title: Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.
abstract: Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3(-/-)), heterozygous (C3(+/-)), and C3 wild-type (C3(+/+)) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3(-/-) mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3(-/-) mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.
authors.affiliation: Department of Medicine, Medical University of South Carolina and the Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sekine
authors.forename: C M
authors.initials: CM
authors.lastname: Reilly
authors.forename: I D
authors.initials: ID
authors.lastname: Molano
authors.forename: G
authors.initials: G
authors.lastname: Garnier
authors.forename: A
authors.initials: A
authors.lastname: Circolo
authors.forename: P
authors.initials: P
authors.lastname: Ruiz
authors.forename: V M
authors.initials: VM
authors.lastname: Holers
authors.forename: S A
authors.initials: SA
authors.lastname: Boackle
authors.forename: G S
authors.initials: GS
authors.lastname: Gilkeson
mesh_terms: D000419:Albuminuria / Q000652:urine; D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003450:Cryoglobulins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006580:Genetic Carrier Screening; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D007132:Immunoglobulin Isotypes / Q000097:blood; D007668:Kidney / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D003176:Complement C3; D003450:Cryoglobulins; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes