III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Institut für Medizinische Biometrie & Epidemiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Front Immunol. 2018 Dec 20;9:3035. doi: 10.3389/fimmu.2018.03035. eCollection 2018.
Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A Receptor 1 (PLAR1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLAR1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLAR1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLAR1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLAR1- or THSD7A-antibodies.
膜性肾病（MN）是一种由循环抗体与肾脏足细胞抗原结合引起的自身免疫性疾病。几十年来，原发性 MN 一直被认为是一种未指明的 IgG4 驱动的自身免疫发生，而继发性 MN 与其他疾病有关，尤其是癌症，与 IgG4 无关。尽管原发性和与恶性肿瘤相关的 MN 的免疫机制被认为是不同的，但这从未被系统地评估过。磷脂酶 A 受体 1（PLAR1）和血小板反应蛋白 1 型域包含 7A（THSD7A）的鉴定作为 MN 的靶抗原允许进行基于发病机制的鉴别诊断。最近的数据表明，肿瘤中 THSD7A 表达增加与 THSD7A 抗体阳性 MN 之间存在分子联系，提示恶性肿瘤相关和原发性 MN 的发病机制相似。为了更好地定义潜在的免疫过程，我们系统地分析了 76 例 PLAR1 相关 MN 和 41 例 THSD7A 相关 MN 患者血清中循环抗原特异性 IgG 亚类与同期恶性肿瘤和疾病结局的关系。研究中有 23 例患者患有恶性肿瘤相关的 MN。我们通过 Western blot 分析了所有患者基线时和 55 名患者随访时血清中抗原特异性 IgG 亚类，应用源自人肾和肺的抗原。在基线时，所有 117 名患者均对 PLAR1 或 THSD7A 产生 IgG4 抗体，而 IgG3、IgG1 和 IgG2 抗体分别在 87%、72%和 26%的患者中发现。原发性与癌症相关的 MN 患者的 IgG 亚类分布无差异，与疾病结局也无关联。此外，PLAR1 和 THSD7A 的免疫荧光和 Western blot 分析显示，足细胞和肺细支气管均表达 PLAR1 和 THSD7A。每种抗原特异性 IgG 亚类在这两种器官中均具有相同的结合，并且自身抗体仅在非还原条件下结合相应的抗原。我们得出结论，抗原特异性 IgG 亚类不能区分原发性与癌症相关的 MN，也不能预测疾病预后。这些数据支持这样一种观点，即一条共同的途径可能导致由 PLAR1 或 THSD7A 抗体引起的原发性和癌症相关的 MN。
