Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B.
In systemic lupus erythematosus, the renal deposition of complement-containing immune complexes initiates an inflammatory cascade resulting in glomerulonephritis. Activation of the classical complement pathway with deposition of C3 is pathogenic in lupus nephritis. Although the alternative complement pathway is activated in lupus nephritis, its role in disease pathogenesis is unknown. To determine the role of the alternative pathway in lupus nephritis, complement factor B-deficient mice were backcrossed to MRL/lpr mice. MRL/lpr mice develop a spontaneous lupus-like disease characterized by immune complex glomerulonephritis. We derived complement factor B wild-type (B+/+), homozygous knockout (B-/-), and heterozygous (B+/-) MRL/lpr mice. Compared with B+/- or B+/+ mice, MRL/lpr B-/- mice developed significantly less proteinuria, less glomerular IgG deposition, and decreased renal scores as well as lower IgG3 cryoglobulin production and vasculitis. Serum C3 levels were normal in the B-/- mice compared with significantly decreased levels in the other two groups. These results suggest that: 1) factor B plays an important role in the pathogenesis of glomerulonephritis and vasculitis in MRL/lpr mice; and 2) activation of the alternative pathway, either by the amplification loop or by IgA immune complexes, has a prominent effect on serum C3 levels in this lupus model.
Watanabe
H
H
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Garnier
G
G
Circolo
A
A
Wetsel
R A
RA
Ruiz
P
P
Holers
V M
VM
Boackle
S A
SA
Colten
H R
HR
Gilkeson
G S
GS
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000936:Antigen-Antibody Complex / Q000097:blood; D003176:Complement C3 / Q000378:metabolism; D011415:Complement Factor B / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics*; D003433:Crosses, Genetic; D003450:Cryoglobulins / Q000378:metabolism; D004247:DNA / Q000276:immunology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005921:Glomerulonephritis / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics; D007136:Immunoglobulins / Q000097:blood; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood; D014657:Vasculitis / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D003176:Complement C3; D003450:Cryoglobulins; D006183:H-2 Antigens; D007136:Immunoglobulins; D004247:DNA; D012217:Rheumatoid Factor; D011415:Complement Factor B