Analysis of Flagellin Specific Adaptive Immnunity Reveals Links to Dysbioss in Patients With Inflammatory Bowel Disease
AuthorCook, L; Lisko, DJ; Wong, MQ; Garcia, R; Himmel, ME; Seidman, EG; Bressler, B; Levings, MK; Steiner, TS
Source TitleCellular and Molecular Gastroenterology and Hepatology
University of Melbourne Author/sCook, Laura
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsCook, L., Lisko, D. J., Wong, M. Q., Garcia, R., Himmel, M. E., Seidman, E. G., Bressler, B., Levings, M. K. & Steiner, T. S. (2020). Analysis of Flagellin Specific Adaptive Immnunity Reveals Links to Dysbioss in Patients With Inflammatory Bowel Disease. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 9 (3), pp.485-506. https://doi.org/10.1016/j.jcmgh.2019.11.012.
Access StatusOpen Access
BACKGROUND & AIMS: Bacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4+ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4+ T cells. We aimed to quantify and characterize flagellin-specific CD4+ T cells in Crohn's disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity. METHODS: Blood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4+ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing. RESULTS: Compared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen-specific CD4+ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4+ T cells. The proportion of flagellin-specific CD4+ T cells that were CXCR3negCCR4+CCR6+ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39+, PD-1+, and integrin β7+ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin. CONCLUSIONS: Both CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4+ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4+ T cells in inflammatory bowel disease.
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