, British Columbia, Canada.

Front Immunol

2022 Mar 23

Tanunliong G, Liu AC, Kaweski S

BACKGROUND: Older adults have been disproportionately affected during the SARS-CoV-2 pandemic, including higher risk of severe disease and long-COVID. Prior exposure to endemic human coronaviruses (HCoV) may modulate the response to SARS-CoV-2 infection and contribute to age-related observations. We hypothesized that cross-reactive antibodies to SARS-CoV-2 are associated with antibodies to HCoV and that both increase with age. METHODS: To assess SARS-CoV-2 unexposed individuals, we drew upon archived anonymized residual sero-surveys conducted in British Columbia (BC), Canada, including before SARS-CoV-2 emergence (May, 2013) and before widespread community circulation in BC (May, 2020). Fifty sera, sex-balanced per ten-year age band, were sought among individuals ≤10 to ≥80 years old, supplemented as indicated by sera from March and September 2020. Sera were tested on the Meso Scale Diagnostics (MSD) electrochemiluminescent multiplex immunoassay to quantify IgG antibody against the Spike proteins of HCoV, including alpha (HCoV-229E, HCoV-NL63) and beta (HCoV-HKU1, HCoV-OC43) viruses, and the 2003 epidemic beta coronavirus, SARS-CoV-1. Cross-reactive antibodies to Spike, Nucleocapsid, and the Receptor Binding Domain (RBD) of SARS-CoV-2 were similarly measured, with SARS-CoV-2 sero-positivity overall defined by positivity on ≥2 targets. RESULTS: Samples included 407 sera from 2013, of which 17 were children ≤10 years. The 2020 samples included 488 sera, of which 88 were children ≤10 years. Anti-Spike antibodies to all four endemic HCoV were acquired by 10 years of age. There were 20/407 (5%) sera in 2013 and 8/488 (2%) in 2020 that were considered sero-positive for SARS-CoV-2 based on MSD testing. Of note, antibody to the single SARS-CoV-2 RBD target was detected in 329/407 (81%) of 2013 sera and 91/488 (19%) of 2020 sera. Among the SARS-CoV-2 overall sero-negative population, age was correlated with anti-HCoV antibody levels and these, notably 229E and HKU1, were correlated with cross-reactive anti-SARS-CoV-2 RBD titres. SARS-CoV-2 overall sero-positive individuals showed higher titres to HCoV more generally. CONCLUSION: Most people have an HCoV priming exposure by 10 years of age and IgG levels are stable thereafter. Anti-HCoV antibodies can cross-react with SARS-CoV-2 epitopes. These immunological interactions warrant further investigation with respect to their implications for COVID-19 clinical outcomes.

154. Erratum: Mechanisms of Particles in Sensitization, Effector Function and Therapy of Allergic Disease.

Front Immunol

2022 Mar 23

Frontiers Production Office.

155. Evaluation of Humoral and Cellular Responses in SARS-CoV-2 mRNA Vaccinated Immunocompromised Patients.

Front Immunol

2022 Mar 22

Oyaert M, De Scheerder MA, Van Herrewege S

BACKGROUND: Immunocompromised patients are at increased risk of severe COVID-19 and impaired vaccine response. In this observational prospective study, we evaluated immunogenicity of the BNT162b2 mRNA vaccine in cohorts of primary or secondary immunocompromised patients. METHODS: Five clinical groups of immunocompromised patients [primary immunodeficiency (PID) (n=57), people living with HIV (PLWH) (n=27), secondary immunocompromised patients with a broad variety of underlying rheumatologic (n=23) and homogeneous (multiple sclerosis) neurologic (n=53) conditions and chronic kidney disease (CKD) (n=39)] as well as a healthy control group (n=54) were included. Systemic humoral and cellular immune responses were evaluated by determination of anti-SARS-CoV-2 Spike antibodies using a TrimericS IgG assay (Diasorin) and through quantification of interferon gamma release in response to SARS-CoV-2 antigen with QuantiFERON SARS-CoV-2 assay (Qiagen), respectively. Responses were measured at pre-defined time-points after complete vaccination. RESULTS: All healthy controls, PLWH and CKD-patients had detectable antibodies 10 to 14 days (T2) and 3 months (T3) after administration of the second vaccination. In contrast, only 94.5% of the PID, 50.0% of the rheumatologic and 48.0% of neurologic patients developed antibodies at T2 and only 89.1% of the PID, 52.4% of the rheumatologic and 50.0% of neurologic patients developed antibodies at T3. At T3 no significant differences in cellular response between the healthy control group and the PLWH and CKD groups were found, while proportions of reactive subjects were lower in PID and rheumatologic patients and higher in neurologic patients. Humoral and cellular immune responses significantly correlated in the healthy control, PID, PLWH groups for all 3 antigens. CONCLUSION: Patients with acquired or inherited immune disorders may show variable immune responses to vaccination with the BNT162b2 mRNA vaccine against SARS-CoV-2. Whether humoral, cellular or both immune responses are delayed depends on the patient group, therapy and individual risk factors. These data may guide the counselling of patients with immune disorders regarding vaccination of SARS-CoV-2.

156. Functional Profile of CD8(+) T-Cells in Response to HLA-A*02:01-Restricted Mutated Epitopes Derived from the Gag Protein of Circulating HIV-1 Strains from Medellín, Colombia.

Front Immunol

2022 Mar 22

Sánchez-Martínez A, Acevedo-Sáenz L, Alzate-Ángel JC

157. Corrigendum: Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation through the Inhibition of STAT3/YKL-40 Axis in Mice with Chronic Cerebral Hypoperfusion-Induced White Matter Lesions.

Front Immunol

2022 Mar 22

Yuan J, Chen L, Wang J

158. Commentary: Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19?

Front Immunol

2022 Mar 22

Speeckaert MM, Delanghe JR.

159. The S1 Subunit of the SARS-CoV-2 Spike Protein Activates Human Monocytes to Produce Cytokines Linked to COVID-19: Relevance to Galectin-3.

Front Immunol

2022 Mar 22

Schroeder JT, Bieneman AP.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly evolved into a pandemic -the likes of which has not been experienced in 100 years. While novel vaccines show great efficacy, and therapeutics continue to be developed, the persistence of disease, with the concomitant threat of emergent variants, continues to impose massive health and socioeconomic issues worldwide. Studies show that in susceptible individuals, SARS-CoV-2 infection can rapidly progress toward lung injury and acute respiratory distress syndrome (ARDS), with evidence for an underlying dysregulated innate immune response or cytokine release syndrome (CRS). The mechanisms responsible for this CRS remain poorly understood, yet hyper-inflammatory features were also evident with predecessor viruses within the β-coronaviridae family, namely SARS-CoV-1 and the Middle East Respiratory Syndrome (MERS)-CoV. It is further known that the spike protein (S) of SARS-CoV-2 (as first reported for other β-coronaviruses) possesses a so-called galectin-fold within the N-terminal domain of the S1 subunit (S1-NTD). This fold (or pocket) shows structural homology nearly identical to that of human galectin-3 (Gal-3). In this respect, we have recently shown that Gal-3, when associated with epithelial cells or anchored to a solid phase matrix, facilitates the activation of innate immune cells, including basophils, DC, and monocytes. A synthesis of these findings prompted us to test whether segments of the SARS-CoV-2 spike protein might also activate innate immune cells in a manner similar to that observed in our Gal-3 studies. Indeed, by immobilizing S components onto microtiter wells, we show that only the S1 subunit (with the NTD) activates human monocytes to produce a near identical pattern of cytokines as those reported in COVID-19-related CRS. In contrast, both the S1-CTD/RBD, which binds ACE2, and the S2 subunit (stalk), failed to mediate the same effect. Overall, these findings provide evidence that the SARS-CoV-2 spike protein can activate monocytes for cytokines central to COVID-19, thus providing insight into the innate immune mechanisms underlying the CRS and the potential for therapeutic interventions.

160. Construction and Validation of a Novel Pyroptosis-Related Four-lncRNA Prognostic Signature Related to Gastric Cancer and Immune Infiltration.

Front Immunol

2022 Mar 22

Wang Z, Cao L, Zhou S

Increasing evidence has demonstrated that pyroptosis, a type of inflammatory programmed cell death, plays an important role in the pathogenesis and progression of gastric cancer. However, it remains unclear whether pyroptosis-related long non-coding RNAs (lncRNAs) can be used to predict the diagnosis and prognosis of gastric adenocarcinoma. This study aimed to evaluate and test the role of the lncRNA signature associated with pyroptosis as a prognostic tool for stomach adenocarcinoma (STAD) and to ascertain their immune value. Relative RNA-sequencing data were extracted from The Cancer Genome Atlas database (TCGA), and data preprocessing was performed for STAD. Pearson correlation analysis was used to determine whether lncRNAs were significantly correlated with pyroptosis based on 23 genes related to pyroptosis. Univariate Cox regression and least absolute shrinkage and selection operator(LASSO) analyses were both adopted to select features and establish the pyroptosis-related lncRNA (PRL) prognostic signature. Kaplan-Meier(KM) survival analysis of the different risk groups was conducted according to the risk scores. We further examined the functional enrichment, tumor microenvironment, and landscape of mutation status among the different risk groups, and these analyses further explained the reasons for the differences in the prediction as well as survival value of the different risk groups. Four lncRNAs, including HAND2-AS1, LINC01354, RP11-276H19.1, and PGM5-AS1, were involved in the PRL signature and used to split STAD patients into two risk groups. Overall survival time(OS) was significantly higher in the low-risk group than in the high-risk group in both the training and validation groups. Functional enrichment analysis was further employed to analyze differentially expressed genes in high- and low-risk groups to identify potential molecular functions and pathways associated with pyroptosis in the gastric cancer microenvironment. Protein-protein interaction (PPI) and Friends analysis identified hub genes that may play a key role in differentially expressed genes in high- and low-risk groups. In addition, there were remarkable discrepancies between the different risk groups in the tumor stage (P < 0.01) and histologic grade (P < 0.05). Furthermore, drug-susceptibility testing indicated potential sensitive chemotherapeutic drugs for each risk group. This study is the first to establish and validate STAD-associated PRLs that can effectively guide the prognosis and the immune microenvironment in STAD patients and provide evidence for the development of molecularly targeted therapies related to pyroptosis.

161. Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not.

Front Immunol

2022 Mar 22

Zheng RZ, Lee KY, Qi ZX

162. Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation.

Front Immunol

2022 Mar 22

Papp A, Papp K, Uzonyi B

Components of the extracellular matrix (ECM), when exposed to body fluids may promote local complement activation and inflammation. Pathologic complement activation at the glomerular basement membrane and at the Bruch's membrane is implicated in renal and eye diseases, respectively. Binding of soluble complement inhibitors to the ECM, including factor H (FH), is important to prevent excessive complement activation. Since the FH-related (FHR) proteins FHR1 and FHR5 are also implicated in these diseases, our aim was to study whether these FHRs can also bind to ECM components and affect local FH activity and complement activation. Both FH and the FHRs showed variable binding to ECM components. We identified laminin, fibromodulin, osteoadherin and PRELP as ligands of FHR1 and FHR5, and found that FHR1 bound to these ECM components through its C-terminal complement control protein (CCP) domains 4-5, whereas FHR5 bound via its middle region, CCPs 3-7. Aggrecan, biglycan and decorin did not bind FH, FHR1 and FHR5. FHR5 also bound to immobilized C3b, a model of surface-deposited C3b, via CCPs 3-7. By contrast, soluble C3, C3(H2O), and the C3 fragments C3b, iC3b and C3d bound to CCPs 8-9 of FHR5. Properdin, which was previously described to bind via CCPs 1-2 to FHR5, did not bind in its physiologically occurring serum forms in our assays. FHR1 and FHR5 inhibited the binding of FH to the identified ECM proteins in a dose-dependent manner, which resulted in reduced FH cofactor activity. Moreover, both FHR1 and FHR5 enhanced alternative complement pathway activation on immobilized ECM proteins when exposed to human serum, resulting in the increased deposition of C3-fragments, factor B and C5b-9. Thus, our results identify novel ECM ligands of FH family proteins and indicate that FHR1 and FHR5 are competitive inhibitors of FH on ECM and, when bound to these ligands, they may enhance local complement activation and promote inflammation under pathological conditions.

