C5a Receptor Deficiency Attenuates T Cell Function and Renal Disease in MRLlpr Mice
Open Access
- 1 December 2005
- journal article
- research article
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 16 (12), 3572-3582
- https://doi.org/10.1681/asn.2005040373
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 MRLlpr genetic background. Evidence is presented that C5aR modulates both renal injury and T cell responses in MRLlpr mouse. C5aR-deficient MRLlpr 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−/−MRLlpr mice. At 20 wk of age C5aR−/−MRLlpr 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−/−MRLlpr 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−/−MRLlpr mice, including diminished production of IL-12p70, IFN-γ, 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 MRLlpr mouse.Keywords
This publication has 39 references indexed in Scilit:
- Evidence for a functional role of the second C5a receptor C5L2The FASEB Journal, 2005
- Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted MicePLoS Biology, 2004
- The anaphylatoxins bridge innate and adaptive immune responses in allergic asthmaMolecular Immunology, 2004
- C5L2, a Nonsignaling C5A Binding ProteinBiochemistry, 2003
- Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by in situ hybridizationKidney International, 2001
- Genetics of Systemic Autoimmunity in Mouse Models of LupusInternational Reviews of Immunology, 2000
- Attenuation of Endothelium-Dependent Dilation of Pig Pulmonary Arterioles After Cardiopulmonary Bypass Is Prevented by Monoclonal Antibody to Complement C5aAnesthesia & Analgesia, 1999
- Structure, function and cellular expression of complement anaphylatoxin receptorsCurrent Opinion in Immunology, 1995
- Expression of the complement C5a anaphylatoxin receptor (C5aR) on non-myeloid cellsImmunology Letters, 1995
- Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains.The Journal of Experimental Medicine, 1978