A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis, 2017, McCoy et al

Andy · Dec 8, 2017

Highlights

•The Bacteroides integrase encodes a low-avidity mimotope of IGRP206-214

•The microbial epitope recruits diabetogenic CD8+ T cells to the gut

•Crossreactive CD8+ T cells suppress colitis by targeting gut DCs

•Suppression of colitis is MHC class I-, Itgb7-, and perforin-dependent

Summary
The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis.
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Paywalled at http://www.cell.com/cell/fulltext/S0092-8674(17)31116-9

Article based on this study.

The gut microbiota exerts a miscellany of protective, structural and metabolic effects on the intestinal mucosa. Although it is well recognized that the composition of the colonizing gut microbiota contributes to normal immunity by educating the host immune system on what to fight, little is known regarding how the gut microbiota, when dysregulated, can promote autoimmunity.

A new study, led by Dr. Kathy McCoy -from the University of Calgary’s Cumming School of Medicine– and Dr. Pere Santamaria from the Autoimmunity Research Group at the August Pi i Sunyer Biomedical Research Institute – IDIBAPS (Barcelona, Spain) and the Department of Microbiology, Immunology, and Infectious Diseases at the University of Calgary (Calgary, Canada), has discovered a new mechanism by which the gut microbiota modulates pro- and anti-inflammatory immune cells.

The researchers found that a protein (called integrase) that acts as a molecular mimic of a human diabetes-linked autoantigen and is expressed by several species of the gut microbial genus Bacteroides -common commensal bacteria found in the guts of both mice and humans- is protective against colitis. In mice, this microbiome-generated protein penetrates into the gut barrier and acts to prevent colitis by rapidly recruiting CD8 T lymphocytes to the gut, where these effector cells suppress inflammation via several molecular mechanisms involving the interaction with the integrase and by targeting gut dendritic cells. Besides this, human peripheral blood mononuclear cells (PBMCs) from healthy volunteers, patients with type 1 diabetes and individuals with Crohn’s disease also recognized the integrase.

These data suggest a new mechanism by which peripheral T cells can inhibit overreactive immune responses against gut microbial antigens and thus modulate homeostasis in the gut-associated lymphoid tissue. According to Dr. Kathy McCoy, “this mechanism is likely involved in preventing most people from developing IBD”.
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http://www.gutmicrobiotaforhealth.c...nnection-gut-microbiota-autoimmune-disorders/

Jonathan Edwards · Dec 8, 2017

Iam afraid this looks like gibberish to me. I cannot see what diabetes has to do with colitis. I think this just shows that weird animal models will do whatever they have been engineered to do.

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A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis, 2017, McCoy et al

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A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis, 2017, McCoy et al

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