Human Microbiota Flagellins Drive Adaptive Immune Responses in Crohn’s Disease

Crohn's disease and ulcerative colitis, another type of inflammatory bowel disease (IBD), are characterized by dysregulated adaptive immune responses to the microbiota in genetically susceptible individuals, but the human specificity of these responses had so far been largely undefined.

Flagellins are building blocks of the hair-like motility flagella that extend from the bacterial cell wall. Flagellin is a potent immune activator and antigen, and it is the only known microbial protein that has three receptors for innate immunity encoded in the host genome, in addition to immunoglobulin and T cell receptors.

Medical Scientists at the University of Alabama at Birmingham (Birmingham, AL, USA) individually probed blood sera from 87 healthy volunteers, 152 patients with Crohn's disease and 170 patients with ulcerative colitis. They used protein arrays of microbiota bacterial flagellins of both mouse and human origin, and they analyzed sera for IgG and IgA antibody responses. Circulating flagellin-reactive T effector (CD4⁺CD154⁺) and T regulatory (CD4⁺CD137⁺) cells were isolated and evaluated in selected patients. Resulting adaptive immune responses were compared with corresponding clinical data to determine relevancy to disease behavior.

The investigators reported that patients with IBD express selective patterns of antibody reactivity to microbiota flagellins. Patients with Crohn’s disease, but not patients with ulcerative colitis, display augmented serum IgG to human ileal-localized Lachnospiraceae flagellins, with a subset of patients having high responses to more than 10 flagellins. Elevated responses to CBir1, a mouse Lachnospiraceae flagellin used clinically to diagnose CD, correlated with multi-Lachnospiraceae flagellin reactivity. In this subset of patients with CD, multi-flagellin reactivity was associated with elevated flagellin-specific CD154⁺CD45RA^– T memory cells, a reduced ratio of flagellin-reactive CD4+ T regulatory to T effector cells, and a high frequency of disease complications.

Charles O. Elson, MD, a Professor of Medicine and Microbiology and senior author of the study, said, “Crohn's disease patients displayed a strong adaptive immune response to human-derived Lachnospiraceae flagellins, which may be targeted for prognosis and future personalized therapies.” The study was originally published on April 9, 2021 in the journal Gastroenterology.

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University of Alabama at Birmingham