Anti-Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases
Anti-Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases
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DOI：
10.4049/jimmunol.1402770
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发表时间：
2015-06-01
影响因子：
4.4
通讯作者：
Dragon-Durey, Marie-Agnes
中科院分区：
文献类型：
--
作者：
Blanc, Caroline;Togarsimalemath, Shambhuprasad Kotresh;Dragon-Durey, Marie-Agnes
针对因子H(FH)的自身抗体是一种主要的补体途径调节蛋白，在非典型溶血性尿毒症综合征(AHUS)中已被很好地描述，但在替代途径介导的肾小球疾病(GP)中的描述较少。在这项研究中，我们研究了17例抗FH抗体阳性的GP患者。收集临床资料，并与抗-FH相关aHUS患者的生物学特征进行比较。与aHUS患者相比，GP患者不存在含FH的循环免疫复合物，其抗FH免疫球蛋白对FH的亲和力较弱。功能研究表明，这些抗体没有引起FH细胞表面保护或FH与其配体结合的干扰。然而，从3例患者中分离的抗FH免疫球蛋白能够影响FH的因子I辅因子活性。表位图谱表明，FH的N-末端结构域是GP患者免疫球蛋白的主要结合部位。在GP患者中未发现与aHUS患者抗FH抗体相关的CFHR1和CFHR3基因纯合性缺失。最后，抗FH抗体在儿童GP患者中经常与C3肾病因子的存在相关，在成人GP患者中，抗FH抗体经常与单克隆性丙种球蛋白病相关，后者在与H因子的反应中经常表现出Ig L链限制。这些数据为深入了解aHUS和GP之间的病理生理差异提供了更深层次的见解，显示了抗FH抗体的异质性。
Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathwaymediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Abassociated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.