Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases.
Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases.
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DOI：
10.3389/fimmu.2016.00542
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发表时间：
2016
影响因子：
7.3
通讯作者：
Pauly D
中科院分区：
文献类型：
--
作者：
Schäfer N;Grosche A;Reinders J;Hauck SM;Pouw RB;Kuijpers TW;Wouters D;Ehrenstein B;Enzmann V;Zipfel PF;Skerka C;Pauly D
人补体因子h相关蛋白-3 （FHR-3）是补体系统的可溶性调节因子。纯合子cfhr3/1缺失是自身免疫性非典型溶血性尿毒症综合征（aHUS）的遗传危险因素，同时也被发现对年龄相关性黄斑变性（AMD）具有保护作用。FHR-3的确切功能还有待进一步研究。我们制备了四种针对FHR-3 （RETC）的小鼠单克隆抗体（mab），与补体因子H （FH）家族无交叉反应性。这些抗体从人血清中检测到FHR-3，平均浓度为1 μg/mL。系统性红斑狼疮、类风湿性关节炎和风湿性多肌痛患者血清中FHR-3水平显著升高，但在AMD或aHUS患者样本中几乎保持不变。此外，通过对老年人类供体视网膜的免疫染色，我们发现小胶质细胞/巨噬细胞在局部产生FHR-3。单克隆抗体RETC-2可调节FHR-3与C3b的结合，但不能调节FHR-3与肝素的结合。有趣的是，FHR-3与FH竞争结合C3b，单克隆抗体RETC-2减少了FHR-3和C3b的相互作用，导致FH结合增加。我们的研究结果揭示了以前未知的FHR-3在类风湿疾病中的全身性参与，以及小胶质细胞/巨噬细胞介导的FHR-3在受损视网膜中的局部作用。我们得出结论，AMD的局部FHR-3/FH平衡是一个潜在的治疗靶点，可以通过我们的特异性单克隆抗体RETC-2调节。
The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.
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影响因子：
30.8
作者：
Hughes, Anne E.;Orr, Nick;Chakravarthy, Usha
通讯作者：
Chakravarthy, Usha
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影响因子：
4.9
作者：
Chen SF;Wang FM;Li ZY;Yu F;Zhao MH;Chen M
通讯作者：
Chen M
DOI：
10.3791/1431
发表时间：
2009-08-03
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Dyballa, Nadine;Metzger, Sabine
通讯作者：
Metzger, Sabine
影响因子：
4.4
作者：
Banda, Nirmal K.;Mehta, Gaurav;Holers, V. Michael
通讯作者：
Holers, V. Michael
DOI：
10.1073/pnas.1219260110
发表时间：
2013-03-19
影响因子：
11.1
作者：
de Jorge, Elena Goicoechea;Caesar, Joseph J. E.;Lea, Susan M.
通讯作者：
Lea, Susan M.