Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy
Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy
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DOI：
10.1172/jci85265
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Stahl, Rolf A. M.
中科院分区：
文献类型：
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作者：
Tomas, Nicola M.;Hoxha, Elion;Stahl, Rolf A. M.
膜性肾病（MN）是成人肾病综合征最常见的原因，三分之一的患者发展为终末期肾病（ESRD）。针对足细胞表面抗原磷脂酶A（2）受体1（PLA（2）R1）和最近鉴定的含血小板反应蛋白1型结构域7A（THSD 7A）的循环自身抗体被认为是大多数患者的疾病原因。然而，这些抗体的致病性尚未得到直接证实。在这里，我们报告了一名男性患者的分析和表征THSD7A相关的MN谁进展到终末期肾病，随后接受肾移植。MN移植后迅速复发。在肾移植物中观察到THSD7A的增强染色，并且在移植前后的血清中存在可检测的抗THSD7A抗体，这表明这些抗体诱导了肾移植物中MN的复发。与PLA（2）R1相反，THSD 7A在人和鼠足细胞上表达，使得能够评估抗THSD 7A抗体是否在小鼠中引起MN。我们证明了人抗THSD7A抗体特异性结合足细胞足突上的鼠THSD7A，诱导蛋白尿，并启动MN典型的组织病理学模式。此外，抗THSD7A抗体在原代鼠肾小球上皮细胞以及人胚肾293细胞中诱导显著的细胞骨架重排。我们的研究结果支持抗THSD7A抗体在MN发展中的致病作用。
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, and one-third of patients develop end-stage renal disease (ESRD). Circulating autoantibodies against the podocyte surface antigens phospholipase A(2) receptor 1 (PLA(2)R1) and the recently identified thrombospondin type 1 domain-containing 7A (THSD7A) are assumed to cause the disease in the majority of patients. The pathogenicity of these antibodies, however, has not been directly proven. Here, we have reported the analysis and characterization of a male patient with THSD7A-associated MN who progressed to ESRD and subsequently underwent renal transplantation. MN rapidly recurred after transplantation. Enhanced staining for THSD7A was observed in the kidney allograft, and detectable anti THSD7A antibodies were present in the serum before and after transplantation, suggesting that these antibodies induced a recurrence of MN in the renal transplant. In contrast to PLA(2)R1, THSD7A was expressed on both human and murine podocytes, enabling the evaluation of whether anti THSD7A antibodies cause MN in mice. We demonstrated that human anti-THSD7A antibodies specifically bind to murine THSD7A on podocyte foot processes, induce proteinuria, and initiate a histopathological pattern that is typical of MN. Furthermore, anti-THSD7A antibodies induced marked cytoskeletal rearrangement in primary murine glomerular epithelial cells as well as in human embryonic kidney 293 cells. Our findings support a causative role of anti-THSD7A antibodies in the development of MN.