The role of complement in cryoglobulin-induced immune complex glomerulonephritis.
Many forms of glomerulonephritis are triggered by Ab localization in the glomerulus, but the mechanisms by which this induces glomerular inflammation are not fully understood. In this study we investigated the role of complement in a mouse model of cryoglobulin-induced immune complex glomerulonephritis. Several complement-deficient mice on a C57BL/6 and BALB/c genetic background were used and compared with strain-matched, wild-type controls. Cryoglobulinemia was induced by i.p. injection of 6-19 hybridoma cells producing an IgG3 cryoglobulin with rheumatoid factor activity against IgG2a of allotype a present in BALB/c, but not C57BL/6, mice. Thus, the cryoprecipitate in C57BL/6 mice consisted of the IgG3 cryoglobulin only (type I cryoglobulinemia) compared with IgG3-IgG2a complexes in BALB/c (type II cryoglobulinemia). The survival of mice was not affected by complement deficiency. Glomerular influx of neutrophils was significantly less in C3-, factor B-, and C5-deficient mice compared with wild-type and C1q-deficient mice. It did not correlate with C3 deposition, but did correlate with the amount of C6 deposited. Deficiency of CD59a, the membrane inhibitor of the membrane attack complex, did not induce an increase in neutrophil infiltration, suggesting that the generation of C5a accounts for the effects observed. There was no apparent difference between cryoglobulinemia types I and II regarding the role of complement. Our results suggest that in this model of cryoglobulin-induced glomerulonephritis the neutrophil influx was mediated by C5 activation with the alternative pathway playing a prominent role in its cleavage. Thus, blocking C5 is a potential therapeutic strategy for preventing renal injury in cryoglobulinemia.
Trendelenburg
Marten
M
Rheumatology Section, Imperial College, London, UK.
Fossati-Jimack
Liliane
L
Cortes-Hernandez
Josefina
J
Turnberg
Daniel
D
Lewis
Margarita
M
Izui
Shozo
S
Cook
H Terence
HT
Botto
Marina
M
D000818:Animals; D003165:Complement System Proteins / Q000172:deficiency / Q000378:metabolism*; D003449:Cryoglobulinemia / Q000145:classification / Q000150:complications* / Q000276:immunology / Q000473:pathology; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006825:Hybridomas / Q000276:immunology / Q000637:transplantation; D007105:Immune Complex Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology
D003165:Complement System Proteins