Integrin αVß6 - autoantigen and driver of epithelial remodeling in colon and bile ducts in primary sclerosing cholangitis and inflammatory bowel disease.

Dominik Roth, Miriam M Düll, Ludwig J Horst, Aylin Lindemann, Xenia Malzer, Kristina Koop, Sebastian Zundler, Marcel Vetter, André Jefremow, Raja Atreya, Carol Geppert, Sören Weidemann, Maximilian J Waldner, Peter Dietrich, Claudia Günther, Luis E Munoz, Martin Herrmann, Alexander Scheffold, Markus F Neurath, Jürgen Siebler, Christoph Schramm, Andreas E Kremer, Moritz Leppkes
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Abstract

Objective: Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified which strongly associate with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti- αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease or other cholestatic liver diseases and their persistence after proctocolectomy.

Design: We detected anti- αVβ6 by an enzyme-linked immunosorbent assay in sera collected at two German tertiary centers, including healthy controls (N=62), UC (N=36), Crohn's disease (CD, N=65), PSC-IBD (78 samples from N=41 patients), PSC without IBD (PSC, 41 samples from N=18 patients), primary biliary cholangitis (PBC, N=24), autoimmune hepatitis (AIH, N=32), secondary sclerosing cholangitis (SSC, N=12) and metabolic dysfunction-associated steatotic liver disease (MASLD, N=24). Additionally, sera after proctocolectomy were studied (44 samples / N= 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections and colon of PSC patients.

Results: Anti- αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti- αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease.

Conclusion: Anti- αVβ6 frequently occur in patients suffering from PSC, especially in PSC-IBD. Anti- αVß6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.

整合素αVß6--原发性硬化性胆管炎和炎症性肠病结肠和胆管上皮重塑的自身抗原和驱动因素。
目的:最近发现,针对上皮粘附蛋白整合素αVβ6的自身抗体与溃疡性结肠炎(UC)密切相关。我们旨在阐明原发性硬化性胆管炎(PSC)、与之相关的炎症性肠病或其他胆汁淤积性肝病中是否存在抗整合素αVβ6(抗αVβ6),以及它们在直肠切除术后是否持续存在:我们通过酶联免疫吸附试验检测了德国两家三级医疗中心采集的血清中的抗αVβ6,包括健康对照组(62例)、UC(36例)、克罗恩病(CD,65例)、PSC-IBD(来自41例患者的78份样本)、原发性胆汁性胆管炎(PBC,24 例)、自身免疫性肝炎(AIH,32 例)、继发性硬化性胆管炎(SSC,12 例)和代谢功能障碍相关性脂肪肝(MASLD,24 例)。此外,还研究了直肠切除术后的血清(44 份样本/10 名患者)。对 PSC 患者的肝脏、手术切除的大胆管和结肠组织样本进行了免疫荧光分析:结果:91%的 UC、17%的 CD、73%的 PSC-IBD、39%的 PSC、4%的 PBC、14%的 AIH 以及 0%的健康对照组、SSC 或 MASLD 患者出现了抗αVβ6。整合素αVβ6在胆管和结肠的疾病相关上皮中选择性表达。抗αVβ6水平与PSC-IBD的肠道疾病活动度有中度相关性,但与胆道疾病的相关性较弱:结论:抗αVβ6经常出现在PSC患者中,尤其是在PSC-IBD患者中。抗αVβ6水平与PSC-IBD中的IBD活动呈正相关,但也可能发生在无临床表现的PSC IBD患者中。
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