163. Necroptosis Contributes to Persistent Inflammation During Acute Leptospirosis.

Front Immunol

2022 Mar 22

Kundu S, Shetty A, Gomes-Solecki M.

164. Extracellular HMGB1 Impairs Macrophage-Mediated Efferocytosis by Suppressing the Rab43-Controlled Cell Surface Transport of CD91.

Front Immunol

2022 Mar 22

Wang Y, Zhang W, Xu Y

165. Contribution of Interleukin-17A to Retinal Degenerative Diseases.

Front Immunol

2022 Mar 22

Zhong H, Sun X.

166. CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD.

Front Immunol

2022 Mar 22

Zhang L, Wang X, Yu W

167. Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment.

Front Immunol

2022 Mar 22

Li Z, Wang R, Qiu C

BACKGROUND: The crucial role of DTL has been previously implicated in genomic stability; however, its prognostic value and its relation with tumor immunity in hepatocellular carcinoma (HCC) remain to be further explored. METHODS: Transcriptional and mutational datasets as well as clinical information were retrieved from the GEO, ICGC, and TCGA databases. Differentially expressed genes (DEGs) were obtained from the comparison of DTLhigh and DTLlow expression groups of the TCGA-HCC cohort. Those genes were under KEGG and gene ontology (GO) analyses to decipher the influence of the DTL gene on the biological behavior of HCC tumor cells. The survival status and mutational characteristics of patients according to DTL levels were depicted and analyzed. The DTL overexpression in HCC and its impact on prognosis were further confirmed by a cohort of 114 HCC patients (validation cohort). The TIMER, GEPIA, and TISIDB databases were adopted to investigate the potential relations between DTL levels and the status of immune cells, as well as immune cell infiltrations. RESULTS: The DTL gene is overexpressed in tumor tissues compared with distant non-malignant liver tissues, and DTL overexpression in HCC would enhance the HCC cells in the activities of cell cycle and division. HCC patients with high DTL expression have unfavorable clinical outcomes and harbor more somatic mutations than those with low DTL expression, and multivariate analysis also revealed that DTL overexpression could act as an independent biomarker for prognosis. Moreover, the DTL gene was positively linked to marker sets of infiltrating activated CD8+ and CD4+ T cells; however, these cells demonstrated to be functionally exhausted. CONCLUSIONS: Patients with a DTL overexpression phenotype in HCC have poorer prognosis than those in the DTLlow group due to the role of the DTL gene in the process of pro-cell proliferation, accompanied by the immunosuppressive microenvironment and T cell exhaustion.

168. Causal Association and Shared Genetics Between Asthma and COVID-19.

Front Immunol

2022 Mar 21

Baranova A, Cao H, Chen J

169. CD8(+) T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation.

Front Immunol

2022 Mar 21

Osuch S, Laskus T, Perlejewski K

BACKGROUND AND AIMS: During chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of "inhibitory" molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes. METHODS: The study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb. RESULTS: There was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1-Tim-3- T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054). CONCLUSIONS: Our results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.

170. Immunogenic SARS-CoV-2 S and N Protein Peptide and Cytokine Combinations as Biomarkers for Early Prediction of Fatal COVID-19.

Front Immunol

2022 Mar 21

Martynova E, Hamza S, Markelova M

171. Activation of Canine, Mouse and Human TLR2 and TLR4 by Inactivated Leptospira Vaccine Strains.

Front Immunol

2022 Mar 21

Novak A, Pupo E, Van't Veld E

Canine Leptospira vaccines contain inactivated strains of pathogenic Leptospira, the causative agents of leptospirosis. For an effective response to vaccination, activation of the innate immune system via pattern recognition receptors such as TLRs is crucial. However, it is not known which TLRs are activated by Leptospira in dogs. To investigate the involvement of canine TLR2, TLR4, and TLR5 in the recognition of Leptospira, we stimulated canine moDC and reporter cells expressing canine TLR2 with either whole-inactivated bacteria or purified LPS of Leptospira strains, representing the serogroups generally used in canine leptospirosis vaccines. Using the endotoxin neutralizing reagent polymyxin B and TLR4 antagonist RS-LPS, we demonstrate that Leptospira LPS and canine TLR4 are involved in IL-1β production as well as in the uptake of inactivated Leptospira in canine moDC. Furthermore, polymyxin B only partially inhibited IL-1β production induced by inactivated Leptospira, suggesting that next to TLR4, also other TLRs may be involved. The observed activation of canine TLR2-expressing reporter cells by inactivated Leptospira strains indicates that TLR2 could be one of these TLRs. Next, we analyzed TLR2 and TLR4 activating capabilities by the same Leptospira strains using human and mouse TLR-expressing reporter cells. Inactivated Leptospira and leptospiral LPS activated not only mouse, but also human TLR4 and this activation was shown to be LPS dependent in both cases. Additionally, inactivated Leptospira activated mouse and human TLR2-expressing reporter cell lines. In our study, we could not identify significant species differences in the recognition of Leptospira by TLR2 and TLR4 between dog, human and mouse. Lastly, we show that these inactivated Leptospira strains are recognized by both mouse and human TLR5 reporter cells only after exposure to additional heat-treatment. Unfortunately, we were not able to confirm this in the canine system. Our data show that TLR2 and TLR4 are involved in the recognition of Leptospira strains used in the production of canine Leptospira vaccines. This study contributes to the understanding of Leptospira-induced innate immune responses in dogs, humans, and mice. Future studies are needed to further explore the role of canine TLR2, TLR4 and TLR5 in the induction of vaccine-mediated immunity against Leptospira.

172. Plasma Cytokine Atlas Reveals the Importance of TH2 Polarization and Interferons in Predicting COVID-19 Severity and Survival.

Front Immunol

2022 Mar 21

Gibellini L, De Biasi S, Meschiari M

173. Why Does Piscirickettsia salmonis Break the Immunological Paradigm in Farmed Salmon? Biological Context to Understand the Relative Control of Piscirickettsiosis.

Front Immunol

2022 Mar 21

Rozas-Serri M.

Piscirickettsiosis (SRS) has been the most important infectious disease in Chilean salmon farming since the 1980s. It was one of the first to be described, and to date, it continues to be the main infectious cause of mortality. How can we better understand the epidemiological situation of SRS? The catch-all answer is that the Chilean salmon farming industry must fight year after year against a multifactorial disease, and apparently only the environment in Chile seems to favor the presence and persistence of Piscirickettsia salmonis. This is a fastidious, facultative intracellular bacterium that replicates in the host's own immune cells and antigen-presenting cells and evades the adaptive cell-mediated immune response, which is why the existing vaccines are not effective in controlling it. Therefore, the Chilean salmon farming industry uses a lot of antibiotics-to control SRS-because otherwise, fish health and welfare would be significantly impaired, and a significantly higher volume of biomass would be lost per year. How can the ever-present risk of negative consequences of antibiotic use in salmon farming be balanced with the productive and economic viability of an animal production industry, as well as with the care of the aquatic environment and public health and with the sustainability of the industry? The answer that is easy, but no less true, is that we must know the enemy and how it interacts with its host. Much knowledge has been generated using this line of inquiry, however it remains insufficient. Considering the state-of-the-art summarized in this review, it can be stated that, from the point of view of fish immunology and vaccinology, we are quite far from reaching an effective and long-term solution for the control of SRS. For this reason, the aim of this critical review is to comprehensively discuss the current knowledge on the interaction between the bacteria and the host to promote the generation of more and better measures for the prevention and control of SRS.

174. Negative Effects of Stromal Neutrophils on T Cells Reduce Survival in Resectable Urothelial Carcinoma of the Bladder.

Front Immunol

2022 Mar 21

Yang M, Wang B, Hou W

175. High Levels of CD244 Rather Than CD160 Associate With CD8(+) T-Cell Aging.

Front Immunol

2022 Mar 21

Wang X, Wang D, Du J

176. Development of Klebsiella pneumoniae Capsule Polysaccharide-Conjugated Vaccine Candidates Using Phage Depolymerases.

Front Immunol

2022 Mar 21

Lin TL, Yang FL, Ren CT

177. Implications of the Immune Landscape in COPD and Lung Cancer: Smoking Versus Other Causes.

Front Immunol

2022 Mar 21

Taucher E, Mykoliuk I, Lindenmann J

178. Distinct Immune Response at 1 Year Post-COVID-19 According to Disease Severity.

Front Immunol

2022 Mar 21

Kang CK, Kim M, Hong J

179. Corrigendum: Eosinophils and Neutrophils Eliminate Migrating Strongyloides ratti Larvae at the Site of Infection in the Context of Extracellular DNA Trap Formation.

Front Immunol

2022 Mar 21

Ehrens A, Rüdiger N, Heepmann L

180. Biallelic, Selectable, Knock-in Targeting of CCR5 via CRISPR-Cas9 Mediated Homology Directed Repair Inhibits HIV-1 Replication.

Front Immunol

2022 Mar 21

Scheller SH, Rashad Y, Saleh FM

181. Immune Cell Proinflammatory Microenvironment and Androgen-Related Metabolic Regulation During Benign Prostatic Hyperplasia in Aging.

Front Immunol

2022 Mar 21

Cao D, Sun R, Peng L

182. Plasma Donor-Derived Cell-Free DNA Levels Are Associated With the Inflammatory Burden and Macrophage Extracellular Trap Activity in Renal Allografts.

Front Immunol

2022 Mar 21

Guo L, Shen J, Lei W

183. Complement C3a Enhances the Phagocytic Activity of B Cells Through C3aR in a Fish.

Front Immunol

2022 Mar 21

Ma ZY, Liang JX, Li WS

184. Extracellular Vesicles and Interleukins: Novel Frontiers in Diagnostic and Therapeutic for Cancer.

Front Immunol

2022 Mar 21

Souza AG, Colli LM.

185. Unsupervised Mining of HLA-I Peptidomes Reveals New Binding Motifs and Potential False Positives in the Community Database.

Front Immunol

2022 Mar 21

Sricharoensuk C, Boonchalermvichien T, Muanwien P

186. Supplementation of Dietary Quercetin and Vitamin E Promotes the Intestinal Structure and Immune Barrier Integrity in Aged Breeder Hens.

Front Immunol

2022 Mar 21

Amevor FK, Cui Z, Du X

In aged animals, the physiological functions of the gastrointestinal tract (GIT) are reduced. Dietary intervention is necessary to re-activate GIT functions. The objective of this study was to investigate the impacts of dietary combination of quercetin (Q) and vitamin E (VE) on the intestinal structure and barrier integrity in aged breeder chickens. A sum of 400 (65-wks-old) Tianfu breeder hens were randomly allotted into four (4) groups with four (4) replicates, and fed with basal diet; basal diet supplemented with 0.4g/kg of Q; basal diet supplemented with 0.2g/kg of VE; and basal diet supplemented with the combination of Q (0.4 g/kg) and VE (0.2 g/kg) for 14 weeks. At the end of the 14th week, serum and gut segments were collected from eight hens per group for analyses. The results showed that Q+VE exerted synergistic effects on intestinal morphology by promoting villi height and crypt depth (P < 0.05), as well as mitigated the intestinal inflammatory damage of the aged hens, but decreased the concentration of serum D-lactate and diamine oxidase; and increased the levels of secretory immunoglobulin A (sIgA) and Mucin-2 mRNA (P < 0.05). Furthermore, the mRNA expression of intestinal tight junction proteins including occludin, ZO1, and claudin-1 was increased by Q+VE (P < 0.05). Moreover, Q+VE decreased the mRNA expression of the pro-inflammatory genes (TNF-α, IL-6, and IL-1β), and increased the expression of anti-inflammatory genes (IL-10 and IL-4) (P < 0.05). These results were consistent with the mRNA expression of Bax and Bcl-2. In addition, Q+VE protected the small intestinal tract from oxidative damage by increasing the levels of superoxide dismutase, total antioxidant capacity, glutathione peroxidase, catalase (P < 0.05), and the mRNA expression of SOD1 and GPx-2. However, Q+VE decreased malondialdehyde levels in the intestine compared to the control (P < 0.05). These results indicated that dietary Q+VE improved intestinal function in aged breeder hens, by protecting the intestinal structure and integrity. Therefore, Q+VE could act as an anti-aging agent to elevate the physiological functions of the small intestine in chickens.

187. Eosinophil-Derived Osteopontin Induces the Expression of Pro-Inflammatory Mediators and Stimulates Extracellular Matrix Production in Nasal Fibroblasts: The Role of Osteopontin in Eosinophilic Chronic Rhinosinusitis.

Front Immunol

2022 Mar 2

Yang HW, Park JH, Jo MS

188. Efficacy and Safety of Anti-PD1/PDL1 in Advanced Biliary Tract Cancer: A Systematic Review and Meta-Analysis.

Front Immunol

2022 Mar 2

Jiang Q, Huang J, Zhang B

BACKGROUND: Anti-programmed cell death protein 1 and its ligand (anti-PD1/PDL1) have been proposed as a promising therapeutic option for advanced biliary tract cancer (aBTC). Given the scarce quantitative analyses of anti-PD1/PDL1 in aBTC, we thus did a meta-analysis to assess the benefits and risks of this emerging treatment strategy in patients with aBTC. METHODS: PubMed, Embase, the Cochrane Library, Web of Science, and meeting resources were searched for relevant studies. The main endpoints were median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), any-grade adverse events (AEs), and grade 3-4 AEs. RESULTS: Twenty-eight studies with 1,338 participants were included. The best curative effect was found in the anti-PD1/PDL1 combined with anti-CTLA4 and chemotherapy group (mPFS: 12.4 months; mOS: 16.0 months; ORR: 45.1%; DCR: 95.0%), followed by the anti-PD1/PDL1 plus chemotherapy group (mPFS: 8.2 months; mOS: 14.8 months; ORR: 36.3%; DCR: 84.6%), the anti-PD1/PDL1 plus antiangiogenesis group (mPFS: 4.9 months; mOS: 10.2 months; ORR: 17.5%; DCR: 68.7%), the anti-PD1/PDL1 plus anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) group (mPFS: 2.9 months; mOS: 8.3 months; ORR: 9.9%; DCR: 36.8%), and the anti-PD1/PDL1 monotherapy group (mPFS: 2.5 months; mOS: 7.6 months; ORR: 6.8%; DCR: 34.7%). Compared with anti-PD1-containing regimens, anti-PDL1-containing regimens achieved preferable mPFS (11.1 vs. 3.8 months), mOS (12.2 vs. 9.8 months), and ORR (23.7% vs. 17.4%), despite a similar DCR (61.1% vs. 61.3%). The mPFS, mOS, ORR, and DCR were 10.6 months, 15.8 months, 42.3%, and 88.6% of first-line anti-PD1/PDL1 and 3.0 months, 9.1 months, 11.6%, and 51.1% of second-line therapy or beyond, respectively. There were 80.6% and 34.0% of the patients suffering any-grade AEs and grade 3-4 AEs. Anti-PD1/PDL1 monotherapy might be considered as a safer alternative than combination regimens. Meanwhile, obvious toxicities in the first-line setting could not be neglected. CONCLUSIONS: Anti-PD1/PDL1 showed encouraging efficacy and acceptable safety profile in aBTC and, thus, could be an alternative treatment.

189. Whole-Process Treatment of Combined Small Cell Lung Cancer Initially Diagnosed as "Lung Squamous Cell Carcinoma": A Case Report and Review of the Literature.

Front Immunol

2022 Mar 2

Dong Y, Li Q, Li D

190. NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond.

Front Immunol

2022 Mar 2

Zhu Y, Chen X, Liu X.

191. Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS.

Front Immunol

2022 Mar 2

Xiao Y, Chen X, Wang Z

192. LINC00520: A Potential Diagnostic and Prognostic Biomarker in Cancer.

Front Immunol

2022 Mar 2

Zhang Q, Shen J, Wu Y

193. HIV-gp140-Specific Antibodies Generated From Indian Long-Term Non-Progressors Mediate Potent ADCC Activity and Effectively Lyse Reactivated HIV Reservoir.

Front Immunol

2022 Mar 2

Dhande JR, Bagul RD, Thakar MR.

Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%-1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7-82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205-0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%-51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%-64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%-9.7%; and % p24 reduction median: 13.84, IQR: 9.863%-17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.

194. Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development.

Front Immunol

2022 Mar 2

Tang J, Li Z, Wu Q

195. Blockade of Autophagy Prevents the Progression of Hyperuricemic Nephropathy Through Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Front Immunol

2022 Mar 2

Hu Y, Shi Y, Chen H

Hyperuricemia has become a common metabolic disease, and is a risk factor for multiple diseases, including chronic kidney disease. Our recent study indicated that following persistent uric acid stimulation, autophagy was activated in rats of hyperuricemic nephropathy (HN) and facilitated the development of renal fibrosis. Nevertheless, the potential mechanism by which autophagy promoted the progression of HN is still not fully elucidated. Thus, in the current study, we investigated the mechanisms of autophagy inhibition on the development of HN. Our data showed that autophagy was activated in human renal tubular cell lines (HK-2) exposure to uric acid. Inhibition of autophagy with 3-methyladenine (3-MA) and transfected with Beclin-1 siRNA prevented uric acid-induced upregulation of α-SMA, Collagen I and Collagen III in HK-2 cells. Moreover, uric acid upregulated autophagy via promoting the p53 pathway. In vivo, we showed that hyperuricemic injury induced the activation of NLRP3 inflammasome and pyroptosis, as evidenced by cleavage of caspase-1 and caspase-11, activation of gasdermin D (GSDMD) and the release of IL-1β and IL-18. Treatment with autophagy inhibitor 3-MA alleviated aforementioned phenomenon. Stimulation with uric acid in HK-2 cells also resulted in NLRP3 inflammasome activation and pyroptotic cell death, however treatment with 3-MA prevented all these responses. Mechanistically, we showed that the elevation of autophagy and degradation of autophagolysosomes resulted in the release of cathepsin B (CTSB), which is related to the activation of NLRP3 inflammasome. CTSB siRNA can inhibit the activation of NLRP3 inflammasome and pyroptosis. Collectively, our results indicate that autophagy inhibition protects against HN through inhibiting NLRP3 inflammasome-mediated pyroptosis. What's more, blockade the release of CTSB plays a crucial role in this process. Thus, inhibition of autophagy may be a promising therapeutic strategy for hyperuricemic nephropathy.

196. Comprehensive Analysis of the Tumor Immune Microenvironment Landscape in Glioblastoma Reveals Tumor Heterogeneity and Implications for Prognosis and Immunotherapy.

Front Immunol

2022 Mar 2

Zhao R, Pan Z, Li B

BACKGROUND: Glioblastoma (GBM) is a fatal brain tumor with no effective treatment. The specific GBM tumor immune microenvironment (TIME) may contribute to resistance to immunotherapy, a tumor therapy with great potential. Thus, an in-depth understanding of the characteristics of tumor-infiltrating immune cells is essential for exploring biomarkers in GBM pathogenesis and immunotherapy. METHODS: We estimated the relative abundances of 25 immune cell types in 796 GBM samples using single sample gene set enrichment analysis (ssGSEA). Unsupervised clustering was used to identify different GBM-associated TIME immune cell infiltration (GTMEI) patterns. The GTMEIscore system was constructed with principal component analysis (PCA) to determine the immune infiltration pattern of individual tumors. RESULTS: We revealed three distinct GTMEI patterns with different clinical outcomes and modulated biological pathways. We developed a scoring system (GTMEIscore) to determine the immune infiltration pattern of individual tumors. We comprehensively analyzed the genomic characteristics, molecular subtypes and clinicopathological features as well as proteomic, phosphoproteomic, acetylomic, lipidomic and metabolomic properties associated with the GTMEIscore and revealed many novel dysregulated pathways and precise targets in GBM. Moreover, the GTMEIscore accurately quantified the immune status of many other cancer types. Clinically, the GTMEIscore was found to have significant potential therapeutic value for chemotherapy/radiotherapy, immune checkpoint inhibitor (ICI) therapy and targeted therapy. CONCLUSIONS: For the first time, we employed a multilevel and multiplatform strategy to construct a multidimensional molecular map of tumors with different immune infiltration patterns. These results may provide theoretical basises for identifying more effective predictive biomarkers and developing more effective drug combination strategies or novel immunotherapeutic agents for GBM.

197. Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation.

Front Immunol

2022 Mar 2

Joudi AM, Reyes Flores CP, Singer BD.

198. Editorial: Immunomodulatory Roles of Extracellular Vesicles in Autoimmune Diseases.

Front Immunol

2022 Mar 18

Gu Z, Kuo WP.

199. Synovial Fibroblast Sialylation Regulates Cell Migration and Activation of Inflammatory Pathways in Arthritogenesis.

Front Immunol

2022 Mar 18

Wang Y, Pan P, Khan A

200. Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation.

Front Immunol

2022 Mar 18

Atene CG, Fiorcari S, Mesini N

201. Evaluation of Spike Protein Epitopes by Assessing the Dynamics of Humoral Immune Responses in Moderate COVID-19.

Front Immunol

2022 Mar 18

Chen L, Pang P, Qi H

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike protein (S) of SARS-CoV-2 is a major target for diagnosis and vaccine development because of its essential role in viral infection and host immunity. Currently, time-dependent responses of humoral immune system against various S protein epitopes are poorly understood. In this study, enzyme-linked immunosorbent assay (ELISA), peptide microarray, and antibody binding epitope mapping (AbMap) techniques were used to systematically analyze the dynamic changes of humoral immune responses against the S protein in a small cohort of moderate COVID-19 patients who were hospitalized for approximately two months after symptom onset. Recombinant truncated S proteins, target S peptides, and random peptides were used as antigens in the analyses. The assays demonstrated the dynamic IgM- and IgG recognition and reactivity against various S protein epitopes with patient-dependent patterns. Comprehensive analysis of epitope distribution along the spike gene sequence and spatial structure of the homotrimer S protein demonstrated that most IgM- and IgG-reactive peptides were clustered into similar genomic regions and were located at accessible domains. Seven S peptides were generally recognized by IgG antibodies derived from serum samples of all COVID-19 patients. The dynamic immune recognition signals from these seven S peptides were comparable to those of the entire S protein or truncated S1 protein. This suggested that the humoral immune system recognized few conserved S protein epitopes in most COVID-19 patients during the entire duration of humoral immune response after symptom onset. Furthermore, in this cohort, individual patients demonstrated stable immune recognition to certain S protein epitopes throughout their hospitalization period. Therefore, the dynamic characteristics of humoral immune responses to S protein have provided valuable information for accurate diagnosis and immunotherapy of COVID-19 patients.

202. A Combined Transcriptomic and Proteomic Approach to Reveal the Effect of Mogroside V on OVA-Induced Pulmonary Inflammation in Mice.

Front Immunol

2022 Mar 18

Dou T, Wang J, Liu Y

203. Integrated Bioinformatics and Validation Reveal IL1B and Its Related Molecules as Potential Biomarkers in Chronic Spontaneous Urticaria.

