Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 Valbonne Sophia Antipolis, France.
Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 Valbonne Sophia Antipolis, France; Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Service de Néphrologie, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France.
Kidney Int. 2019 Mar;95(3):666-679. doi: 10.1016/j.kint.2018.10.024.
Autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) are emerging as biomarkers to classify membranous nephropathy (MN) and to predict outcome or response to treatment. Anti-THSD7A autoantibodies are detected by Western blot and indirect immunofluorescence test (IIFT). Here, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) optimized for quantitative detection of anti-THSD7A autoantibodies. Among 1012 biopsy-proven MN patients from 6 cohorts, 28 THSD7A-positive patients were identified by ELISA, indicating a prevalence of 2.8%. By screening additional patients, mostly referred because of PLA2R1-unrelated MN, we identified 21 more cases, establishing a cohort of 49 THSD7A-positive patients. Twenty-eight patients (57%) were male, and male patients were older than female patients (67 versus 49 years). Eight patients had a history of malignancy, but only 3 were diagnosed with malignancy within 2 years of MN diagnosis. We compared the results of ELISA, IIFT, Western blot, and biopsy staining, and found a significant correlation between ELISA and IIFT titers. Anti-THSD7A autoantibodies were predominantly IgG4 in all patients. Eight patients were double positive for THSD7A and PLA2R1. Levels of anti-THSD7A autoantibodies correlated with disease activity and with response to treatment. Patients with high titer at baseline had poor clinical outcome. In a subgroup of patients with serial titers, persistently elevated anti-THSD7A autoantibodies were observed in patients who did not respond to treatment or did not achieve remission. We conclude that the novel anti-THSD7A ELISA can be used to identify patients with THSD7A-associated MN and to monitor autoantibody titers during treatment.
抗磷脂酶 A2 受体 1（PLA2R1）和血小板反应蛋白 1 型域包含 7A（THSD7A）自身抗体作为分类膜性肾病（MN）和预测治疗效果或反应的生物标志物而出现。抗 THSD7A 自身抗体通过 Western blot 和间接免疫荧光试验（IIFT）检测。在此，我们开发了一种优化的用于定量检测抗 THSD7A 自身抗体的敏感酶联免疫吸附试验（ELISA）。在来自 6 个队列的 1012 例经活检证实的 MN 患者中，通过 ELISA 鉴定出 28 例 THSD7A 阳性患者，表明患病率为 2.8%。通过对主要因 PLA2R1 无关 MN 而转诊的额外患者进行筛查，我们又鉴定出 21 例病例，建立了一个包含 49 例 THSD7A 阳性患者的队列。28 例患者（57%）为男性，男性患者比女性患者年龄大（67 岁比 49 岁）。8 例患者有恶性肿瘤病史，但只有 3 例在 MN 诊断后 2 年内被诊断为恶性肿瘤。我们比较了 ELISA、IIFT、Western blot 和活检染色的结果，发现 ELISA 和 IIFT 滴度之间存在显著相关性。在所有患者中，抗 THSD7A 自身抗体主要为 IgG4。8 例患者 THSD7A 和 PLA2R1 均为双阳性。抗 THSD7A 自身抗体水平与疾病活动度和治疗反应相关。基线时滴度高的患者临床结局较差。在具有系列滴度的患者亚组中，未对治疗有反应或未达到缓解的患者观察到抗 THSD7A 自身抗体持续升高。我们的结论是，新型抗 THSD7A ELISA 可用于鉴定 THSD7A 相关 MN 患者，并在治疗期间监测自身抗体滴度。
