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Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease
Gut ( IF 23.0 ) Pub Date : 2017-08-01 , DOI: 10.1136/gutjnl-2017-314548
Lowiek M Hubers , Harmjan Vos , Alex R Schuurman , Robin Erken , Ronald P Oude Elferink , Boudewijn Burgering , Stan F J van de Graaf , Ulrich Beuers

Objective Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD. Design We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry. Results Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. Conclusion Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

中文翻译:

在 IgG4 相关疾病中,膜联蛋白 A11 被 IgG4 和 IgG1 自身抗体靶向

目的免疫球蛋白 G4 相关疾病(IgG4-RD)是一种多器官免疫介导的疾病,主要累及胆道(IgG4 相关胆管炎,IAC)和胰腺(自身免疫性胰腺炎,AIP)。我们最近在 IAC/AIP 患者的血液和受影响的组织中发现了高度扩增的 IgG4+ B 细胞受体克隆,表明参与启动和/或维持炎症反应的特定(自身)抗原刺激。本研究旨在鉴定负责 IgG4-RD 中 IgG4+ B 细胞克隆扩增的(自身)抗原。设计 我们筛选了 IAC/AIP 患者 (n=50) 的血清,与原发性硬化性胆管炎 (PSC) 和胰胆管恶性肿瘤 (n=47) 患者的对照血清相比,在免疫印迹上对人 H69 胆管细胞裂解物的反应性。随后,对靶抗原进行免疫沉淀并通过质谱法进行分析。结果 在暴露于 9 名 IAC/AIP 患者血清的人 H69 胆管细胞裂解物中检测到对 56 kDa 蛋白的显着反应性。亲和纯化和质谱分析鉴定了膜联蛋白 A11,一种钙依赖性磷脂结合蛋白。仅在胆道/胰腺/唾液腺 IgG4-RD 患者的血清中检测到膜联蛋白 A11 特异性 IgG4 和 IgG1 抗体,而在具有 PSC 和胰胆管恶性肿瘤的疾病模拟物中未检测到。表位分析显示,在 IAC/AIP 患者之间共有 IgG1 和 IgG4 自身抗体靶向的两个膜联蛋白 A11 表位,并且 IgG4 抗体阻断了 IgG1 抗体与共有的膜联蛋白 A11 表位的结合。
更新日期:2017-08-01
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