Front Immunol

2022 Mar 18

Peng S, Zhang T, Zhang S

BACKGROUND: The etiopathogenesis of chronic spontaneous urticaria (CSU) has not been fully understood, and there has been extensive interest in the interaction between inflammatory dermatosis and pyroptosis. This study intends to investigate the molecular mechanism of pyroptosis-related genes in CSU via bioinformatic ways, aiming at identifying the potential key biomarker. METHODS: GSE72540, the RNA expression profile dataset of CSU, was utilized as the training set, and GSE57178 as the validation set. Differently expressed pyroptosis-related genes (DEPRGs), GO, KEGG, and DO analyses were performed. The hub genes were explored by the protein-protein interaction analysis. Moreover, CIBERSORT was employed for estimating immune cell types and proportions. Then, we constructed a DEmRNA-miRNA-DElncRNA ceRNA network and a drug-gene interaction network. Finally, ELISA was used for gene expression analysis. RESULTS: We recognized 17 DEPRGs, whose enrichment analyses showed that they were mostly enriched in inflammatory response and immunomodulation. Moreover, 5 hub genes (IL1B, TNF, and IRF1 are upregulated, HMGB1 and P2RX7 are downregulated) were identified via the PPI network and verified by a validation set. Then immune infiltration analysis displayed that compared with normal tissue, CSU owned a significantly higher proportion of mast cells activated, but a lower proportion of T cells CD4 naive and so on. Furthermore, IL1B was statistically and positively associated with mast cells activated in CSU, and SNHG3, the upstream factor of IL1B in the ceRNA we constructed, also related with mast cells in CSU. Further analysis exhibited that the protein subcellular localization of IL1B was extracellular, according with its intercellular regulation role; IL1B was significantly correlated with key immune checkpoints; and the NOD-like receptor signaling pathway was the mainly involved pathway of IL1B based on the couple databases. What is more, the result of ELISA of CSU patients was the same as the above analyses about IL1B. In addition, the drug-gene interaction network contained 15 potential therapeutic drugs targeting IL1B, and molecular docking might make this relationship viable. CONCLUSION: IL1B and its related molecules might play a key role in the development of CSU and could be potential biomarkers in CSU.

204. Chronic Alcohol Exposure Among People Living with HIV Is Associated with Innate Immune Activation and Alterations in Monocyte Phenotype and Plasma Cytokine Profile.

Front Immunol

2022 Mar 18

Underwood ML, Park B, Uebelhoer LS

205. Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy.

Front Immunol

2022 Mar 18

Ruppel KE, Fricke S, Köhl U

Cancer immunotherapies utilize the capabilities of the immune system to efficiently target malignant cells. In recent years, chimeric antigen receptor (CAR) equipped T cells showed promising results against B cell lymphomas. Autologous CAR-T cells require patient-specific manufacturing and thus extensive production facilities, resulting in high priced therapies. Along with potentially severe side effects, these are the major drawbacks of CAR-T cells therapies. Natural Killer (NK) cells pose an alternative for CAR equipped immune cells. Since NK cells can be safely transferred from healthy donors to cancer patients, they present a suitable platform for an allogeneic "off-the-shelf" immunotherapy. However, administration of activated NK cells in cancer therapy has until now shown poor anti-cancer responses, especially in solid tumors. Genetic modifications such as CARs promise to enhance recognition of tumor cells, thereby increasing anti-tumor effects and improving clinical efficacy. Although the cell biology of T and NK cells deviates in many aspects, the development of CAR-NK cells frequently follows within the footsteps of CAR-T cells, meaning that T cell technologies are simply adopted to NK cells. In this review, we underline the unique properties of NK cells and their potential in CAR therapies. First, we summarize the characteristics of NK cell biology with a focus on signaling, a fine-tuned interaction of activating and inhibitory receptors. We then discuss why tailored NK cell-specific CAR designs promise superior efficacy compared to designs developed for T cells. We summarize current findings and developments in the CAR-NK landscape: different CAR formats and modifications to optimize signaling, to target a broader pool of antigens or to increase in vivo persistence. Finally, we address challenges beyond NK cell engineering, including expansion and manufacturing, that need to be addressed to pave the way for CAR-NK therapies from the bench to the clinics.

206. Predicting Blood Parasite Load and Influence of Expression of iNOS on the Effect Size of Clinical Laboratory Parameters in Acute Trypanosoma cruzi Infection With Different Inoculum Concentrations in C57BL/6 Mice.

Front Immunol

2022 Mar 18

Rodrigues WF, Miguel CB, Marques LC

In Chagas disease, the initial responses of phagocyte-mediated innate immunity are strongly associated with the control of Trypanosoma cruzi and are mediated by various signaling pathways, including the inducible nitric oxide synthetase (iNOS) pathway. The clinical and laboratory manifestations of Chagas disease depend on the parasite-host relationship, i.e., the responsive capacity of the host immune system and the immunogenicity of the parasite. Here, we evaluated effect sizes in clinical and laboratory parameters mediated by acute infection with different concentrations of T. cruzi inoculum in mice immunosuppressed via iNOS pathway inactivation. Infection was induced in C57BL/6 wild-type and iNOS-/- mice with the "Y" strain of T. cruzi at three inoculum concentrations (3 × 102, 3 × 103, and 3 × 104). Parasitemia and mortality in both mouse strains were monitored. Immunohistochemistry was performed to quantify amastigotes in cardiac tissues and cardiac musculature cells. Biochemical parameters, such as blood urea nitrogen, sodium, albumin, and globulin concentrations, among others, were measured, and cytokine concentrations were also measured. Effect sizes were determined by the eta squared formula. Compared with that in wild-type animals, mice with an absence of iNOS expression demonstrated a greater parasite load, with earlier infection and a delayed parasitemia peak. Inoculum concentration was positively related to death in the immunosuppressed subgroup. Nineteen parameters (hematological, biochemical, cytokine-related, and histopathological) in the immunocompetent subgroup and four in the immunosuppressed subgroup were associated with parasitemia. Parasitemia, biochemical parameters, and hematological parameters were found to be predictors in the knockout group. The impact of effect sizes on the markers evaluated based on T. cruzi inoculum concentration was notably high in the immunocompetent group (Cohen's d = 88.50%; p <.001). These findings contribute to the understanding of physiopathogenic mechanisms underlying T. cruzi infection and also indicate the influence of the concentration of T. cruzi during infection and the immunosuppression through the iNOS pathway in clinical laboratory heterogeneity reported in acute Chagas disease.

207. Lipid Metabolism: Immune Regulation and Therapeutic Prospectives in Systemic Lupus Erythematosus.

Front Immunol

2022 Mar 18

Sun W, Li P, Cai J

208. Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy.

Front Immunol

2022 Mar 18

Wang Y, Huang B, Jin T

209. Improving Assignments for Therapeutic and Prophylactic Treatment Within TB Households. A Potential for Immuno-Diagnosis?

Front Immunol

2022 Mar 17

Sivakumaran D, Jenum S, Ritz C

Delays in diagnosis and treatment of pulmonary tuberculosis (TB) can lead to more severe disease and increased transmission. Contact investigation among household contacts (HHCs) of TB patients is crucial to ensure optimal outcomes. In the context of a prospective cohort study in Palamaner, Southern India, this study attempted to assess the potential of 27 different soluble immune markers to accurately assign HHCs for appropriate treatment. A multiplex bead assay was applied on QuantiFERON (QFT)-nil supernatants collected from 89 HHCs grouped by longitudinal QFT status; M. tuberculosis (Mtb) infected (QFT positive at baseline and follow-up, n = 30), recent QFT converters (QFT-negative at baseline, n = 27) and converted to QFT-positivity within 6 months of exposure (at follow-up, n = 24) and QFT consistent negatives (n = 32). The 29 TB index cases represented Active TB. Active TB cases and HHCs with Mtb infection produced significantly different levels of both pro-inflammatory (IFNγ, IL17, IL8, IP10, MIP-1α, MIP1β, and VEGF) and anti-inflammatory (IL9 and IL1RA) cytokines. We identified a 4-protein signature (bFGF, IFNγ, IL9, and IP10) that correctly classified HHCs with Mtb infection vs. Active TB with a specificity of 92.6%, suggesting that this 4-protein signature has the potential to assign HHCs for either full-length TB treatment or preventive TB treatment. We further identified a 4-protein signature (bFGF, GCSF, IFNγ, and IL1RA) that differentiated HHCs with Mtb infection from QFT consistent negatives with a specificity of 62.5%, but not satisfactory to safely assign HHCs to no preventive TB treatment. QFT conversion, reflecting new Mtb infection, induced an elevated median concentration in nearly two-thirds (19/27) of the analyzed soluble markers compared to the levels measured at baseline. Validation in other studies is warranted in order to establish the potential of the immune biosignatures for optimized TB case detection and assignment to therapeutic and preventive treatment of Mtb infected individuals.

210. How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism.

Front Immunol

2022 Mar 17

Ernst LM, Puntes V.

211. Transcriptome Sequencing Reveals the Antiviral Innate Immunity by IFN-γ in Chinese Sturgeon Macrophages.

Front Immunol

2022 Mar 17

Ding G, Zheng C, Wang B

212. Case Report: Severe Rhabdomyolysis and Multiorgan Failure After ChAdOx1 nCoV-19 Vaccination.

Front Immunol

2022 Mar 17

Cirillo E, Esposito C, Giardino G

213. Photobiomodulation Attenuates Neurotoxic Polarization of Macrophages by Inhibiting the Notch1-HIF-1α/NF-κB Signalling Pathway in Mice With Spinal Cord Injury.

Front Immunol

2022 Mar 17

Ma Y, Li P, Ju C

Spinal cord injury (SCI) is a catastrophic disease with a complex pathogenesis that includes inflammation, oxidative stress, and glial scar formation. Macrophages are the main mediators of the inflammatory response and are distributed in the epicentre of the SCI. Macrophages have neurotoxic and neuroprotective phenotypes (also known as classically and alternatively activated macrophages or M1 and M2 macrophages) that are associated with pro- or anti- inflammatory gene expression. Our previous study demonstrated that photobiomodulation (PBM) alters the polarization state of macrophages in the SCI region towards the M2 phenotype and promotes the recovery of motor function in rats with SCI. However, the mechanism by which PBM promotes SCI repair remains largely undefined. This study is based on the replacement of conventional percutaneous irradiation with implantable biofibre optic in vivo irradiation. The aim was to further investigate the effects of PBM on SCI in mice under new irradiation patterns and its potential mechanisms of action. PBM was administered to male mice with clamped SCI for four consecutive weeks and significantly promoted the recovery of motor function in mice. Analysis of the macrophage phenotypes in the epicentre of the SCI in mice showed that PBM mainly inhibited the neurotoxic activation of macrophages in the SCI area and reduced the secretion of inflammatory factors such as IL-1α and IL-6; PBM had no effect on M2 macrophages. Immediately afterwards, we constructed in vitro models of the inflammatory polarization of macrophages and PBM intervention. We found that PBM attenuated the neurotoxicity of M1 macrophages on VSC 4.1 motor neurons and dorsal root ganglion (DRG) neurons. The effects of PBM on neurotoxic macrophages and the possible mechanisms of action were analysed using RNA sequencing (RNA-seq), which confirmed that the main role of PBM was to modulate the inflammatory response and immune system processes. Analysis of the differentially expressed genes (DEGs) associated with the inflammatory response showed that PBM had the most significant regulatory effects on genes such as interleukin (IL)-1α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and had obvious inhibitory effects on inflammation-related Notch1 and hypoxia-inducible factor-1α (HIF-1α) pathway genes. RNA-seq analysis of the effect of PBM on gene expression in resting-state macrophages and M2 macrophages did not show significant differences (data not shown). In conclusion, PBM promoted better motor recovery after SCI in mice by inhibiting the neurotoxic polarization of macrophages and the release of inflammatory mediators by acting on the Notch1-HIF-1α/NF-κB Signalling Pathway.

214. The Insider: Impact of the Gut Microbiota on Cancer Immunity and Response to Therapies in Multiple Myeloma.

Front Immunol

2022 Mar 17

Brevi A, Cogrossi LL, Lorenzoni M

215. Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases.

Front Immunol

2022 Mar 17

Feng Y, Chen Z, Tu SQ

216. Effect of Infant RSV Infection on Memory T Cell Responses at Age 2-3 Years.

Front Immunol

2022 Mar 17

Chirkova T, Rosas-Salazar C, Gebretsadik T

217. O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System.

Front Immunol

2022 Mar 17

Dos Passos Junior RR, Bomfim GF, Giachini FR

218. Editorial: Mechanisms of Lung Fibrosis: Is Immunity Back in the Game?

Front Immunol

2022 Mar 17

Froidure A, Antoniou K, Bocchino M

219. Editorial: Oral Immune-Enhancing Research in Fish.

Front Immunol

2022 Mar 17

Galindo-Villegas J, Bossier P, Reyes-López FE.

220. Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis.

Front Immunol

2022 Mar 17

Wu J, Li Y, Rendahl A

221. Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More.

Front Immunol

2022 Mar 17

Herrmann T, Karunakaran MM.

222. Model-Based Meta-Analysis on the Efficacy of Biologics and Small Targeted Molecules for Crohn's Disease.

Front Immunol

2022 Mar 17

Yu B, Zhao L, Jin S

223. Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium.

Front Immunol

2022 Mar 17

Hirano KI, Hosokawa H, Yahata T

224. Short-Term Instantaneous Prophylaxis and Efficient Treatment Against SARS-CoV-2 in hACE2 Mice Conferred by an Intranasal Nanobody (Nb22).

Front Immunol

2022 Mar 17

Wu X, Wang Y, Cheng L

225. CD56-Negative Extranodal Natural Killer/T-Cell Lymphoma: A Retrospective Study in 443 Patients Treated by Chemotherapy With or Without Asparaginase.

Front Immunol

2022 Mar 17

Yang J, Li P, Piao Y

OBJECTIVE: Extranodal natural killer/T cell lymphoma (NKTCL) is an aggressive EBV-related lymphoma, originating from NK cells or T cells. Previous study demonstrated that CD56 negative NKTCL should be recognized as a distinct subtype. In this study, the value of CD56 in NKTCL is validated in the era of asparaginase, and genomic analysis was done to dissect the differences between CD56-negative and positive NKTCL. METHODS: 443 patients with newly diagnosed NKTCL were enrolled in this retrospective study, and correlation between CD56 positivity and survival outcomes was analyzed. The gene sequencing data was downloaded (http://www.biosino.org/node/project/detail/OEP000498), and bioinformatics analysis was done to delineate the tumor microenvironment and differentially expressed genes. RESULTS: CD56 was expressed in 337 patients (76.1%). Within a median follow-up time of 51 months, the 5-year overall survival (OS) and progression free survival (PFS) rates were 63.8% and 51.9%, respectively. For the whole cohort, patients who were CD56-positive had superior OS (5-year OS, 86.2% vs. 51.9%, p=0.019) and PFS (5-year PFS, 55.9% vs. 40.1%, p=0.016). For patients in early stage disease, CD56 positivity was associated with superior OS and PFS (p=0.008 and 0.005, respectively). In patients who received non-asparaginase-based chemotherapy, CD56-negative was associated with shorter OS and PFS (p<0.001), and in patients who received asparaginase-based chemotherapy, CD56-negative was not related to inferior OS and PFS (p=0.093 and p=0.829, respectively). The genomic analysis demonstrated that CD56 positive NKTCL probably originated from NK cells and CD56 negative NKTCL originated from T cells. CD56 positive NKTCL had significantly higher proportion of resting NK cells, activated NK cells, and activated CD8+ and CD4+ T cells in the tumor microenvironment. CONCLUSIONS: CD56 negative NKTCL differs from CD56 positive NKTCL in both the tumor microenvironment and survival outcomes, and asparaginase-based treatment may overcome the poor prognosis brought by CD56 negativity.

226. Epigenetic Signatures Discriminate Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis From Patients With Ulcerative Colitis.

Front Immunol

2022 Mar 16

de Krijger M, Hageman IL, Li Yim AYF

227. CD90 Marks a Mesenchymal Program in Human Thymic Epithelial Cells In Vitro and In Vivo.

Front Immunol

2022 Mar 16

Sun S, Li JY, Nim HT

228. The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes.

Front Immunol

2022 Mar 16

Sun J, Zhong X, Fu X

229. MiR-223 as a Regulator and Therapeutic Target in Liver Diseases.

Front Immunol

2022 Mar 16

Gu J, Xu H, Chen Y

230. Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation.

Front Immunol

2022 Mar 16

Pathni A, Özçelikkale A, Rey-Suarez I

Cytotoxic T lymphocytes (CTLs) play an integral role in the adaptive immune response by killing infected cells. Antigen presenting cells (APCs), such as dendritic cells, present pathogenic peptides to the T cell receptor on the CTL surface and co-stimulatory signals required for complete activation. Activated CTLs secrete lytic granules containing enzymes that trigger target cell death at the CTL-target contact, also known as the immune synapse (IS). The actin and microtubule cytoskeletons are instrumental in the killing of CTL targets. Lytic granules are transported along microtubules to the IS, where granule secretion is facilitated by actin depletion and recovery. Furthermore, actomyosin contractility promotes target cell death by mediating mechanical force exertion at the IS. Recent studies have shown that inflammatory cytokines produced by APCs, such as interleukin-12 (IL-12), act as a third signal for CTL activation and enhance CTL proliferation and effector function. However, the biophysical mechanisms mediating such enhanced effector function remain unclear. We hypothesized that the third signal for CTL activation, IL-12, modulates cytoskeletal dynamics and force exertion at the IS, thus potentiating CTL effector function. Here, we used live cell total internal reflection fluorescence (TIRF) microscopy to study actomyosin and microtubule dynamics at the IS of murine primary CTLs activated in the presence of peptide-MHC and co-stimulation alone (two signals), or additionally with IL-12 (three signals). We found that three signal-activated CTLs have altered actin flows, myosin dynamics and microtubule growth rates as compared to two signal-activated CTLs. We further showed that lytic granules in three-signal activated CTLs are less clustered and have lower velocities than in two-signal activated CTLs. Finally, we used traction force microscopy to show that three signal-activated CTLs exert greater traction forces than two signal-activated CTLs. Our results demonstrate that activation of CTLs in the presence of IL-12 leads to differential modulation of the cytoskeleton, thereby augmenting the mechanical response of CTLs to their targets. This indicates a potential physical mechanism via which the third signal can enhance the CTL response.

231. ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions.

Front Immunol

2022 Mar 16

Du Y, Ma Z, Zheng J

232. HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil.

Front Immunol

2022 Mar 16

Pereira LMS, França EDS, Costa IB

INTRODUCTION: Immune reconstitution failure after HIV treatment is a multifactorial phenomenon that may also be associated with a single polymorphism of human leukocyte antigen (HLA); however, few reports include patients from the Brazilian Amazon. Our objective was to evaluate the association of the immunogenic profile of the "classical" HLA-I and HLA-II loci with treatment nonresponse in a regional cohort monitored over 24 months since HIV diagnosis. MATERIALS AND METHODS: Treatment-free participants from reference centers in the state of Pará, Brazil, were enrolled. Infection screening was performed using enzyme immunoassays (Murex AG/AB Combination DiaSorin, UK) and confirmed by immunoblots (Bio-Manguinhos, FIOCRUZ). Plasma viral load was quantified by real-time PCR (ABBOTT, Chicago, Illinois, USA). CD4+/CD8+ T lymphocyte quantification was performed by immunophenotyping and flow cytometry (BD Biosciences, San Jose, CA, USA). Infection was monitored via test and logistics platforms (SISCEL and SICLOM). Therapeutic response failure was inferred based on CD4+ T lymphocyte quantification after 1 year of therapy. Loci A, B and DRB1 were genotyped using PCR-SSO (One Lambda Inc., Canoga Park, CA, USA). Statistical tests were applied using GENEPOP, GraphPad Prism 8.4.3 and BioEstat 5.3. RESULTS: Of the 270 patients monitored, 134 responded to treatment (CD4+ ≥ 500 cells/µL), and 136 did not respond to treatment (CD4+ < 500 cells/µL). The allele frequencies of the loci were similar to heterogeneous populations. The allelic profile of locus B was statistically associated with treatment nonresponse, and the B*13, B*35 and B*39 alleles had the greatest probabilistic influence. The B*13 allele had the highest risk of treatment nonresponse, and carriers of the allele had a detectable viral load and a CD4+ T lymphocyte count less than 400 cells/µL with up to 2 years of therapy. The B*13 allele was associated with a switch in treatment regimens, preferably to efavirenz (EFZ)-based regimens, and among those who switched regimens, half had a history of coinfection with tuberculosis. CONCLUSIONS: The allelic variants of the B locus are more associated with non-response to therapy in people living with HIV (PLHIV) from a heterogeneous population in the Brazilian Amazon.

233. Targeting Neutrophils for Promoting the Resolution of Inflammation.

Front Immunol

2022 Mar 16

Filep JG.

234. Tenascin-C can Serve as an Indicator for the Immunosuppressive Microenvironment of Diffuse Low-Grade Gliomas.

Front Immunol

2022 Mar 16

Zhang P, Liu G, Hu J

235. The uPA System Differentially Alters Fibroblast Fate and Profibrotic Ability in Skin Fibrosis.

Front Immunol

2022 Mar 16

Zou ML, Teng YY, Chen ZH

236. Different Spatial and Temporal Roles of Monocytes and Monocyte-Derived Cells in the Pathogenesis of an Imiquimod Induced Lupus Model.

Front Immunol

2022 Mar 15

Nomura A, Mizuno M, Noto D

Mounting evidence indicates the importance of aberrant Toll-like receptor 7 (TLR7) signaling in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of disease progression remains unclear. An imiquimod (IMQ)-induced lupus model was used to analyze the lupus mechanism related to the aberrant TLR7 signals. C57BL/6 mice and NZB/NZW mice were treated with topical IMQ, and peripheral blood, draining lymph nodes, and kidneys were analyzed focusing on monocytes and monocyte-related cells. Monocytes expressed intermediate to high levels of TLR7, and the long-term application of IMQ increased Ly6Clo monocytes in the peripheral blood and Ly6Clo monocyte-like cells in the lymph nodes and kidneys, whereas Ly6Chi monocyte-like cell numbers were increased in lymph nodes. Ly6Clo monocyte-like cells in the kidneys of IMQ-induced lupus mice were supplied by bone marrow-derived cells as demonstrated using a bone marrow chimera. Ly6Clo monocytes obtained from IMQ-induced lupus mice had upregulated adhesion molecule-related genes, and after adoptive transfer, they showed greater infiltration into the kidneys compared with controls. RNA-seq and post hoc PCR analyses revealed Ly6Clo monocyte-like cells in the kidneys of IMQ-induced lupus mice had upregulated macrophage-related genes compared with peripheral blood Ly6Clo monocytes and downregulated genes compared with kidney macrophages (MF). Ly6Clo monocyte-like cells in the kidneys upregulated Il6 and chemoattracting genes including Ccl5 and Cxcl13. The higher expression of Il6 in Ly6Clo monocyte-like cells compared with MF suggested these cells were more inflammatory than MF. However, MF in IMQ-induced lupus mice were characterized by their high expression of Cxcl13. Genes of proinflammatory cytokines in Ly6Chi and Ly6Clo monocytes were upregulated by stimulation with IMQ but only Ly6Chi monocytes upregulated IFN-α genes upon stimulation with 2'3'-cyclic-GMP-AMP, an agonist of stimulator of interferon genes. Ly6Chi and Ly6Clo monocytes in IMQ-induced lupus mice had different features. Ly6Chi monocytes responded in the lymph nodes of locally stimulated sites and had a higher expression of IFN-α upon stimulation, whereas Ly6Clo monocytes were induced slowly and tended to infiltrate into the kidneys. Infiltrated monocytes in the kidneys likely followed a trajectory through inflammatory monocyte-like cells to MF, which were then involved in the development of nephritis.

237. Corrigendum: PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip.

Front Immunol

2022 Mar 15

Peng H, Wang J, Song X

238. BmCPV-Derived Circular DNA vcDNA-S7 Mediated by Bombyx mori Reverse Transcriptase (RT) Regulates BmCPV Infection.

Front Immunol

2022 Mar 15

Zhu M, Pan J, Tong X

239. Pyolysin of Trueperella pyogenes Induces Pyroptosis and IL-1β Release in Murine Macrophages Through Potassium/NLRP3/Caspase-1/Gasdermin D Pathway.

