A novel CRIg‐targeted complement inhibitor protects cells from complement damage
A novel CRIg‐targeted complement inhibitor protects cells from complement damage
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DOI：
10.1096/fj.14-258046
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发表时间：
2014-11
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通讯作者：
Q. Qiao;Xiaoyan Teng;Na Wang;R. Lu;Lin Guo;Xin Zhang;Yiqun Du;Wenjuan Wang;Suning Chen;Qian Wu;Guangsheng He;Yingwei Wang;Weiguo Hu
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作者：
Q. Qiao;Xiaoyan Teng;Na Wang;R. Lu;Lin Guo;Xin Zhang;Yiqun Du;Wenjuan Wang;Suning Chen;Qian Wu;Guangsheng He;Yingwei Wang;Weiguo Hu
补体的不适当激活可能导致各种免疫性疾病。旁路途径（AP）在补体激活过程中占主导地位，无论起始途径如何。因此，主要的AP调节因子H（FH）作为一种有吸引力的治疗干预具有很大的潜力。此外，免疫球蛋白超家族的补体受体（CRIg）已被证明抑制AP，并且更值得注意的是，仍然特异性结合C3 b/iC 3b。因此，我们通过连接CRIg和FH的功能结构域开发了新型CRIg靶向补体抑制剂，我们将其称为CRIg-FH和CRIg-L-FH。CRIg-L-FH比CRIg-FH略强，可显著抑制AP和经典途径（CP）介导的溶血，并成功消除C3 b/iC 3b沉积。动力学分析进一步揭示，CRIg/FH的结合亲和力常数（KD）在微摩尔范围内，与其与补体攻击的细胞的持久结合一致。CRIg‐L‐FH有效保护阵发性睡眠性血红蛋白尿症（PNH）患者的异常红细胞免受AP和CP介导的补体损伤（IC 50分别为22.43和64.69 nM）。此外，在系膜增生性肾小球肾炎（MPGN）大鼠模型中，发现CRIg-L-FH可抑制抗Thy 1抗体诱导的补体激活。因此，CRIg-L-FH保护肾小球系膜细胞（GMC）免受补体介导的损伤和增殖性病变。这些发现强烈表明CRIg/FH是一系列补体介导疾病的潜在治疗药物候选者。乔启刚，Teng，X.，王，N.，卢，R.，Guo，L.，中国科学院，张，X.，杜，Y.，王伟，陈淑仪，吴昆，他，G.，王玉，和Hu，W.，一种新型CRIg靶向补体抑制剂可保护细胞免受补体损伤。FASEB J.28，4986-4999（2014）。www.fasebj.org
The inappropriate activation of complement may contribute to various immune diseases. The alternative pathway (AP) predominates during complement activation regardless of the initiating pathways. Hence, the main AP regulator factor H (FH) holds great potential as an attractive therapeutic intervention. In addition, complement receptor of the immunoglobulin superfamily (CRIg) has been demonstrated to inhibit AP and, more notably, still specifically binds to C3b/iC3b. We thus developed novel CRIg‐targeted complement inhibitors by connecting the functional domains of CRIg and FH, which we termed CRIg‐FH and CRIg‐L‐FH. CRIg‐L‐FH, slightly more potent than CRIg‐FH, considerably inhibited both AP‐ and also classical pathway (CP)‐mediated hemolysis and successfully eliminated the deposition of C3b/iC3b. Kinetic analysis further revealed that the binding affinity constant (KD) of CRIg/FH was in the micromolar range, consistent with its long‐lasting binding to complement‐attacked cells. CRIg‐L‐FH efficiently protected aberrant erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH) from AP‐and CP‐mediated complement damage (IC50 was 22.43 and 64.69 nM, respectively). Moreover, CRIg‐L‐FH was found to inhibit complement activation induced by the anti‐Thy1 antibody in a mesangiopro‐liferative glomerulonephritis (MPGN) rat model. Hence, CRIg‐L‐FH protects glomerular mesangial cells (GMCs) from complement‐mediated injury and proliferative lesions. These findings strongly suggest that CRIg/FH is a potential therapeutic drug candidate for a range of complement‐mediated diseases.—Qiao, Q., Teng, X., Wang, N., Lu, R., Guo, L., Zhang, X., Du, Y., Wang, W., Chen, S., Wu, Q., He, G., Wang, Y., and Hu, W., A novel CRIg‐targeted complement inhibitor protects cells from complement damage. FASEB J. 28, 4986–4999 (2014). www.fasebj.org