University of Leicester, Mayer IgA Nephropathy Laboratory, University Road, LE1 7RH, Leicester, United Kingdom.
University of Leicester, Mayer IgA Nephropathy Laboratory, University Road, LE1 7RH, Leicester, United Kingdom.
J Autoimmun. 2019 Dec;105:102309. doi: 10.1016/j.jaut.2019.102309. Epub 2019 Aug 9.
IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a major cause of chronic kidney disease and failure. IgAN is driven by an autoimmune reaction against galactose-deficient IgA1 that results in the generation of autoantibodies and large IgG-IgA immune complexes. Immune complexes accumulate in the glomerular mesangium causing chronic inflammation and renal scarring. A significant proportion of IgAN patients develop end-stage kidney disease and require dialysis or transplantation. Currently, there are no approved specific therapies that can ameliorate the systemic autoimmune reaction in IgAN and no biomarkers that can predict renal inflammation and scarring. In this study, we used shotgun LC-MS/MS proteomics to compare small volumes of urine from healthy subjects and IgAN patients. We identified multiple urine proteins with unknown renal or IgAN function. Our attention was captured by the increase of phosphatidylethanolamine binding protein-4 (PEBP4) in IgAN urine. The function of PEBP4 in IgAN or renal disease is unknown. Increased levels of urine and serum PEBP4 were subsequently validated in different cohorts of IgAN patients and PEBP4 was linked to declining kidney function in IgAN. Strong PEBP4 staining was sporadically seen in IgAN kidney biopsies, colocalising with IgA in glomeruli and in the lumen of kidney tubules. In a small number of IgAN biopsies, PEBP4 colocalised with IgA and CD19 while the increased excretion of PEBP4 in IgAN urine was accompanied by increased excretion of classic B-cell factors BAFF, BCMA and TACI as well as IgA and IgG. PEBP4 is a new IgAN-related protein with unknown function and a likely renal disease marker in urine and serum.
IgA 肾病（IgAN）是全球最常见的肾小球肾炎，也是慢性肾脏病和衰竭的主要原因。IgAN 是由针对半乳糖缺乏 IgA1 的自身免疫反应驱动的，导致产生自身抗体和大 IgG-IgA 免疫复合物。免疫复合物在肾小球系膜中积聚，导致慢性炎症和肾脏瘢痕形成。相当一部分 IgAN 患者发展为终末期肾病，需要透析或移植。目前，尚无批准的专门疗法可以改善 IgAN 中的系统性自身免疫反应，也没有可以预测肾脏炎症和瘢痕形成的生物标志物。在这项研究中，我们使用鸟枪法 LC-MS/MS 蛋白质组学比较了健康受试者和 IgAN 患者的小体积尿液。我们鉴定出了多种具有未知肾脏或 IgAN 功能的尿液蛋白。我们注意到 IgAN 尿液中磷酸乙醇胺结合蛋白 4（PEBP4）的增加。PEBP4 在 IgAN 或肾脏疾病中的功能尚不清楚。随后在不同队列的 IgAN 患者中验证了尿液和血清中 PEBP4 水平的升高，并且发现 PEBP4 与 IgAN 患者的肾功能下降有关。IgAN 肾活检中偶尔可见强的 PEBP4 染色，与肾小球和肾小管腔中的 IgA 共定位。在少数 IgAN 活检中，PEBP4 与 IgA 和 CD19 共定位，而 IgAN 尿液中 PEBP4 的排泄增加伴随着经典 B 细胞因子 BAFF、BCMA 和 TACI 以及 IgA 和 IgG 的排泄增加。PEBP4 是一种新的与 IgAN 相关的蛋白，其功能未知，可能是尿液和血清中的肾脏疾病标志物。
