Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulonephritis 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 Cfh −/− 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.