Primary membranous nephropathy (MN) is caused by circulating autoantibodies binding to antigens on the podocyte surface. PLA₂R1 is the main target antigen in 70%–80% of cases, but the pathogenesis is unresolved in 10%–15% of patients.

We used native western blotting to identify IgG4 autoantibodies, which bind an antigen endogenously expressed on podocyte membranes, in the serum of the index patient with MN. These IgG4 autoantibodies were used to immunoprecipitate the target antigen, and mass spectrometry was used to identify Netrin G1 (NTNG1). Using native western blot and ELISA, NTNG1 autoantibodies were analyzed in cohorts of 888 patients with MN or other glomerular diseases.

NTNG1 was identified as a novel target antigen in MN. It is a membrane protein expressed in healthy podocytes. Immunohistochemistry confirmed granular NTNG1 positivity in subepithelial glomerular immune deposits. In prospective and retrospective MN cohorts, we identified three patients with NTNG1-associated MN who showed IgG4-dominant circulating NTNG1 autoantibodies, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits. No NTNG1 autoantibodies were identified in 561 PLA₂R1 autoantibodies–positive patients, 27 THSD7A autoantibodies–positive patients, and 77 patients with other glomerular diseases. In two patients with available follow-up of 2 and 4 years, both NTNG1 autoantibodies and proteinuria persisted.

NTNG1 expands the repertoire of target antigens in patients with MN. The clinical role of NTNG1 autoantibodies remains to be defined.

原发性膜性肾病 (MN) 是由循环自身抗体与足细胞表面抗原结合引起的。PLA ₂ R1是70%–80%病例的主要靶抗原，但10%–15%患者的发病机制尚未解决。

我们使用天然蛋白质印迹法来鉴定 MN 指标患者血清中的 IgG4 自身抗体，该抗体与足细胞膜上内源表达的抗原结合。这些 IgG4 自身抗体用于免疫沉淀靶抗原，并使用质谱法来鉴定 Netrin G1 (NTNG1)。使用天然蛋白质印迹和 ELISA，对 888 名 MN 或其他肾小球疾病患者的队列中的 NTNG1 自身抗体进行了分析。

NTNG1 被确定为 MN 中的新靶抗原。它是在健康足细胞中表达的膜蛋白。免疫组织化学证实上皮下肾小球免疫沉积物中颗粒状 NTNG1 阳性。在前瞻性和回顾性 MN 队列中，我们确定了三名 NTNG1 相关 MN 患者，他们表现出 IgG4 为主的循环 NTNG1 自身抗体、肾脏中 NTNG1 表达增强以及肾小球 IgG4 沉积。_{在 561 名 PLA 2} R1 自身抗体阳性患者、27 名 THSD7A 自身抗体阳性患者和 77 名其他肾小球疾病患者中未发现 NTNG1 自身抗体。在随访 2 年和 4 年的两名患者中，NTNG1 自身抗体和蛋白尿持续存在。

NTNG1 扩展了 MN 患者的靶抗原库。NTNG1 自身抗体的临床作用仍有待确定。