Characterization of reciprocal Lmb1-4 interval MRL-Faslpr and C57BL/6-Faslpr congenic mice reveals significant effects from Lmb3.
Susceptibility to severe lupus in MRL-Fas(lpr) mice requires not only the lpr mutation but also other predisposing genes. Using (MRL-Fas(lpr) x B6-Fas(lpr))F2 (where B6 represents C57BL/6) intercrosses that utilize the highly susceptible MRL and poorly susceptible B6 backgrounds, we previously mapped CFA-enhanced systemic lupus-like autoimmunity to four loci, named Lmb1-4, on chromosomes 4, 5, 7, and 10. In the current study, we generated and analyzed reciprocal interval congenic mice for susceptibility to CFA-enhanced autoimmunity at all four Lmb loci. Although all loci had at least a slight effect on lymphoproliferation, only Lmb3 demonstrated a major effect on lymphoproliferation and anti-chromatin Ab levels. Further characterization of Lmb3, primarily by comparing MRL-Fas(lpr) with MRL.B6-Lmb3 Fas(lpr) congenic mice, revealed that it also played a significant role in spontaneous lupus, modifying lymphoproliferation, IgG and autoantibody levels, kidney disease, and survival. The less susceptible B6 Lmb3 locus was associated with a marked reduction in numbers of CD4(+) and double-negative (CD4(-)CD8(-)) T cells, particularly in lymph nodes, as well as reduced T cell proliferation and enhanced T cell apoptosis, both in vivo and in vitro. IFN-gamma-producing CD4(+) T cells were also reduced in MRL.B6-Lmb3 Fas(lpr) mice. Further mapping using subinterval congenic mice placed Lmb3 in the telomeric portion of chromosome 7. Thus, Lmb3, primarily through its effects on CD4(+) and double-negative T cells, appears to be a highly penetrant lupus-modifying locus. Identification of the underlying genetic alteration responsible for this quantitative trait locus should provide new insights into lupus-modifying genes.
Santiago-Raber
Marie-Laure
ML
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Haraldsson
M Katarina
MK
Theofilopoulos
Argyrios N
AN
Kono
Dwight H
DH
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002875:Chromosomes / Q000235:genetics*; D053222:Fas Ligand Protein / Q000235:genetics; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D007668:Kidney / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D040641:Quantitative Trait Loci
D001323:Autoantibodies; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D007371:Interferon-gamma