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Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus¹

Hideharu Sekine^2,*, Kareem L. Graham, Shenru Zhao, Margaret K. Elliott^*, Philip Ruiz, Paul J. Utz and Gary S. Gilkeson^*

^* Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina and the Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Pathology, University of Miami School of Medicine, Miami, FL 33125

We previously described a renal protective effect of factor B deficiency in MRL/lpr mice. Factor B is in the MHC cluster; thus, the deficient mice were H2^b, the haplotype on which the knockout was derived, whereas the wild-type littermates were H2^k, the H2 of MRL/lpr mice. To determine which protective effects were due to H2 vs factor B deficiency, we derived H2^b congenic MRL/lpr mice from the 129/Sv (H2^b) strain. Autoantibody profiling using autoantigen microarrays revealed that serum anti-Smith and anti-small nuclear ribonucleoprotein complex autoantibodies, while present in the majority of H2^k/k MRL/lpr mice, were absent in the H2^b/b MRL/lpr mice. Surprisingly, 70% of MRL/lpr H2^b/b mice were found to be serum IgG3 deficient (with few to no IgG3-producing B cells). In addition, H2^b/b IgG3-deficient MRL/lpr mice had significantly less proteinuria, decreased glomerular immune complex deposition, and absence of glomerular subepithelial deposits compared with MRL/lpr mice of any H2 type with detectable serum IgG3. Despite these differences, total histopathologic renal scores and survival were similar among the groups. These results indicate that genes encoded within or closely linked to the MHC region regulate autoantigen selection and isotype switching to IgG3 but have minimal effect on end-organ damage or survival in MRL/lpr mice.

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¹ This work was supported by the Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center and National Institutes of Health Grant AI47469. K.L.G. was supported by a National Institutes of Health National Research Service Award Fellowship AI10663. P.J.U. was supported by the Northern California Chapter of the Arthritis Foundation, the Dana Foundation, the Stanford Program in Molecular and Genetic Medicine, National Institutes of Health Grants DK61934, AI50864, AI01514, and AR49328, National Heart, Lung, and Blood Institute Proteomics Contract N01-HV-28183, an Arthritis Foundation Arthritis Investigator Award, and a Baxter Foundation Award.

² Address correspondence and reprint requests to Dr. Hideharu Sekine, 96 Jonathon Lucas Street, Suite 912, P.O. Box 250637, Charleston, SC 29425. E-mail address: sekineh{at}musc.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein complex; NZB, New Zealand Black; NZW, New Zealand White; RF, rheumatoid factor; Sm, Smith; DFU, digital fluorescence unit; SAM, significance analysis of microarray; GA, glomerular Ag; TMB, 3,3',5,5'-tetramethylbenzidine; BBS, borate-buffered saline; EM, electron microscopy; GBM, glomerular basement membrane.