Bacterial flagellin is a dominant antigen in Crohn disease

Abstract

Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.

Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria

“…An increase in the production of IgG specific for luminal bacteria is also associated with the development of experimental colitis (28,29). The bacterial antigens, which are recognized by such IgGs, are often identical to the antigens that drive the pathogenic T cell responses, as was recently shown for bacterial flagellins (30). Therefore, it is also possible that FcRnmediated retrieval of enteric bacterial antigens as IgG immune complexes may be -in some situations -involved in the pathogenesis of chronic colitis by activating harmful acquired immune responses.…”

The fundamental basis of inflammatory bowel disease

“…nent of the bacterial flora (32). In both of these examples, dysregulated mucosal immune responses are involved because the repleting cell populations lack Tregs that ordinarily moderate responses to bacterial antigens.…”

“…One possible explanation for these findings is that the response to gut microflora during inflammation is characterized by "epitope spreading," i.e., a phenomenon frequently observed in autoimmune states whereby a primary autoimmune response to a dominant autoantigen is subsequently accompanied by a response to many autoantigens because the inflammatory state enables secondary abrogation of tolerance to many secondary autoantigens (36). Evidence in support of this possibility and the existence of a dominant autoantigen came from studies using a technique known as serological expression cloning, in which it was shown that a relatively high proportion (about 25%) of the antigens reacting with antibodies in sera from C3H/HeJBir mice (and other mouse models of inflammation) were in fact flagellins (32). This, along with the facts that C3H/HeJBir T cells reacting with flagellin can cause colitis when transferred to immunodeficient mice (as noted above) and that anti-flagellin antibodies are frequently present in Crohn disease patients (but not ulcerative colitis patients), led to the view that flagellin was a dominant antigen in both experimental colitis and in patients with Crohn disease (32,37).…”

“…Evidence in support of this possibility and the existence of a dominant autoantigen came from studies using a technique known as serological expression cloning, in which it was shown that a relatively high proportion (about 25%) of the antigens reacting with antibodies in sera from C3H/HeJBir mice (and other mouse models of inflammation) were in fact flagellins (32). This, along with the facts that C3H/HeJBir T cells reacting with flagellin can cause colitis when transferred to immunodeficient mice (as noted above) and that anti-flagellin antibodies are frequently present in Crohn disease patients (but not ulcerative colitis patients), led to the view that flagellin was a dominant antigen in both experimental colitis and in patients with Crohn disease (32,37). However, the data at hand is equally consistent with the views that many bacterial antigens elicit responses from a dysregulated immune system and that the anti-flagellin response seems dominant only because it is a powerful antigen that rapidly assumes prominence in an autoreactive milieu.…”

Deletion of TLR5 results in spontaneous colitis in mice

“…Gut epithelial cells (by far the most numerous cell type in the intestine) derived from a number of sources (i.e., cell lines) uniformly exhibit robust proinflammatory gene expression in response to flagellin while such cells have mostly been observed to be relatively hyporesponsive to the quintessential TLR agonist LPS (5,6) and respond nonclassically to TLR2 ligands (2). Flagellin has been suggested to be a major target of innate and adaptive immunity in Crohn disease and, in some ethnicities, heterozygous carriage of a dominant negative TLR5 allele is associated with protection from Crohn disease (7)(8)(9). Consequently, we hypothesized that mice lacking the flagellin receptor TLR5 might exhibit a reduced tendency to develop intestinal inflammation.…”