Laminin 511 is a target antigen in autoimmune pancreatitis
Laminin 511 is a target antigen in autoimmune pancreatitis
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DOI：
10.1126/scitranslmed.aaq0997
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发表时间：
2018-08-08
影响因子：
17.1
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
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作者：
Shiokawa, Masahiro;Kodama, Yuzo;Chiba, Tsutomu
自身免疫性胰腺炎（AIP）是免疫球蛋白G4相关疾病（IgG4-RD）的主要表现，是一种免疫介导的疾病，但目标自身抗原仍不清楚。我们之前报道过 AIP 患者的 IgG 通过结合细胞外基质 (ECM) 诱导小鼠胰腺损伤。在当前的研究中，我们在 AIP 患者中鉴定出了针对层粘连蛋白 511-E8（一种截短的层粘连蛋白 511，ECM 蛋白之一）的自身抗体。通过酶联免疫吸附测定，51 名 AIP 患者中有 26 名 (51.0%) 存在抗层粘连蛋白 511-E8 IgG，但 122 名对照者中只有 2 名 (1.6%) 存在抗层粘连蛋白 511-E8 IgG。由于其他器官中其他层粘连蛋白家族成员的截短形式已被报道，我们证实截短形式的层粘连蛋白511也存在于人和小鼠的胰腺中。对患者胰腺组织的组织学研究显示患者 IgG 和层粘连蛋白 511 共定位。用人层粘连蛋白 511-E8 免疫小鼠可诱导抗体和胰腺损伤，满足人 AIP 的病理标准。 25 名没有层粘连蛋白 511-E8 抗体的 AIP 患者中，有 4 名具有针对整合素 α 6 β 1（一种层粘连蛋白 511 配体）的抗体。携带层粘连蛋白511-E8抗体的AIP患者表现出独特的临床特征，携带层粘连蛋白511-E8抗体的患者患恶性肿瘤或过敏性疾病的频率明显低于未携带层粘连蛋白511-E8抗体的患者。这些自身抗体的发现应有助于了解 AIP 的病理生理学，并可能改善 AIP 的诊断。
Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4-related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti-laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin alpha 6 beta 1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 anti-bodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.