The major murine systemic lupus erythematosus susceptibility locus Sle1 results in abnormal functions of both B and T cells.
Sle1 is a major susceptibility locus in the NZM2410 murine model of systemic lupus erythematosus. When isolated on a C57BL/6 background in the B6.Sle1 congenic strain, Sle1 results in the production of high levels of anti-chromatin IgG Abs, histone-specific T cells, and increased B and T cell activation. We have shown by mixed bone marrow chimeras with allotypic markers that Sle1 is expressed in B cells. Using the same technique, we now show that it is also expressed in T cells. To assess whether Sle1 results in intrinsic defects in B or T cells, we have bred the muMT and Tcralpha(-/-) mutations onto B6.Sle1 resulting in the absence of circulating B cells and alphabeta T cells in B6.Sle1.muMT and B6.Sle1.Tcralpha(-/-), respectively. The immune phenotypes in these two strains were compared with that of B6.Sle1 and B6.muMT or B6.Tcralpha(-/-). Sle1-expressing B cells broke tolerance to chromatin in the absence of T cells, as shown by high levels of anti-ssDNA IgM Abs in B6.Sle1.Tcralpha(-/-) mice, and had an increased expression of activation markers. Conversely, increased expression of activation markers and increased cytokine production were observed in Sle1-expressing T cells in the absence of B cells in B6.Sle1.muMT mice. However, the production of IgG antinuclear Abs required the presence of both T and B cells. These experiments showed that Sle1 expression results in both B and T cells intrinsic defects and demonstrate that the documented involvement of each cell compartment in the production of anti-chromatin Abs corresponds to genetic defects rather than bystander effects.
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville 32610, USA.
Eric S
ES
Sobel
Minoru
M
Satoh
Yifang
Y
Chen
Edward K
EK
Wakeland
Laurence
L
Morel
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*