Dataset Information

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

ABSTRACT: Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, Fc?RIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in Fc?RIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating Fc?R signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident Fc?R-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1? (IL-1?) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage Fc?R signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1?-dependent type 17 immunity. The identification of an important contribution of IgG-Fc?R-dependent inflammation to UC has therapeutic implications.

SUBMITTER: Castro-Dopico T

PROVIDER: S-EPMC6477154 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

Castro-Dopico Tomas T Dennison Thomas W TW Ferdinand John R JR Mathews Rebeccah J RJ Fleming Aaron A Clift Dean D Stewart Benjamin J BJ Jing Chenzhi C Strongili Konstantina K Labzin Larisa I LI Monk Edward J M EJM Saeb-Parsy Kourosh K Bryant Clare E CE Clare Simon S Parkes Miles M Clatworthy Menna R MR

Immunity 20190312 4

Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a ...[more]

PMID: 30876876

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Project description:ObjectiveUlcerative Colitis (UC) manifests as a chronic inflammatory condition of the intestines, marked by ongoing immune system dysregulation. Disulfidptosis, a newly identified cell death mechanism, is intimately linked to the onset and advancement of inflammation. However, the role of disulfidptosis in UC remains unclear.MethodsWe screened differentially expressed genes (DEGs) associated with disulfidptosis in multiple UC datasets, narrowed down the target gene number using lasso regression, and conducted immune infiltration analysis and constructed a clinical diagnostic model. Additionally, we explored the association between disulfidptosis-related key genes and disease remission in UC patients receiving biologic therapy. Finally, we confirmed the expression of key genes in FHC cells and UC tissue samples.ResultsIn the differential analysis, we identified 20 DEGs associated with disulfidptosis. Immune infiltration results revealed that five genes (PDLIM1, SLC7A11, MYH10, NUBPL, OXSM) exhibited strong correlations with immune cells and pathways. Using GO, KEGG and WGCNA analyses, we discovered that gene modules highly correlated with disulfidptosis-related gene expression were significantly enriched in inflammation-related pathways. Additionally, we developed a nomogram based on these five immune-related disulfidptosis genes for UC diagnosis, showing robust diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant link between changes in the expression levels of these cell genes and disease remission in UC patients receiving biologic therapy. In line with previous studies, similar expression changes of the target gene were seen in both UC cell models and tissue samples.ConclusionsThis study utilized bioinformatic analysis and machine learning to identify and analyze features associated with disulfidptosis in multiple UC datasets. This enhances our comprehension of the role disulfidptosis plays in intestinal immunity and inflammation in UC, providing new perspectives for developing innovative treatments for UC.

Dataset Information

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

Publications

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

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