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

Jessy J. Alexander^*, Matthew C. Pickering, Mark Haas, Iyabo Osawe^* and Richard J. Quigg^*

^* Section of Nephrology, The University of Chicago, Chicago, Illinois; Rheumatology Section, Imperial College, Hammersmith Campus, London, United Kingdom; and the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence to: Dr. Jessy J. Alexander, Section of Nephrology, The University of Chicago, 5841 S. Maryland Avenue, MC5100, Chicago, IL 60637, Phone: 773-702-4796; Fax: 773-702-5818; jalexand{at}medicine.bsd.uchicago.edu

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.

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