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Adaptive Immunity to Flagellin in IBD Andrew Gewirtz, Ph.D. Department of Pathology and Lab Medicine Emory University, Atlanta GA Background E. Coli Flagella Flagellin monomers (About 70,000 per flagella) Inestinal epithelial cell ? NF-kB Adaptive Immunity Y TLR5 Innate Immunity Acute Inflammation Cytokines Neutrophil Influx Hypothesis: Flagellin may be a target and promoter of adaptive immunity in IBD Methods 1. Isolate Serum from IBD patients and control subjects Fl ag A e lla fl a te ge d b lla a te cte ba ria ct er ia 2. Assess immunoreactivity to flagellins via western blotting or ELISA. protein L-coated Detect bound Ab with anti-IgA or IgG-HRP flagellin-coated LPS-coated Detect product-specific Ab with anti-IgA or anti-IgG-HRP 14 CD #1 CD #3 Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli CD #2 Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli Normal #2 Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli 50 34 20 Normal #1 Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli MW 205 97 Salmonella Aflagellate Salmonella E. coli Aflagellate E. coli Increased Immunoreactivity to Bacterial Extracts in Crohn’s Disease UC#1 Flagellin is a Target of Adaptive Immunity in Crohn’s Disease LPS-specific IgG Flagellin-specific IgG 1.25 Relative Total [IgG] 0.30 1.5 1.00 0.20 0.75 1.0 Optical density 0.50 0.10 0.5 0.25 0 Con CD UC 0 Con CD UC 0 LPS-specific IgA Flagellin-specific IgA Con CD UC Relative total [IgA] 0.75 0.30 1.5 0.50 0.20 1.0 0.25 0.10 0.5 0 Con CD UC 0 Con CD UC 0 Con CD UC Measuring immune responses to flagellin in mice Inject flagellin (or controls) intraperitoneally Innate Response Cytokines at 90 min Adaptive Response Antibodies at 2 weeks Mouse results/interpretation Y Flagellin PC IEC Y BC TLR5 TNFα, IL-6 TC APC Y Y Carriage Of TLR5-stop Reduces Natural Acquisition Of Adaptive Immunity To Flagellin 1.6 1.0 0.8 1.2 1.0 OD650 IgA IgG 1.4 0.6 0.8 0.4 0.6 0.4 0.2 0.2 0.0 WT Het 1:100 * WT Het 0.0 1:500 *: p<0.01 WT Het 1:100 WT Het 1:500 * * Reduced Rate of Crohn’s Disease In Persons Carrying TLR5-stop (Jewish Cohort) Number of subjects Het-TLR5-stop # (%) Healthy Relatives 296 16 (5.4%) Crohn’s Disease 215 2 (0.9%) Ulcerative Colitis 185 11 (6.0%) Ethnic Controls 416 27 (6.5%) Conclusions 1. Common gram-negative flagellins (i.e. E. coli) are antigenic targets of the elevated adaptive immune response in Crohn’s disease. 2. Adaptive immunity to flagellin is regulated by TLR5-mediated innate immunity. 3. Cytokines (e.g. IL-6 and TNFα) produced by nonhematopoietic cells, may link mucosal detection of flagellin to adaptive immune response. 4. Adaptive immunity to flagellin may promote development of Crohn’s Disease. Acknowledgements Emory University Ifor Williams Vijay Kumar Dan Moore Cathy Sanders Cedars-Sinai/UCLA Stephan Targan University of Chicago Judy Cho Host Defense, Osaka, JP Shizuo Akira