Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo: α-Enolase and Annexin Al
Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo: α-Enolase and Annexin Al
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DOI：
10.1681/asn.2013090987
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发表时间：
2014-11-01
影响因子：
13.6
通讯作者：
Ghiggeri, Gian Marco
中科院分区：
文献类型：
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作者：
Bruschi, Maurizio;Sinico, Renato Alberto;Ghiggeri, Gian Marco
人类狼疮性肾炎(LN)自身免疫的肾脏靶点尚不清楚。我们试图从LN患者的肾活检样本中识别自身抗体和肾小球靶标抗原，并确定是否可以在循环中检测到相同的自身抗体。从20例LN患者的肾活检标本中显微解剖肾小球，并用蛋白质组学技术对其进行特征分析。对系统性红斑狼疮(SLE)合并和不合并LN及其他肾小球肾炎患者的血清样本进行了检测。肾小球免疫球蛋白识别11种足细胞抗原，其反应性因LN病理而异。值得注意的是，分别在11个活检样本和10个活检样本中检测到了针对阿尔法烯醇化酶和膜联蛋白AI的IgG2自身抗体，并且这些抗体在其他自身抗体中占主导地位。免疫组织化学显示肾小球内α-烯醇化酶或膜联蛋白AI与IgG2共存。大多数LN患者血清抗-α-烯醇化酶(>；15 mg/L)IgG2和/或抗Annexin A1(>；2.7 mg/L)IgG2水平较高，而其他肾小球肾炎患者则未检测到，并确定了两个队列：抗-α-enolase高/低抗Annexin A1-IgG2组和低抗-α-enolase/高抗Annexin Al-IgG2组。LN患者治疗12个月后，两种自身抗体水平均显著下降。抗α-烯醇化酶IgG2识别α-烯醇化酶的特定表位，且不与dsDNA交叉反应。此外，来自易患狼疮的MRL-LPR/LPR小鼠的致肾病单抗IgG2(克隆H147)识别人类α-烯醇化酶，这表明动物模型与人类LN之间存在同源性。这些数据显示了LN中的多抗体成分，其中针对阿尔法烯醇化酶和膜联蛋白A1的IgG2自身抗体在肾小球中占主导地位，并可在血清中检测到。
Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against alpha-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of a-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-alpha-enolase (>15 mg/L) IgG2 and/or anti-annexin Al (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-alpha-enolase/low anti-annexin Al IgG2 and patients with low anti-alpha-enolase/high anti-annexin Al IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-alpha-enolase IgG2 recognized specific epitopes of alpha-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human alpha-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against alpha-enolase and annexin Al predominate in the glomerulus and can be detected in serum.