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Originally published online as doi:10.2353/ajpath.2008.080487 on October 30, 2008

Published online before print October 30, 2008
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(American Journal of Pathology. 2008;173:1647-1656.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080487

Fc Gamma Receptor Signaling in Mast Cells Links Microbial Stimulation to Mucosal Immune Inflammation in the Intestine

Xiao Chen*{dagger}, Bai-Sui Feng*{dagger}{ddagger}, Peng-Yuan Zheng{ddagger}, Xue-Qing Liao*{dagger}, Jasmine Chong*{dagger}, Shang-Guo Tang{dagger} and Ping-Chang Yang*{dagger}

From the Brain Body Institute* and the Department of Pathology & Molecular Medicine,{dagger} McMaster University, Ontario, Canada; and the Department of Gastroenterology,{ddagger} Zhengzhou University School of Medicine, Zhengzhou, China

Microbes and microbial products are closely associated with the pathogenesis of inflammatory bowel disease (IBD); however, the mechanisms behind this connection remain unclear. It has been previously reported that flagellin-specific antibodies are increased in IBD patient sera. As mastocytosis is one of the pathological features of IBD, we hypothesized that flagellin-specific immune responses might activate mast cells that then contribute to the initiation and maintenance of intestinal inflammation. Thirty-two colonic biopsy samples were collected from IBD patients. A flagellin/flagellin-specific IgG/Fc gamma receptor I complex was identified on biopsied mast cells using both immunohistochemistry and co-immunoprecipitation experiments; this complex was shown to co-localize on the surfaces of mast cells in the colonic mucosa of patients with IBD. In addition, an ex vivo study showed flagellin-IgG was able to bind to human mast cells. These cells were found to be sensitized to flagellin-specific IgG; re-exposure to flagellin induced the mast cells to release inflammatory mediators. An animal model of IBD was then used to examine flagellin-specific immune responses in the intestine. Mice could be sensitized to flagellin, and repeated challenges with flagellin induced an IBD-like T helper 1 pattern of intestinal inflammation that could be inhibited by pretreatment with anti-Fc gamma receptor I antibodies. Therefore, flagellin-specific immune responses activate mast cells in the intestine and play important roles in the pathogenesis of intestinal immune inflammation.






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Copyright © 2008 by the American Society for Investigative Pathology.