Front Immunol

2022 Mar 15

Liang H, Wang B, Wang J

240. Changes of IgG N-Glycosylation in Thyroid Autoimmunity: The Modulatory Effect of Methimazole in Graves' Disease and the Association With the Severity of Inflammation in Hashimoto's Thyroiditis.

Front Immunol

2022 Mar 15

Trzos S, Link-Lenczowski P, Sokołowski G

The N-glycome of immunoglobulin G (IgG), the most abundant glycoprotein in human blood serum, reflects pathological conditions of autoimmunity and is sensitive to medicines applied in disease therapy. Due to the high sensitivity of N-glycosylation, the IgG N-glycan profile may serve as an indicator of an ongoing inflammatory process. The IgG structure and its effector functions are strongly dependent on the composition of N-glycans attached to the Fc fragment, and the binding of antigens is regulated by Fab sugar moieties. Because of the crucial role of N-glycans in IgG function, remodeling of its N-oligosaccharides can induce pathological changes that ultimately contribute to the development of autoimmunity; restoration of their physiological structure is critical to the reduction of disease symptoms. Our recently published data have shown that the pathology of autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is accompanied by alterations of the composition of IgG N-glycans. The present study is a more in-depth investigation of IgG glycosylation in both AITDs, designed to determine the relationship between the severity of thyroid inflammation and IgG N-glycan structures in HT, and to assess the impact of immunosuppressive therapy on the N-glycan profile in GD patients. The study material consisted of human serum samples collected from donors with elevated anti-thyroglobulin (Tg) and/or anti-thyroperoxidase (TPO) IgGs without symptoms of hypothyroidism (n=68), HT patients characterized by high autoantibody titers and advanced destruction of the thyroid gland (n=113), GD patients with up-regulated IgG against thyroid-stimulating hormone receptor (TSHR) before (n=62) and after (n=47) stabilization of TSH level as a result of methimazole therapy (study groups), and healthy donors (control group, n=90). IgG was isolated from blood serum using protein G affinity chromatography. N-glycans were released from IgG by PNGase F digestion and analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) after 2-aminobenzamide (2-AB) labeling. UPLC-MS chromatograms were integrated into 25 peaks (GP) in the Waters UNIFI Scientific Information System, and N-glycans were assigned based on the glucose unit values and mass-to-charge ratios (m/z) of the detected ions. The Kruskal-Wallis non-parametric test was used to determine the statistical significance of the results (p<0.05). The obtained results suggest that modifications of IgG sialylation, galactosylation and core-fucosylation are associated with the severity of HT symptoms. Methimazole therapy implemented in GD patients affected the IgG N-glycan profile; as a result, the content of the sialylated and galactosylated oligosaccharides with core fucose differed after treatment. Our results suggest that N-glycosylation of IgG undergoes dynamic changes during the intensification of thyroiditis in HT, and that in GD autoimmunity it is affected significantly by immunosuppressive therapy.

241. The Transcription of ZIP9 Is Associated With the Macrophage Polarization and the Pathogenesis of Hepatocellular Carcinoma.

Front Immunol

2022 Mar 15

Gou Y, Yang D, Tian T

Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT) like protein transporters (ZIPs) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each ZIP involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of ZIPs in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of ZIPs between DSCs tissues and healthy controls. Notably, the transcription levels of ZIP2, ZIP5, ZIP8, ZIP9 and ZIP14 were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of Zips in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl4) inducing mouse model of HCC were established. Consistently, the mRNA levels of Zip2, Zip9, and Zip14 in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1/M2 macrophages in vitro, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of ZIPs. Our results showed that both Zip2 and Zip9 were up-regulated in M2-polarized macrophages. Zip2 transcript was also up-regulated M1-polarized macrophages, but Zip9 was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in ZIP9 transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that Zip9, but not Zip2, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, Zip9 enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/β to inhibit M1 macrophage polarization. Together, our results indicate that ZIP9 may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.

242. The Diversity of Serum Anti-DSG3 IgG Subclasses Has a Major Impact on Pemphigus Activity and Is Predictive of Relapses After Treatment With Rituximab.

Front Immunol

2022 Mar 15

Golinski ML, Lemieux A, Maho-Vaillant M

243. Editorial: Targeting the Immune System to Treat Hepatitis B Virus Infection.

Front Immunol

2022 Mar 15

Meng Z, Liu J, Kosinska AD

244. Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs.

Front Immunol

2022 Mar 15

Storm BS, Ludviksen JK, Christiansen D

INTRODUCTION: Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation in vitro in human whole blood. Since these findings have not been verified in vivo, we aimed to examine the effects of air embolism in pigs on thromboinflammation. METHODS: Forty-five landrace pigs, average 17 kg (range 8.5-30), underwent intravenous air infusion for 300 or 360 minutes (n=29) or served as sham (n=14). Fourteen pigs were excluded due to e.g. infections or persistent foramen ovale. Blood was analyzed for white blood cells (WBC), complement activation (C3a and terminal C5b-9 complement complex [TCC]), cytokines, and hemostatic parameters including thrombin-antithrombin (TAT) using immunoassays and rotational thromboelastometry (ROTEM). Lung tissue was analyzed for complement and cytokines using qPCR and immunoassays. Results are presented as medians with interquartile range. RESULTS: In 24 pigs receiving air infusion, WBC increased from 17×109/L (10-24) to 28 (16-42) (p<0.001). C3a increased from 21 ng/mL (15-46) to 67 (39-84) (p<0.001), whereas TCC increased only modestly (p=0.02). TAT increased from 35 µg/mL (28-42) to 51 (38-89) (p=0.002). ROTEM changed during first 120 minutes: Clotting time decreased from 613 seconds (531-677) to 538 (399-620) (p=0.006), clot formation time decreased from 161 seconds (122-195) to 124 (83-162) (p=0.02) and α-angle increased from 62 degrees (57-68) to 68 (62-74) (p=0.02). In lungs from pigs receiving air compared to sham animals, C3a was 34 ng/mL (14-50) versus 4.1 (2.4-5.7) (p<0.001), whereas TCC was 0.3 CAU/mL (0.2-0.3) versus 0.2 (0.1-0.2) (p=0.02). Lung cytokines in pigs receiving air compared to sham animals were: IL-1β 302 pg/mL (190-437) versus 107 (66-120), IL-6 644 pg/mL (358-1094) versus 25 (23-30), IL-8 203 pg/mL (81-377) versus 21 (20-35), and TNF 113 pg/mL (96-147) versus 16 (13-22) (all p<0.001). Cytokine mRNA in lung tissue from pigs receiving air compared to sham animals increased 12-fold for IL-1β, 121-fold for IL-6, and 17-fold for IL-8 (all p<0.001). CONCLUSION: Venous air embolism in pigs activated C3 without a corresponding C5 activation and triggered thromboinflammation, consistent with a C3-dependent mechanism. C3-inhibition might represent a therapeutic approach to attenuate this response.

245. Evaluation of a Novel Adjuvanted Vaccine for Ultrashort Regimen Therapy of Artemisia Pollen-Induced Allergic Bronchial Asthma in a Mouse Model.

Front Immunol

2022 Mar 15

Tabynov K, Babayeva M, Nurpeisov T

Wormwood (Artemisia) pollen is among the top 10 aeroallergens globally that cause allergic rhinitis and bronchial asthma. Allergen-specific immunotherapy (ASIT) is the gold standard for treating patients with allergic rhinitis, conjunctivitis, and asthma. A significant disadvantage of today's ASIT methods is the long duration of therapy and multiplicity of allergen administrations. The goal of this study was to undertake a pilot study in mice of a novel ultrashort vaccine immunotherapy regimen incorporating various adjuvants to assess its ability to treat allergic bronchial asthma caused by wormwood pollen. We evaluated in a mouse model of wormwood pollen allergy candidates comprising recombinant Art v 1 wormwood pollen protein formulated with either newer (Advax, Advax-CpG, ISA-51) or more traditional [aluminum hydroxide, squalene water emulsion (SWE)] adjuvants administered by the intramuscular or subcutaneous route vs. intranasal administration of a mucosal vaccine formulation using chitosan-mannose nanoparticle entrapped with Art v 1 protein. The vaccine formulations were administered to previously wormwood pollen-sensitized animals, four times at weekly intervals. Desensitization was determined by measuring decreases in immunoglobulin E (IgE), cellular immunity, ear swelling test, and pathological changes in the lungs of animals after aeroallergen challenge. Art v 1 protein formulation with Advax, Advax-CpG, SWE, or ISA-51 adjuvants induced a significant decrease in both total and Art v 1-specific IgE with a concurrent increase in Art v 1-specific IgG compared to the positive control group. There was a shift in T-cell cytokine secretion toward a Th1 (Advax-CpG, ISA-51, and Advax) or a balanced Th1/Th2 (SWE) pattern. Protection against lung inflammatory reaction after challenge was seen with ISA-51, Advax, and SWE Art v 1 formulations. Overall, the ISA-51-adjuvanted vaccine group induced the largest reduction of allergic ear swelling and protection against type 2 and non-type 2 lung inflammation in challenged animals. This pilot study shows the potential to develop an ultrashort ASIT regimen for wormwood pollen-induced bronchial asthma using appropriately adjuvanted recombinant Art v 1 protein. The data support further preclinical studies with the ultimate goal of advancing this therapy to human clinical trials.

246. The Small GTPase RHOA Links SLP65 Activation to PTEN Function in Pre B Cells and Is Essential for the Generation and Survival of Normal and Malignant B Cells.

Front Immunol

2022 Mar 15

Vadakumchery A, Faraidun H, Ayoubi OE

247. Editorial: Immunity to Emerging Pathogens in Poikilothermic Vertebrates.

Front Immunol

2022 Mar 15

Edholm ES, Grayfer L.

248. Induction of IDO1 and Kynurenine by Serine Proteases Subtilisin, Prostate Specific Antigen, CD26 and HtrA: A New Form of Immunosuppression?

Front Immunol

2022 Mar 15

Clanchy FIL, Huang YS, Ogbechi J

249. Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease.

Front Immunol

2022 Mar 15

Bos A, Aleyd E, van der Steen LPE

250. Novel Insight Into Nutritional Regulation in Enhancement of Immune Status and Mediation of Inflammation Dynamics Integrated Study In Vivo and In Vitro of Teleost Grass Carp (Ctenopharyngodon idella): Administration of Threonine.

Front Immunol

2022 Mar 14

Dong YW, Jiang WD, Wu P

This study aims to investigate the effects of threonine (Thr) on immunoregulation in vivo and in vitro of teleost grass carp (Ctenopharyngodon idella). Juveniles (9.53 ± 0.02 g) were reared for 8 weeks with respective Thr diet (3.99, 7.70, 10.72, 14.10, 17.96, and 21.66 g/kg) and then challenged with Aeromonas hydrophila for in vivo study. Macrophages isolated from head kidney were treated in vitro for 48 h with L-Thr (0, 0.5, 1.0, 2.0, 4.0, and 8.0 mM) after 6 h of lipopolysaccharide induction. The results showed that, compared with Thr deficiency (3.99 g/kg), the optimal dietary Thr (14.10g/kg) affected the immunocyte activation in the head kidney (HK) and spleen (SP) by downregulating the mRNA expressions of MHC-II and upregulating CD4 (not CD8), and it mediated the innate immune by enhancing the activities of lysozyme (LZ), acid phosphatase content of complement 3 (C3) and C4, increasing the mRNA abundances of hepcidin, liver expressed antimicrobial peptide-2A (LEAP-2A), LEAP-2B, β-defensin1, downregulating tumor necrosis factor α (TNF-α), IL-6, IL-1β, IL-12p35, IL-12p40, IL-17AF1, and IL-17D partly by attenuating RORγ1 transcriptional factor and nuclear factor kappa B p65 (NF-κBp65) signaling cascades [IKKβ/IκBα/NF-κBp65] and upregulating transforming growth factor β1 (TGF-β1), IL-4/13A, -4/13B, IL-10, and IL-22 partly by GATA-3. Besides these, the optimal dietary Thr regulated the adaptive immune by upregulating the mRNAs of immunoglobulin M (IgM) and IgZ (not IgD). Moreover, 2 mM Thr downregulated in vitro the mRNA abundances of colony stimulating factor-1, inducible nitric oxide synthase, mannose receptor 1, matrix metalloproteinase2 (MMP-2), and MMP-9 significantly (P < 0.05), indicating that Thr could attenuate the M1-type macrophages' activation. Moreover, L-Thr downregulated the mRNA transcripts of TNF-α, IL-6, and IL-1β associated with impairing the SOCS1/STAT1 signaling and upregulated IL-10 and TGF-β1 partly by accentuating the SOCS3/STAT3 pathway. The above-mentioned observations suggested that Thr improved the immune status in the immune organs of fish by enhancing the immune defense and mediating the inflammation process. Finally, based on the immune indices of LZ activity in HK and C3 content in SP, the optimal Thr for immune enhancement in juvenile grass carp (9.53-53.43 g) was determined to be 15.70 g/kg diet (4.85 g/100 g protein) and 14.49 g/kg diet (4.47 g/100 g protein), respectively.

