特发性膜性肾病的分子发病机制

doi:10.3877/cma.j.issn.2095-3216.2015.06.008

特发性膜性肾病( IMN)是国内外常见的引起成人肾病综合征的病理类型之一。在中国人群中，近年来特发性膜性肾病在原发性肾小球疾病中所占比例明显升高。由于病因及发病机制仍不清楚，以及缺乏预测疾病活动性的生物学标志物，因此目前治疗所带来的经济负担以及药物毒性仍具有争议和挑战。IMN是一种器官特异性的自身免疫性疾病，非炎症性自身抗体与足细胞上的靶抗原结合，在基底膜外侧上皮下形成原位免疫复合物，激活补体，从而引起足细胞损伤和蛋白尿。Heymann肾炎模型是经典的膜性肾病动物模型，然而其靶抗原Megalin并不是人类膜性肾病发生的原因。之后，中性肽链内切酶(NEP)被证实为母胎同种异体产前膜性肾病的靶抗原。直到2009年，磷脂酶A2受体(PLA2R)被证实为IMN的靶抗原。在IMN患者血浆中检测到抗PLA2R-IgG4，其特异性高达100%，敏感性约为70%～80%。抗PLA2R-IgG4滴度可以预测疾病的活动性，其与PLA2R抗原结合形成原位免疫复合物，激活补体凝集素途径，形成C5b-9膜攻击复合物沉积在足细胞上，引起足细胞损伤，导致蛋白尿形成。HLA-DQA1与PLA2R基因多态性均与IMN的发病相关，二者的风险基因具有叠加效应。综上所述，IMN的发生是多种因素共同作用的结果，包括易感基因、靶抗原、自身抗体、补体等，这些研究进展对于IMN的诊断和治疗具有重要意义。

关键词: 特发性膜性肾病, 动物模型, 足细胞, 磷脂酶A2受体, 人类白细胞抗原-DQA1

Idiopathic membranous nephropathy (IMN) is one of the common pathological types of adult nephrotic syndrome in the world. In China, the proportion of IMN among primary glomerular diseases increased obviously in recent years. Because the etiology and the pathogenesis of IMN are not well-known, and there is a lack of biomarkers for predicting activity of IMN, the economic burden and drugs toxicity caused by the treatment remain to be controversial and challenging. IMN is an organ-specific autoimmune disease, in which non-inflammatory autoantibodies can bind target antigens on podocytes, forming subepithelial in-situ immunocomplex on the outside of the glomerular basement membrane that provokes local complement activation so as to cause podocyte injury and proteinuria. The Heymann nephritis model is a classical animal model for MN. However, megalin, which was the target antigen of this model, was not the cause of human IMN. Then, neutral endopeptidase (NEP) was found to be the target antigen of maternal-fetal alloimmunization with antenatal MN. To 2009, phospholipase A2 receptor (PLA2R) was confirmed as the target antigen of IMN. Anti-PLA2R-IgG4 was detected in serum with high specificity of 100% and sensitivity of 70%-80% in IMN patients. Anti-PLA2R-IgG4 could bind PLA2R antigen. Complement lectin pathway was activated by these in-situ immune complex and C5b-9 was generated. C5b-9 membrane attack complex could cause podocytes injury and production of proteinuria. In addition, the level of anti-PLA2R antibodies can predict the activity of the disease. HLA-DQA1 and PLA2R loci are associated with the onset of IMN, and the risk allels of both genes have additive effects. All in all, many factors are involved in the onset of IMN, such as genetic predisposition, target antigens, autoantibodies and complement, etc. These findings are of great significance for the diagnosis and treatment of IMN .

Key words: Idiopathic membranous nephropathy, Animal model, Podocyte, PLA2R, HLA-DQA1

图1 磷脂酶A2受体相关特发性膜性肾病的发病机制

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The molecular pathogenesis of idiopathic membranous nephropathy

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The molecular pathogenesis of idiopathic membranous nephropathy