title: C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice.
abstract: The development and progression of systemic lupus erythematosus (SLE) is strongly associated with complement activation and deposition. To characterize the role of C5a and its receptor (C5aR) in SLE, C5aR-deficient mice were backcrossed nine generations onto the lupus-like MRL(lpr) genetic background. Evidence is presented that C5aR modulates both renal injury and T cell responses in MRL(lpr) mouse. C5aR-deficient MRL(lpr) mice had prolonged viability, with a mean survival time of 33.0 wk compared with 22.6 wk in control mice. Renal injury was also attenuated in the C5aR-/- MRL(lpr) mice. At 20 wk of age C5aR-/- MRL(lpr) mice had a complete absence of glomerular crescents and marked reductions in glomerular hypercellularity. There was no difference in the degree of glomerular C3 deposition; however, IgG deposits were reduced in the C5aR-/- MRL(lpr) mice. The reduction in glomerular injury was also associated with a four-fold decrease in renal CD4+ T cell infiltrates. Whereas there were modest differences in total IgG anti-dsDNA antibody titers, C5aR-deficient mice had 3.5-fold higher levels of IgG1 and 15-fold lower levels of IgG2a anti-dsDNA antibody titers compared to controls. The differences in anti-dsDNA IgG subclasses were associated with reduced CD4+ Th-1 responses in the C5aR-/- MRL(lpr) mice, including diminished production of IL-12p70, IFN-gamma, and increased expression of the Th-2 transcription factor GATA-3. These findings indicate that the C5aR plays a major role in modulating complement-dependent renal injury and T helper cell Th-1 responses in the MRL(lpr) mouse.
authors.affiliation: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Wenderfer
authors.forename: Baozhen
authors.initials: B
authors.lastname: Ke
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Hollmann
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Braun
mesh_terms: D000818:Animals; D001483:Base Sequence; D001707:Biopsy, Needle; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007674:Kidney Diseases / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency*; D012016:Reference Values; D012680:Sensitivity and Specificity; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology
chemical_list: D044087:Receptor, Anaphylatoxin C5a