251. The CCR5 Gene Edited CD34(+)CD90(+) Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy.

Front Immunol

2022 Mar 14

Karuppusamy KV, Demosthenes JP, Venkatesan V

252. IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.

Front Immunol

2022 Mar 14

Liu J, Qian B, Zhou L

253. Mapping the Mechanical and Immunological Profiles of Polymeric Microneedles to Enable Vaccine and Immunotherapy Applications.

Front Immunol

2022 Mar 14

Shah SA, Oakes RS, Kapnick SM

254. Anti-Nuclear Antibodies Patterns in Patients With Systemic Lupus Erythematosus and Their Correlation With Other Diagnostic Immunological Parameters.

Front Immunol

2022 Mar 14

Al-Mughales JA.

BACKGROUND: Antinuclear antibodies (ANA) are major immunodiagnostic tools in systemic lupus erythematosus (SLE); however, their clinical and pathogenic roles are not yet elucidated and are a subject of controversy. OBJECTIVES: The aim of the study is to explore the pathogenic significance of ANA patterns among SLE patients, by analyzing their association with ANA titers, complement levels and other pathogenic immune markers, namely, anti-double-stranded DNA (anti-dsDNA), complements C3 and C4, rheumatoid factor (RF), anticardiolipin antibodies IgG (ACL IgG) and IgM (ACL IgM), Beta-2 Glycoprotein 1 Antibodies (β2-GP) IgG (β2-IgM) and IgM (β2-IgM), and lupus anticoagulant (LA). METHOD: A comparative cross-sectional study was conducted among 495 SLE patients, who were diagnosed and classified by consultant rheumatologists according to the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 criteria. SLE immunodiagnostic profiles were analyzed including the following parameters: ANA antibody titers and staining patterns, anti-dsDNA, C3 and C4 levels, aCL, and anti-β2-GP and LA. RESULT: The most frequently observed ANA patterns were the speckled (52.1%) and homogeneous (35.2%) patterns, while other patterns were rare representing less than 7% of the patients each. ANA titers were highest in patients with mixed pattern followed by the speckled pattern. Of all the investigated patterns, the peripheral pattern showed the most pathogenic immune profile, namely, highest levels of anti-dsDNA, lowest levels of C4, and highest levels of aCL and β2-GP IgG and IgM. CONCLUSION: This retrospective study showed that speckled followed by homogeneous ANA patterns were predominant accounting for 52.1 and 35.2% of the patients. The ANA pattern showed several associations with other immune markers that are documented to have significant clinical implications in SLE. Peripheral, mixed, and speckled patterns were associated with higher profiles of immune markers indicative of a potential prognostic value of these patterns in SLE.

255. Activated CD8(+)CD38(+) Cells Are Associated With Worse Clinical Outcome in Hospitalized COVID-19 Patients.

Front Immunol

2022 Mar 14

Bobcakova A, Barnova M, Vysehradsky R

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that spread around the world during the past 2 years, has infected more than 260 million people worldwide and has imposed an important burden on the healthcare system. Several risk factors associated with unfavorable outcome were identified, including elderly age, selected comorbidities, immune suppression as well as laboratory markers. The role of immune system in the pathophysiology of SARS-CoV-2 infection is indisputable: while an appropriate function of the immune system is important for a rapid clearance of the virus, progression to the severe and critical phases of the disease is related to an exaggerated immune response associated with a cytokine storm. We analyzed differences and longitudinal changes in selected immune parameters in 823 adult COVID-19 patients hospitalized in the Martin University Hospital, Martin, Slovakia. Examined parameters included the differential blood cell counts, various parameters of cellular and humoral immunity (serum concentration of immunoglobulins, C4 and C3), lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, NK cells, CD4+CD45RO+), expression of activation (HLA-DR, CD38) and inhibition markers (CD159/NKG2A). Besides already known changes in the differential blood cell counts and basic lymphocyte subsets, we found significantly higher proportion of CD8+CD38+ cells and significantly lower proportion of CD8+NKG2A+ and NK NKG2A+ cells on admission in non-survivors, compared to survivors; recovery in survivors was associated with a significant increase in the expression of HLA-DR and with a significant decrease of the proportion of CD8+CD38+cells. Furthermore, patients with fatal outcome had significantly lower concentrations of C3 and IgM on admission. However, none of the examined parameters had sufficient sensitivity or specificity to be considered a biomarker of fatal outcome. Understanding the dynamic changes in immune profile of COVID-19 patients may help us to better understand the pathophysiology of the disease, potentially improve management of hospitalized patients and enable proper timing and selection of immunomodulator drugs.

256. The COVID Complex: A Review of Platelet Activation and Immune Complexes in COVID-19.

Front Immunol

2022 Mar 14

Jevtic SD, Nazy I.

257. Electron-Beam Inactivation of Human Rotavirus (HRV) for the Production of Neutralizing Egg Yolk Antibodies.

Front Immunol

2022 Mar 14

Skrobarczyk JW, Martin CL, Bhatia SS

258. Longitudinal Tracking of Immune Responses in COVID-19 Convalescents Reveals Absence of Neutralization Activity Against Omicron and Staggered Impairment to Other SARS-CoV-2 Variants of Concern.

Front Immunol

2022 Mar 14

Odak I, Schultze-Florey CR, Hammerschmidt SI

259. TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial-Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma.

Front Immunol

2022 Mar 14

Zhang D, Yang H, Dong XL

260. Perioperative Outcomes of Minimally Invasive Esophagectomy After Neoadjuvant Immunotherapy for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma.

Front Immunol

2022 Mar 11

Cheng J, Guo M, Yang Y

261. Porcine Plasmacytoid Dendritic Cells Are Unique in Their Expression of a Functional NKp46 Receptor.

Front Immunol

2022 Mar 11

Mair KH, Stadler M, Razavi MA

262. Seeking Relevant Biomarkers in Common Variable Immunodeficiency.

Front Immunol

2022 Mar 11

Ho HE, Cunningham-Rundles C.

263. Type I Interferon-Induced TMEM106A Blocks Attachment of EV-A71 Virus by Interacting With the Membrane Protein SCARB2.

Front Immunol

2022 Mar 11

Guo X, Zeng S, Ji X

264. Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3(+) Regulatory T Cell Development and Function: Implications for Osteoclastogenesis.

Front Immunol

2022 Mar 11

Dohnke S, Moehser S, Surnov A

265. N6-Methyladenosine Regulator-Mediated Immue Patterns and Tumor Microenvironment Infiltration Characterization in Glioblastoma.

Front Immunol

2022 Mar 11

Xiong W, Li C, Wan B

266. Regulation of SIRT1 and Its Roles in Inflammation.

Front Immunol

2022 Mar 11

Yang Y, Liu Y, Wang Y

267. New Insights Into the Lineage-Specific Expansion and Functional Diversification of Lamprey AID/APOBEC Family.

Front Immunol

2022 Mar 11

Chen Y, Luo L, Deng L

268. Two CIDP Variants Patients With Anti-Caspr1 Antibodies in South China.

Front Immunol

2022 Mar 11

Li C, Zheng H, Yuan C

269. Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors.

Front Immunol

2022 Mar 11

Nigi L, Brusco N, Grieco GE

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.

270. Characterization of Monoclonal Antibodies Recognizing Citrulline-Modified Residues.

Front Immunol

2022 Mar 11

Chen Y, Weng L, Liu W

271. Concurrent IgA Nephropathy and Membranous Nephropathy, Is It an Overlap Syndrome?

Front Immunol

2022 Mar 11

He JW, Cui DF, Zhou XJ

272. The Roles of Monocytes and Macrophages in Behçet's Disease With Focus on M1 and M2 Polarization.

Front Immunol

2022 Mar 11

Hirahara L, Takase-Minegishi K, Kirino Y

273. Natural Human Immunity Against Staphylococcal Protein A Relies on Effector Functions Triggered by IgG3.

Front Immunol

2022 Mar 11

Boero E, Cruz AR, Pansegrau W

274. Tissue-Dependent Adaptations and Functions of Innate Lymphoid Cells.

Front Immunol

2022 Mar 10

Murphy JM, Ngai L, Mortha A

275. PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases.

Front Immunol

2022 Mar 10

Sandker GGW, Adema G, Molkenboer-Kuenen J

BACKGROUND: Programmed death-ligand 1 (PD-L1) regulates immune homeostasis by promoting T-cell exhaustion. It is involved in chronic infections and tumor progression. Nuclear imaging using radiolabeled anti-PD-L1 antibodies can monitor PD-L1 tissue expression and antibody distribution. However, physiological PD-L1 can cause rapid antibody clearance from blood at imaging doses. Therefore, we hypothesized that inflammatory responses, which can induce PD-L1 expression, affect anti-PD-L1 antibody distribution. Here, we investigated the effects of three different infectious stimuli on the pharmacokinetics and tumor targeting of radiolabeled anti-PD-L1 antibodies in tumor-bearing mice. MATERIALS/METHODS: Anti-mouse-PD-L1 and isotype control antibodies were labelled with indium-111 ([111In]In-DTPA-anti-mPD-L1 and [111In]In-DTPA-IgG2a, respectively). We evaluated the effect of inflammatory responses on the pharmacokinetics of [111In]In-DTPA-anti-mPD-L1 in RenCa tumor-bearing BALB/c mice in three conditions: lipopolysaccharide (LPS), local Staphylococcus aureus, and heat-killed Candida albicans. After intravenous injection of 30 or 100 µg of [111In]In-DTPA-anti-mPD-L1 or [111In]In-DTPA-IgG2a, blood samples were collected 1, 4, and 24 h p.i. followed by microSPECT/CT and ex vivo biodistribution analyses. PD-L1 expression, neutrophil, and macrophage infiltration in relevant tissues were evaluated immunohistochemically. RESULTS: In 30 µg of [111In]In-DTPA-anti-mPD-L1 injected tumor-bearing mice the LPS-challenge significantly increased lymphoid organ uptake compared with vehicle controls (spleen: 49.9 ± 4.4%ID/g versus 21.2 ± 6.9%ID/g, p < 0.001), resulting in lower blood levels (3.6 ± 1.6%ID/g versus 11.5 ± 7.2%ID/g; p < 0.01) and reduced tumor targeting (8.1 ± 4.5%ID/g versus 25.2 ± 5.2%ID/g, p < 0.001). Local S. aureus infections showed high PD-L1+ neutrophil influx resulting in significantly increased [111In]In-DTPA-anti-mPD-L1 uptake in affected muscles (8.6 ± 2.6%ID/g versus 1.7 ± 0.8%ID/g, p < 0.001). Heat-killed Candida albicans (Hk-C. albicans) challenge did not affect pharmacokinetics. Increasing [111In]In-DTPA-anti-mPD-L1 dose to 100 µg normalized blood clearance and tumor uptake in LPS-challenged mice, although lymphoid organ uptake remained higher. Infectious stimuli did not affect [111In]In-DTPA-IgG2a pharmacokinetics. CONCLUSIONS: This study shows that anti-PD-L1 antibody pharmacokinetics and tumor targeting can be significantly altered by severe inflammatory responses, which can be compensated for by increasing the tracer dose. This has implications for developing clinical PD-L1 imaging protocols in onco-immunology. We further demonstrate that radiolabeled anti-PD-L1 antibodies can be used to evaluate PD-L1 expression changes in a range of infectious diseases. This supports the exploration of using these techniques to assess hosts' responses to infectious stimuli.

