C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice.
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.
Wenderfer
Scott E
SE
Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, TX 77030, USA.
Ke
Baozhen
B
Hollmann
Travis J
TJ
Wetsel
Rick A
RA
Lan
Hui Yao
HY
Braun
Michael C
MC
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
D044087:Receptor, Anaphylatoxin C5a