Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex-Induced Arthritis
Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex-Induced Arthritis
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DOI：
10.4049/jimmunol.1203271
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发表时间：
2013-04-01
影响因子：
4.4
通讯作者：
Holers, V. Michael
中科院分区：
文献类型：
--
作者：
Banda, Nirmal K.;Mehta, Gaurav;Holers, V. Michael
因子H（fH）是旁路途径（AP）的内源性负调节剂，其结合聚阴离子以及补体激活片段C3 b和C3 d。AP对于小鼠中胶原蛋白Ab诱导的关节炎（CAIA）的发展是必要且充分的; AP的正常控制被克服并且损伤发展的机制是未知的。虽然fH主要是一种可溶性循环蛋白，但它也可以以依赖于含有短共有重复序列19和20的羧基末端结构域的方式与组织结合。我们通过给予含有短共有重复序列19和20（rfH 19 -20）的重组负抑制剂（其在体外损害fH功能并放大表面AP活化）来阻断其与组织的结合，从而研究了fH在CAIA中的作用。施用rfH 19 -20而非对照rfH 3 -5显著恶化了野生型和fH（+/-）小鼠的临床疾病活动、组织病理学损伤和滑膜和软骨中的C3沉积。体外研究表明，rfH 19 -20增加了软骨提取物和损伤的成纤维细胞样滑膜细胞上的补体活化，这是关节中补体沉积的两个主要靶标。我们得出结论，内源性fH作出了显着的贡献，通过结合到免疫复合物形成和补体激活的网站，在CAIA的AP抑制。免疫学杂志，2013，190：3560-3569。
Factor H (fH) is an endogenous negative regulator of the alternative pathway (AP) that binds polyanions as well as complement activation fragments C3b and C3d. The AP is both necessary and sufficient to develop collagen Ab-induced arthritis (CAIA) in mice; the mechanisms whereby normal control of the AP is overcome and injury develops are unknown. Although primarily a soluble circulating protein, fH can also bind to tissues in a manner dependent on the carboxyl-terminal domain containing short consensus repeats 19 and 20. We examined the role of fH in CAIA by blocking its binding to tissues through administration of a recombinant negative inhibitor containing short consensus repeats 19 and 20 (rfH19-20), which impairs fH function and amplifies surface AP activation in vitro. Administration of rfH19-20, but not control rfH3-5, significantly worsened clinical disease activity, histopathologic injury, and C3 deposition in the synovium and cartilage in wild-type and fH(+/-) mice. In vitro studies demonstrated that rfH19-20 increased complement activation on cartilage extracts and injured fibroblast-like synoviocytes, two major targets of complement deposition in the joint. We conclude that endogenous fH makes a significant contribution to inhibition of the AP in CAIA through binding to sites of immune complex formation and complement activation. The Journal of Immunology, 2013, 190: 3560-3569.