Bacterial flagellin is a dominant antigen in Crohn disease.
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.
Lodes
Michael J
MJ
Corixa Corp, Seattle, Washington, USA.
Cong
Yingzi
Y
Elson
Charles O
CO
Mohamath
Raodoh
R
Landers
Carol J
CJ
Targan
Stephan R
SR
Fort
Madeline
M
Hershberg
Robert M
RM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002432:Cecum / Q000382:microbiology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004926:Escherichia coli / Q000378:metabolism; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015704:CD4 Antigens; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D005408:Flagellin