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

Abstract

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. 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. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cfh

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

“…Consistent with past studies in this model, the albuminuria was relatively mild. 10,11 At each time point, DAF KO and DKO mice tended to have higher urinary albumin excretion, although the differences among the four groups did not reach statistical significance. All BUN levels obtained at 3 and 6 weeks of CSS were within the normal range (data not shown), indicating that the ICGN induced in this model did not appear to affect glomerular filtration.…”

“…[59][60][61] Factor H is also important in the CSS model of ICGN, as it leads to C3b inactivation in the glomerular capillary wall, a key factor to dampen inflammation in this model. 10,62 Taking all available information together, it appears that DAF and CFH are relevant to C3 activation in glomerular capillary wall cellular and non-cellular sites, respectively.…”

“…7,8 IC-mediated GN in this model clearly has a dependence on complement activation. [9][10][11][12] To dissect the roles of early and late complement activation cascades in this disease model, we focused on their relevant complement regulators, DAF and CD59. CSS was induced in DAF-and CD59-deficient mice, as well as mice doubly deficient in both.…”

Abnormal Immune Complex Processing and Spontaneous Glomerulonephritis in Complement Factor H-Deficient Mice with Human Complement Receptor 1 on Erythrocytes

“…The spontaneous disease in CFH 2/2 mice requires C5 (but not C6) and C factor I, presumably to generate proinflammatory C5a and to create iC3b as ligand for b2-integrins on inflammatory cells, respectively (18,20,21). Whereas C57BL/6 CFH 2/2 mice have no evident glomerular disease, and wild type C57BL/6 are resistant to developing GN in chronic serum sickness *Department of Medicine and (CSS) induced by repetitive immunization with heterologous apoferritin, all C57BL/6 CFH 2/2 mice develop GN in CSS (22).…”

Involvement of Protein Kinase C in Reduction of Aggregated Protein and Phosphorylation of CREB in Glomeruli

“…iC is associated with the development of glomerulonephritis through the activation of complements and the infiltration of neutrophils and monocytes into glomeruli [1,2].…”