甘露糖结合凝集素（MBL）缺失参与IgA肾病的发病机制研究

IgA nephropathy (IgAN) is the most common primary glomerular nephropathy with unclear pathogenesis. Episodic gross hematuria within several days of infection is a characteristic clinical feature of IgAN. Mannose binding lectin (MBL) is an important protein in innate immunity. In our previous work, we found that there were significantly more patients with IgAN in MBL deficiency group than MBL sufficiency group who experienced prodromic infection and gross hematuria. The renal survival for the composite outcome was significantly lower in patients with MBL deficient IgAN. MBL deficiency, which is an independent risk factor for IgAN, may be involved in the mechanisms of IgAN pathogenesis. In our preliminary study, patients with IgAN in MBL deficiency group present higher level of galactose deficient IgA1 (Gd-IgA1)，which was proved to be the pathogenic IgA deposited in the mesangial area of glomeruli. In this study, we aimed to elucidate whether the MBL deficiency was involved in the pathogenesis of IgAN through affecting the micro-environment, disturbing more Gd-IgA1 secretion by B cells. This study would illuminate one of the etiologies of IgAN and be meaningful in providing new directions for the diagnosis and treatment of this disease.

IgA肾病是全球最常见的原发性肾小球疾病，该病具体的发病机制目前尚未阐明。IgA肾病患者最典型的一个临床表现是感染后出现发作性肉眼血尿。甘露糖结合凝集素（MBL）是天然免疫重要蛋白，发挥免疫屏障作用。申请者前期研究发现MBL缺失的IgA肾病患者表现出较高比例的前驱感染及肉眼血尿；MBL缺失是影响IgA肾病预后的独立危险因素。提示MBL缺失在IgA肾病的发病及疾病进展中起到了重要的作用，但具体的致病机制不详。在申请者的前期预实验中发现MBL缺失的IgA肾病患者，循环中具有较高水平的O-糖基化异常的IgA1(Gd-IgA1)。既往已明确IgA肾病患者肾组织沉积的致病性的IgA主要为Gd-IgA1。本研究拟通过体外实验，探讨MBL缺失对免疫微环境的影响，从而介导B淋巴细胞产生更多的Gd-IgA1，继而参与本病的发病及进展，为临床防治该病提供新的理论和实验依据。

IgA肾病（IgA nephropathy）是全球最常见的原发性肾小球疾病，在我国IgA肾病占原发性肾小球疾病的比例高达58.2%。该病常累积青壮年且呈慢性进展，约四分之一的患者二十年内进展至终末期肾病，需要透析或移植等肾脏替代治疗，对患者家庭以及社会带来沉重的疾病负担。目前IgA肾病的发病机制并不十分清楚，因此探讨IgA肾病的发病机制成为国内外研究的热点。.IgA肾病患者临床及病理表现多样。其中最重要最典型的一个临床表现是黏膜感染后24-72小时内出现发作性的肉眼血尿。近年来报道，甘露糖结合凝集素（MBL）作为凝集素途径重要的起始蛋白，其血浆中水平过高或过低都影响IgA肾病的肾脏预后。且MBL缺失的IgA肾病患者表现出较高比例的前驱感染及肉眼血尿。本研究纳入2019年1月至2019年12月在我院肾活检病理诊断IgA肾病患者63例，其中MBL缺失的患者5例，占7.9%。本研究发现IgA患者血浆APRIL水平和BAFF水平较正常对照高；MBL缺失的IgA肾病患者血浆APRIL水平和BAFF水平较非MBL缺失的IgA肾病患者高；MBL缺失的IgA肾病患者血浆Gd-IgA1水平较非MBL缺失的IgA肾病患者高；IgA肾病患者血浆中Gd-IgA1与血浆APRIL和BAFF水平呈正相关。与非MBL缺失的IgA肾病患者相比，外周血B淋巴细胞中APRIL、BAFF及TACI和BCMA的mRNA的表达在MBL缺失的IgA肾病患者中较高；商品化来源的APRIL刺激IgA肾病患者来源外周血B淋巴细胞，测上清液中Gd-IgA1水平较刺激前升高；商品化来源的APRIL刺激MBL缺失的IgA肾病患者及非MBL缺失的肾病患者的外周血B淋巴细胞，培养液中Gd-IgA1水平在MBL缺失组明显高于非MBL缺失组，但升高的水平在MBL缺失组及非MBL缺失组间无显著差异。.MBL缺失的IgA肾病患者可能通过B细胞的APRIL的上调表达，通过活化APRIL-TACI/BCMA通路，引起Gd-IgA1水平的升高，进而参与IgA肾病的发生与发展。