Complement factor H limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness
Complement factor H limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness
复制标题
DOI：
10.1681/asn.2004090778
复制
发表时间：
2005-01-01
影响因子：
13.6
通讯作者：
Quigg, RJ
中科院分区：
文献类型：
--
作者：
Alexander, JJ;Pickering, MC;Quigg, RJ
因子H是血浆中的主要补体调节剂。在人类和实验动物的膜增生性肾小球肾炎中都涉及到H因子的缺失。已经表明啮齿动物血小板上的H因子在其将免疫复合物运输到单核吞噬细胞系统的作用方面与人红细胞补体受体1类似。用异源脱铁铁蛋白每天免疫C57 BL/6因子H缺陷小鼠（Cfh（-/-））和野生型（wt）对照，持续5周，以研究慢性血清病GN模型。在6至8周龄小鼠中开始免疫，这是在一些Cfh（-/-）动物中自发性膜增生性肾小球肾炎发生之前。与野生型小鼠相比，Cf-/-小鼠肾小球中IgG免疫复合物的肾小球沉积定性和定量增加。与肾小球免疫复合物的增加一致，可能是由于旁路途径补体激活，Cfh（-/-）小鼠肾小球C3沉积增加。野生型小鼠未出现肾小球病变。相反，Cfh（-/-）小鼠出现弥漫性增生性GN伴局灶性新月体和肾小球硬化。此外，Cfh（-/-）肾小球中IV型胶原、纤连蛋白和层粘连蛋白mRNA的表达显著增加。这些数据表明血小板相关因子H在处理免疫复合物和限制其在肾小球中的积累中的作用。一旦沉积在肾小球中，过度的补体活化可导致肾小球炎症和瘢痕形成表型的快速发展。
Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulortephritis in both humans and experimental animals. It has been shown that factor H on rodent platelets functions analogously to human erythrocyte complement receptor 1 in its role to traffic immune complexes to the mononuclear phagocyte system. C57BL/6 factor H-deficient mice (Cfh(-/-)) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model. Immunizations were started in 6- to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh(-/-) animals. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cf-/- mice compared with wt mice. Consistent with the increase in glomerular immune complexes and possibly because of alternative pathway complement activation, Cfh(-/-) mice had increased glomerular C3 deposition. Wt mice developed no glomerular pathology. In contrast, Cfh(-/-) mice developed diffuse proliferative GN with focal crescents and glomerulosclerosis. In addition, there was significantly increased expression of collagen IV, fibronectin, and laminin mRNA in Cfh(-/-) glomeruli. These data show a role for platelet-associated factor H to process immune complexes and limit their accumulation in glomeruli. Once deposited in glomeruli, excessive complement activation can lead to glomerular inflammation and the rapid development of a scarring phenotype.