Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus.
MRL-lpr/lpr (MRL/lpr) mice are a model of human autoimmune disease. They exhibit a number of characteristics of systemic lupus erythematosus, including anti-DNA Abs, anti-cardiolipin Abs, immune complex-mediated vasculitis, lymphadenopathy, and severe glomerulonephritis. Although the autoimmune disorder is mediated primarily by mutation of the Fas gene (lpr), which interferes with lymphocyte apoptosis, MRL/lpr mice also have other predisposing genetic factors. In an effort to identify these additional factors, we have applied quantitative trait locus (QTL) mapping using an intercross between MRL/lpr mice and the nonautoimmune inbred strain BALB/cJ. A complete linkage map spanning the entire genome was constructed for 189 intercross progeny, and genetic loci contributing to features of the autoimmunity were identified using statistical analytic procedures. As expected, the primary genetic determinant of autoimmune disease in this cross was the Fas gene on mouse chromosome 19, exhibiting a lod score of 60. In addition, two novel loci, one on chromosome 2 (lod score, 4.3) and one on chromosome 11 (lod score, 3.1), were found to contribute to levels of anti-DNA Abs. Interestingly, the chromosome 19 and chromosome 11 QTLs, but not the chromosome 2 QTL, also exhibited associations with anti-cardiolipin Abs (lod scores, 38.4 and 2.6). We further examined the effects of these QTLs on the development of coronary vasculitis in the F2 mice. Our results indicate that the QTLs on chromosomes 11 and 19 also control the development of vasculitis, demonstrating common genetic determinants of autoantibody levels and vasculitis.
Gu
L
L
Department of Medicine, University of California, Los Angeles 90095, USA.
Weinreb
A
A
Wang
X P
XP
Zack
D J
DJ
Qiao
J H
JH
Weisbart
R
R
Lusis
A J
AJ
D000818:Animals; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D002791:Cholesterol, Dietary / Q000633:toxicity; D002874:Chromosome Mapping; D003327:Coronary Disease / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008055:Lipids / Q000032:analysis; D008126:Lod Score; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D014657:Vasculitis / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D008055:Lipids