The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease.
The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease.
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DOI：
10.1074/jbc.m114.630871
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发表时间：
2015-04-10
期刊：
影响因子：
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通讯作者：
Jokiranta TS
中科院分区：
文献类型：
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作者：
Bhattacharjee A;Reuter S;Trojnár E;Kolodziejczyk R;Seeberger H;Hyvärinen S;Uzonyi B;Szilágyi Á;Prohászka Z;Goldman A;Józsi M;Jokiranta TS
背景：目前尚不清楚为什么具有补体因子 H (CFH) 自身抗体的患者缺乏同源 CFHR1 蛋白。结果：鉴定出CFH上的自身抗体表位，并解析了CFHR1相应部分的结构。结论：CFH的自身抗原表位与CFHR1的同源位点结构不同。意义：获得了对自身免疫性非典型溶血性尿毒症综合征中 CFHR1 缺陷导致自身抗体形成的合理解释。非典型溶血性尿毒症综合征 (aHUS) 的特点是补体蛋白突变或补体因子 H (CFH) 自身抗体对宿主细胞进行补体攻击。目前尚不清楚为什么几乎所有自身免疫性 aHUS 患者都缺乏 CFHR1（CFH 相关蛋白 1）。这些患者具有针对 CFH 结构域 19 和 20 (CFH19-20) 的自身抗体，与 CFHR1 结构域 4 和 5 (CFHR14-5) 几乎相同。在这里，使用突变 CFH19-20 构建体对 17 名患者的自身抗体进行结合位点图谱显示，在结构域 20 的环内有一个自身抗体表位簇，紧邻 CFH19-20 和 CFHR14-5 中不同的两个埋藏残基。 CFHR14-5的晶体结构揭示了CFH和CFHR1 C端结构域中自身抗原环构象的差异，解释了一些aHUS患者的自身抗体与CFH19-20和CFHR14-5结合的变化。 CFH 上的自身抗原环似乎总体上是灵活的，因为先前发表的与微生物蛋白 OspE 和唾液酸聚糖结合的 CFH19-20 结构中的构象有所改变。总的来说，我们的数据表明，CFHR1 缺陷与自身免疫性 aHUS 的关联可能是由于 CFHR1 和自身抗原 CFH 表位之间的结构差异所致，这为自身免疫性 aHUS 发病机制中 CFHR1 缺陷提供了新的解释。
Background: It is unknown why patients with autoantibodies against complement factor H (CFH) lack homologous CFHR1 protein. Results: The autoantibody epitope on CFH was identified, and the structure of the corresponding part of CFHR1 was solved. Conclusion: The autoantigenic epitope of CFH and its homologous site in CFHR1 are structurally different. Significance: A plausible explanation for formation of autoantibodies due to CFHR1 deficiency in autoimmune atypical hemolytic uremic syndrome was obtained. Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against complement factor H (CFH). It is unknown why nearly all patients with autoimmune aHUS lack CFHR1 (CFH-related protein-1). These patients have autoantibodies against CFH domains 19 and 20 (CFH19–20), which are nearly identical to CFHR1 domains 4 and 5 (CFHR14–5). Here, binding site mapping of autoantibodies from 17 patients using mutant CFH19–20 constructs revealed an autoantibody epitope cluster within a loop on domain 20, next to the two buried residues that are different in CFH19–20 and CFHR14–5. The crystal structure of CFHR14–5 revealed a difference in conformation of the autoantigenic loop in the C-terminal domains of CFH and CFHR1, explaining the variation in binding of autoantibodies from some aHUS patients to CFH19–20 and CFHR14–5. The autoantigenic loop on CFH seems to be generally flexible, as its conformation in previously published structures of CFH19–20 bound to the microbial protein OspE and a sialic acid glycan is somewhat altered. Cumulatively, our data suggest that association of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between CFHR1 and the autoantigenic CFH epitope, suggesting a novel explanation for CFHR1 deficiency in the pathogenesis of autoimmune aHUS.