Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.
Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.
复制标题
DOI：
10.1056/nejmoa1409354
复制
发表时间：
2014-12-11
期刊：
影响因子：
--
通讯作者：
Lambeau G
中科院分区：
文献类型：
--
作者：
Tomas NM;Beck LH Jr;Meyer-Schwesinger C;Seitz-Polski B;Ma H;Zahner G;Dolla G;Hoxha E;Helmchen U;Dabert-Gay AS;Debayle D;Merchant M;Klein J;Salant DJ;Stahl RAK;Lambeau G
特发性膜性肾病是一种自身免疫性疾病。在大约70%的患者中，它与抗磷脂酶A2受体1(PLA2R1)的自身抗体有关。其余患者的抗原靶向尚不清楚。使用Western blotting，我们筛选了特发性膜性肾病患者、其他肾小球疾病患者和健康对照组的血清样本，以检测针对人类天然肾小球蛋白的抗体。我们部分纯化了一个可能的新抗原，用消化后的多肽进行了鉴定，并通过重组蛋白表达分析、免疫沉淀和免疫组织化学分析对结果进行了验证。欧洲队列中44名患者中的6名患者和波士顿队列中110名抗PLA2R1阴性的特发性膜性肾病患者中的9名患者的血清样本识别出一种大小为250kD的肾小球蛋白。74例抗PLA2R1抗体阳性的特发性膜性肾病患者、76例其他肾小球疾病患者和44例健康对照的血清标本均未出现抗PLA2R1抗体反应。虽然这个新发现的抗原与PLA2R1明显不同，但它具有一些生化特征，如N-糖基化、膜定位以及仅在非还原条件下与血清发生反应。质谱仪鉴定该抗原为凝血酶敏感蛋白-1结构域7A(THSD7A)。所有反应血清样本均识别重组THSD7A和免疫沉淀的THSD7A来自肾小球裂解物。此外，患者活检标本的免疫组织化学分析显示，THSD7A定位于足细胞，其中一例标本中的IgG是THSD7A的特异性抗体。在我们的队列中，154名特发性膜性肾病患者中有15名患者有抗THSD7A的循环自身抗体，但没有抗PLA2R1的自身抗体，这一发现表明有一组独特的患者患有这种疾病。(由法国国家科学研究中心和其他机构资助。)
Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1–negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were sero-positive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A. In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.)