276. Direct Effects of Glyphosate on In Vitro T Helper Cell Differentiation and Cytokine Production.

Front Immunol

2022 Mar 10

Maddalon A, Iulini M, Galbiati V

277. Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy.

Front Immunol

2022 Mar 10

Qi X, Li Q, Che X

278. Mind the "Vaccine Fatigue".

Front Immunol

2022 Mar 10

Su Z, Cheshmehzangi A, McDonnell D

279. The Interplay Between Cervicovaginal Microbial Dysbiosis and Cervicovaginal Immunity.

Front Immunol

2022 Mar 10

Wang Y, Wang X, Zhu M

280. Editorial: Humanized Mouse Models to Study Immune Responses to Human Infectious Organisms.

Front Immunol

2022 Mar 10

Wong MXY, Chen Q.

281. The Neuroimmune Interplay in Joint Pain: The Role of Macrophages.

Front Immunol

2022 Mar 10

Vasconcelos DP, Jabangwe C, Lamghari M

282. Serum Antibody Binding and Cytotoxicity to Pig Cells in Chinese Subjects: Relevance to Clinical Renal Xenotransplantation.

Front Immunol

2022 Mar 10

Li T, Feng H, Du J

Kidney xenotransplantation is expected to contribute to resolving the shortage of kidneys from deceased human donors. Although progress in experimental life-supporting pig renal xenotransplantation has been encouraging, there are still issues to be considered before a clinical trial can be initiated. We attempted to clarify some of these by an in vitro study. Blood was drawn from healthy volunteers (Volunteers, n=20), patients with end-stage renal disease (ESRD, n=20) pre-operation (Pre), and on Day 1 (POD 1) and Day 14 (POD 14) after renal allotransplantation, brain-dead organ donors (DBD, n=20), and renal allotransplant recipients who were currently experiencing T cell-mediated rejection (Allo-TCMR, n=20). Serum IgM/IgG binding to, and complement-dependent cytotoxicity (CDC) of, PBMCs and RBCs from (a) wild-type (WT), (b) α1,3-galactosyltransferase gene-knockout (GTKO), (c) GTKO/beta-1,4-N-acety1 galactosaminyltransferase 2-knockout (GTKO/β4GalNT2KO), (d) GTKO/cytidine monophosphate-N-acetylneuraminic acid hydroxylase-knockout (GTKO/CMAHKO), and (e) GTKO/β4GalNT2KO/CMAHKO/hCD55 (TKO/hCD55) pigs were measured by flow cytometry. We obtained the following results: (i) Serum IgM/IgG binding and CDC in Volunteers were significantly greater to WT, GTKO, and GTKO/β4GalNT2KO PBMCs or RBCs than to GTKO/CMAHKO and TKO/hCD55 cells; (ii) ESRD, DBD, and Allo-TCMR serum antibody binding and CDC to WT pig PBMCs were significantly greater than to GTKO, GTKO/β4GalNT2KO, GTKO/CMAHKO, and TKO/hCD55 cells; (iii) antibody binding to GTKO/CMAHKO pig cells was significantly lower in hemodialysis than peritoneal dialysis patients. (iv) Two of twenty allotransplantation recipients' serum IgG binding to GTKO pig PBMCs increased on POD14 compared with Pre, but IgG binding to GTKO pig RBCs did not; (v) In all sera, the lowest antibody binding and CDC were to GTKO/CMAHKO and TKO/CD55 pig cells. We conclude (i) CMAHKO in the pig may be critical to the success of clinical pig kidney xenotransplantation, and may be the most important after GTKO, at least in Chinese patients; (ii) subjects with ESRD, or who are immunosuppressed after kidney allotransplantation, and DBD, have lower levels of antibody binding and CDC to genetically-engineered pig cells than do volunteers; (iii) TKO pigs with selected human 'protective' transgenes, e.g., CD55, are likely to prove to be the optimal sources of kidneys for clinical xenotransplantation.

283. Three-Dimensional Visualization With Tissue Clearing Uncovers Dynamic Alterations of Renal Resident Mononuclear Phagocytes After Acute Kidney Injury.

Front Immunol

2022 Mar 10

Kim K, Kim YG, Jung SW

Traditional histologic methods are limited in detecting dynamic changes in immune cells during acute kidney injury (AKI). Recently, optical tissue clearing combined with multiphoton microscopy (MPM) or light sheet fluorescence microscopy (LSFM) has become an emerging method for deep tissue evaluation and three-dimensional visualization. These new approaches have helped expand our understanding of tissue injury and repair processes, including tracing the changes in immune cells. We designed this study to investigate the morphological and functional alterations of renal mononuclear phagocytes (MNPs) in lipopolysaccharide (LPS)-induced AKI using renal clearing in CD11c-YFP mice. We also evaluated the effect of the NLRP3 inhibitor MCC950 to determine whether NLRP3 inhibition attenuates the activation of CD11c+ cells in an LPS-induced AKI model. Transverse sectioned whole mouse kidney imaging by LSFM showed that CD11c+ cells were mainly distributed in the cortex, especially the tubulointerstitial area. The number of CD11c+ cells was significantly more densely interspersed, particularly in periglomerular and perivascular lesions, in the saline-treated LPS-exposed kidney than in the control kidney. Deep imaging of the kidney cortex by MPM demonstrated an increased number of CD11c+ cells in the saline-treated LPS group compared with the control group. This quantitative alteration of CD11c+ cells in AKI was accompanied by morphological changes at high resolution, showing an increased number and level of dendrites. These morphological and behavioral changes in the saline-treated LPS group were accompanied by increased MHC class II and CD86 on CD11c-YFP+ cells. MCC950 attenuated the activation of CD11c+ cells after AKI and improved renal function. In conclusion, wide and deep three-dimensional visualization using MPM or LSFM combined with kidney clearing uncovers dynamic changes of renal MNPs, which are directly linked to renal function in AKI.

284. Case Report: Lessons Learned From Subsequent Autologous and Allogeneic Hematopoietic Stem Cell Transplantations in a Pediatric Patient With Relapsing Polychondritis.

Front Immunol

2022 Mar 10

Veldkamp SR, Jansen MHA, Swart JF

285. Long Lasting Cellular Immune Response Induced by mRNA Vaccination: Implication for Prevention Strategies.

Front Immunol

2022 Mar 10

Vitiello L, Gatta L, Ilari S

286. CASE REPORT: Serial Cases of False-Positive Flow-Cytometry T Cell Crossmatch Associated With Anti-Blood Type Antibodies in Patients Undergoing ABO-Incompatible Kidney Transplantation.

Front Immunol

2022 Mar 10

Hayashi A, Yamamoto I, Kawabe M

287. Prevalence, Abundance, and Virulence of Adherent-Invasive Escherichia coli in Ulcerative Colitis, Colorectal Cancer, and Coeliac Disease.

Front Immunol

2022 Mar 10

López-Siles M, Camprubí-Font C, Gómez Del Pulgar EM

BACKGROUND & AIMS: Adherent-invasive E. coli (AIEC) has largely been implicated in the pathogenesis of Crohn's disease (CD). E. coli strains with similar genetic backgrounds and virulence genes profiles have been associated with other intestinal disorders, such as ulcerative colitis (UC), colorectal cancer (CRC), and coeliac disease (CeD), but the role of AIEC in these diseases remains unexplored. We aimed to assess the distribution, abundance, and pathogenic features of AIEC in UC, CRC, and CeD. METHODS: The AIEC phenotype was investigated in 4,233 E. coli isolated from the ileum and colon of 14 UC and 15 CRC patients and in 38 fecal E. coli strains obtained from 17 CeD and 10 healthy (H) children. AIEC prevalence and abundance were compared with previous data from CD patients and H controls. Clonality, virulence gene carriage, and phylogenetic origin were determined for the AIEC identified. RESULTS: In UC, AIEC prevalence was intermediate between CD and H subjects (UC: 35.7%, CD: 55.0%, H: 21.4%), and similar to CD patients with colonic disease (C-CD: 40.0%). In CRC, the prevalence was lower (6.7%) than these groups. In patients with AIEC, the estimated abundance was similar across all intestinal conditions. All AIEC strains isolated from UC and CRC belonged to the B1 phylogroup, except for a strain of the A phylogroup, and the majority (75% of clonally distinct AIEC) harbored the Afa/Dr operon and the cdt gene. None of the E. coli isolated from the CeD cohort were AIEC. Nonetheless, E. coli strains isolated from active CeD patients showed higher invasion indices than those isolated from H and inactive CeD pediatric patients. CONCLUSION: We support the hypothesis that AIEC-like strains can be involved not only in CD but also in UC. Further works are needed to study the virulence particularities of these groups of strains and to determine if there is a causative link between AIEC and UC. In contrast, we rule out the possible association of AIEC with CRC. In addition, to further study the E. coli strains in CeD for their possible pathogenic role would be of interest.

288. Impact of Hypogammaglobulinemia on the Course of COVID-19 in a Non-Intensive Care Setting: A Single-Center Retrospective Cohort Study.

Front Immunol

2022 Mar 10

Scarpa R, Dell'Edera A, Felice C

BACKGROUND: Severity and mortality of COVID-19 largely depends on the ability of the immune system to clear the virus. Among various comorbidities potentially impacting on this process, the weight and the consequences of an antibody deficiency have not yet been clarified. METHODS: We used serum protein electrophoresis to screen for hypogammaglobulinemia in a cohort of consecutive adult patients with COVID-19 pneumonia, hospitalized in non-intensive care setting between December 2020 and January 2021. The disease severity, measured by a validated score and by the need for semi intensive (sICU) or intensive care unit (ICU) admission, and the 30-day mortality was compared between patients presenting hypogammaglobulinemia (HYPO) and without hypogammaglobulinemia (no-HYPO). Demographics, comorbidities, COVID-19 specific treatment during the hospital stay, disease duration, complications and laboratory parameters were also evaluated in both groups. RESULTS: We enrolled 374 patients, of which 39 represented the HYPO cohort (10.4%). In 10/39 the condition was previously neglected, while in the other 29/39 hematologic malignancies were common (61.5%); 2/39 were on regular immunoglobulin replacement therapy (IgRT). Patients belonging to the HYPO group more frequently developed a severe COVID-19 and more often required sICU/ICU admission than no-HYPO patients. IgRT were administered in 8/39 during hospitalization; none of them died or needed sICU/ICU. Among HYPO cohort, we observed a significantly higher prevalence of neoplastic affections, of active oncologic treatment and bronchiectasis, together with higher prevalence of viral and bacterial superinfections, mechanical ventilation, convalescent plasma and SARS-CoV-2 monoclonal antibodies administration during hospital stay, and longer disease duration. Multivariate logistic regression analysis and Cox proportional hazard regression confirmed the impact of hypogammaglobulinemia on the COVID-19 severity and the probability of sICU/ICU admission. The analysis of the mortality rate in the whole cohort showed no significant difference between HYPO and no-HYPO. CONCLUSIONS: Hypogammaglobulinemia, regardless of its cause, in COVID-19 patients hospitalized in a non-intensive care setting was associated to a more severe disease course and more frequent admission to s-ICU/ICU, particularly in absence of IgRT. Our findings emphasize the add-value of routine serum protein electrophoresis evaluation in patients admitted with COVID-19 to support clinicians in patient care and to consider IgRT initiation during hospitalization.

289. Effects of Gut Microbiota on Host Adaptive Immunity Under Immune Homeostasis and Tumor Pathology State.

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290. Control of Dendritic Cell Function Within the Tumour Microenvironment.

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291. The Heterogeneity of Immune Cell Infiltration Landscape and Its Immunotherapeutic Implications in Hepatocellular Carcinoma.

Front Immunol

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Guo Y, Yang J, Ren K