Flagellin identified as dominant antigen in Crohn's disease

Abstract

It is now recognized that inflammatory bowel disease (IBD) results from an aberrant immunologic response to intestinal microflora in genetically susceptible individuals. However, the specific bacterial products that stimulate this response are largely unknown. In this study, the investigators used serologic expression cloning (involving the screening of DNA expression libraries in lambda phage with defined antisera) to identify commensal bacterial proteins that could contribute to disease pathogenesis in murine models of IBD. This led to the identification of 55 clones, of which 15 were flagellin-like sequences. The investigators focused on analysis of the immune response against two of the flagellin clones, Cbir1 and Fla-X. Antibody reactivity to these proteins was composed of the IgG2a subclass (suggesting TH1 responses) and correlated with disease activity. In addition, they isolated flagellin-specific T-cell clones and demonstrated that they could induce IBD when adoptively transferred into immunocompromised mice. Finally, the investigators demonstrated high levels of serum IgG against specific flagellins in patients with Crohn's disease but not in patients with ulcerative colitis or in healthy individuals. Because the receptor for flagellin is the Toll-like receptor 5, these results not only provide insights into the antigens involved in disease pathogenesis but also highlight the important link between IBD and innate immunity. As such, the results suggest that specific flagellin molecules might represent novel targets for antigen-based therapies for IBD.