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.
Alexander
Jessy J
JJ
Section of Nephrology, The University of Chicago, 5841 S. Maryland Avenue, MC5100, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Pickering
Matthew C
MC
Haas
Mark
M
Osawe
Iyabo
I
Quigg
Richard J
RJ
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001792:Blood Platelets / Q000276:immunology; D002908:Chronic Disease; D017242:Complement Factor H / Q000235:genetics* / Q000276:immunology*; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012713:Serum Sickness / Q000150:complications / Q000276:immunology* / Q000473:pathology
D000936:Antigen-Antibody Complex; C493495:CFH protein, human; D017242:Complement Factor H