Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy
Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy
复制标题
神经表皮生长因子样蛋白1（NELL-1）相关性膜性肾病
DOI：
10.1016/j.kint.2019.09.014
复制
发表时间：
2020-01-01
影响因子：
19.6
通讯作者：
Ronco, Pierre
中科院分区：
文献类型：
--
作者：
Sethi, Sanjeev;Debiec, Hanna;Ronco, Pierre
膜性肾病的特征是免疫复合物沿肾小球基底膜沉积。 PLA2R 和 THSD7A 分别是 70% 和 1-5% 原发性膜性肾病病例的靶抗原。在其余情况下，目标抗原未知。在此，使用肾小球激光显微切割和质谱分析来鉴定 PLA2R 阴性膜性肾病中的新抗原。对 35 例 PLA2R 阴性膜性肾病患者进行的初步质谱研究显示，在 6 例患者中，编码具有 EGF 样重复序列的神经组织蛋白 NELL-1 的光谱计数很高。质谱法未能在 23 名 PLA2R 相关膜性肾病和 88 名对照者中检测到 NELL-1。通过免疫组织化学对 NELL-1 进行定位，所有 6 例病例的肾小球基底膜均出现明亮的颗粒状 NELL-1 染色。接下来，在 91 例 PLA2R 阴性膜性肾病病例的发现队列中，通过免疫组织化学鉴定出另外 23 例 NELL-1 阳性膜性肾病病例，其中 14 例通过质谱法确诊。因此，126 名 PLA2R 阴性病例中有 29 名 NELL-1 呈阳性。 PLA2R 相关膜性肾病和对照的 NELL-1 染色呈阴性。然后，我们在来自法国和比利时的两个验证队列中的 84 例 PLA2R 和 THSD7A 阴性病例中鉴定出 5 例 NELL-1 阳性膜性肾病病例。通过共聚焦显微镜，IgG 和 NELL-1 共定位于肾小球基底膜。蛋白质印迹分析显示五种可用血清中对 NELL-1 有反应性，但对照血清中没有反应性。 NELL-1阳性膜性肾病的临床和活检结果显示原发性膜性肾病的特征。因此，一部分膜性肾病与 NELL-1 和 IgG 沿肾小球基底膜的积累和共定位以及血清中的抗 NELL-1 抗体相关。因此，NELL-1 定义了原发性膜性肾病的一种独特类型。
Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 colocalized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with antiNELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy.