Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany.
Department of Rheumatology, University of Schleswig-Holstein, Lübeck, Germany.
Inflamm Bowel Dis. 2020 Nov 19;26(12):1856-1868. doi: 10.1093/ibd/izaa069.
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.
黏附侵袭性大肠杆菌被认为在炎症性肠病（IBD）的病理生理学中起关键作用。针对细菌黏附素 FimH 的肠道受体糖蛋白 2（GP2）的不同剪接变体的自身抗体在 IBD 患者中经常出现。因此，我们旨在从功能上表征针对 GP2 的自身抗体，将其作为 IBD 病理生理学的一个潜在部分。在体外，GP2 剪接变体 4（GP2#4）而非变体 2在肠道 M 或 L 细胞上表达，在 IBD 患者中表达模式升高。肿瘤坏死因子（TNF）-α可诱导体外表达 GP2#4。与 IBD 相关的 GP2 自身抗体可抑制 FimH 与 GP2#4 的结合，并在接受抗 TNF-α 治疗的具有回肠结肠炎表现的克罗恩病患者中减少。在体内，在黏附侵袭性细菌感染前针对 GP2 进行免疫的小鼠显示出更严重的肠道炎症。总之，针对肠道表达的 GP2#4 的自身免疫反应导致有鞭毛的细菌更紧密地附着在肠上皮上，从而可能推动 IBD 的病理生理学。
