Inflammatory Bowel Disease–associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria

• Published in: Inflammatory bowel diseases Vol. 26; no. 12; pp. 1856 - 1868
• Main Authors: Derer, Stefanie, Brethack, Ann-Kathrin, Pietsch, Carlotta, Jendrek, Sebastian T, Nitzsche, Thomas, Bokemeyer, Arne, Hov, Johannes R, Schäffler, Holger, Bettenworth, Dominik, Grassl, Guntram A, Sina, Christian
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.12.2020; Lippincott-Raven Publishers
• Subjects: Autoantibodies; Autoimmunity; Bacteria; Escherichia coli; Gastrointestinal diseases; Tumor necrosis factor; Germany; ulcerative colitis; L cells; M cells; anti-GP2 autoantibodies; FimH; Crohn’s disease
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1093/ibd/izaa069

Abstract Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD’s pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn’s disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD’s pathophysiology.