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”.
“While we looked specifically at IBD, it is likely there are many proteins in the gut that contribute to the development of other autoimmune disorders via similar mechanisms,” said Dr. Pere Santamaria.
However, this beneficial mechanism that helps fight the autoimmune response of colitis has a counterpart. According to the researchers, T lymphocytes -a kind of white blood cell responsible for slowing down inflammation- can also overreact to a similar antigen expressed by pancreatic cells, leading to a higher risk of type 1 diabetes. The problem may lie with the fact that the proteins expressed by Bacteroides are almost identical to those expressed by host cells, in this case of the pancreas, which can create confusion in the CD8 lymphocytes and give rise to autoimmune diseases.
The authors discussed in the paper that the idea that the CD8 T cells have an anti-inflammatory action in the intestine but pro-inflammatory action in the pancreas could have an evolutionary explanation. If immune cells that can cause inflammation in the pancreas have developed and persisted, maybe it is because they could have a beneficial role for our survival.
In conclusion, the microbiome-generated protein integrase acts as a molecular mimic of a human diabetes-linked autoantigen and is protective against host colitis. Exploring molecular mimicry between gut microbiota-generated molecules and self-antigens may contribute to a better understanding of gut homeostasis.
The discovery of this new mechanism by which the gut microbiota may specifically regulate the immune system may open the door to the development of treatments for managing autoimmune disorders. Indeed, the same research group has developed a therapeutic platform based on nanoparticles that could be applied to emulate or potentiate the action of the microbiota and contribute to the suppression of autoimmune disorders.
Hebbandi Nanjundappa R, Ronchi F, Wang J, et al. A gut microbial mimic that hijacks diabetogenic autoreactivity to suppress colitis. Cell. 2017; 171(3):655-67. doi: 10.1016/j.cell.2017.09.022.
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