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

Author:

Derer Stefanie1,Brethack Ann-Kathrin1,Pietsch Carlotta1,Jendrek Sebastian T2,Nitzsche Thomas13,Bokemeyer Arne4,Hov Johannes R56,Schäffler Holger7,Bettenworth Dominik4,Grassl Guntram A8ORCID,Sina Christian19

Affiliation:

1. Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany

2. Department of Rheumatology, University of Schleswig-Holstein, Lübeck, Germany

3. Institute for Experimental Immunology, Euroimmun Corp., Lübeck, Germany

4. Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany

5. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

6. Norwegian PSC Research Center, Section of Gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway

7. Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany

8. Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover Medical School, Hannover, Germany

9. 1st Department of Medicine, Section of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

Abstract

AbstractAdherent-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.

Funder

Else-Kröner-Fresenius-Stiftung

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,Immunology and Allergy

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