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United States Department of Agriculture

Agricultural Research Service

Research Project: GENOMIC AND IMMUNOLOGICAL ANALYSIS OF SPIROCHETE DISEASES Title: Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus

Authors
item Sekine, Hideharu - MEDICAL UNIV. OF SC
item Graham, Kareem - STANFORD UNIVERSITY
item Zhao, Shenru - STANFORD UNIVERSITY
item Elliott, Margaret
item Ruiz, Philip - UNIVERSITY OF MIAMI
item Utz, Paul - STANFORD UNIVERSITY
item Gilkeson, Gary - MEDICAL UNIV. OF SC

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 24, 2006
Publication Date: November 15, 2006
Citation: Sekine, H., Graham, K.L., Zhao, S., Elliott, M., Ruiz, P., Utz, P.J., Gilkeson, G.S. 2006. Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus. Journal of Immunology. 177(10):7423-34.

Interpretive Summary: Autoimmune diseases affect humans and animals. One important part of the manifestation of autoimmunity is kidney disease. A mouse model exists to study autoimmunity with kidney involvement. This model uses the MRL/lpr mouse. MRL/lpr mice develop an autoimmune disease that is fatal, often because of kidney failure. In a previous study, we knocked out an immune component, factor B, and found reduced disease and increased survival in these mice. Mice without factor B also inherited a different group of immune genes in a gene segment called H-2k. Here, we conducted a study to determine the affect of H-2k group of genes on kidney disease and survival in this model. We found that MRL/lpr mice with H-2k genes produce less autoantibodies and less of some types of normal antibodies compared to regular MRL/lpr mice. However, they still developed kidney disease and the survival rate was unchanged. These results tell us that some element within the H-2k gene segment controls which autoantibodies are produced and pays a role in normal antibody production. Finding out which genes are directly involved in the development of autoantibodies may lead to screening tests for diagnosis as well as to therapies for persons and livestock with autoimmune disease.

Technical Abstract: 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 H2b, the haplotype on which the knockout was derived, whereas the wild-type littermates were H2k, the H2 of MRL/lpr mice. To determine which protective effects were due to H2 vs factor B deficiency, we derived H2b congenic MRL/lpr mice from the 129/Sv (H2b) strain. Autoantibody profiling using autoantigen microarrays revealed that serum anti-Smith and anti-small nuclear ribonucleoprotein complex autoantibodies, while present in the majority of H2k/k MRL/lpr mice, were absent in the H2b/b MRL/lpr mice. Surprisingly, 70% of MRL/lpr H2b/b mice were found to be serum IgG3 deficient (with few to no IgG3-producing B cells). In addition, H2b/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.

Last Modified: 4/16/2014
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