| Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease with complex etiology, with genetic factors playing a significant role in determining susceptibility. The centromeric region of chromosome 7 in mouse has been repeatedly linked to lupus susceptibility in multiple models. In a (MRL-Faslpr x B6-Faslpr ) F2 screen, this region, named Lmb3, is associated with splenomegaly, lymphadenopathy, and anti-dsDNA antibodies. To dissect the contribution of this locus derived from the MRL mice on lupus pathogenesis, we analyzed B6 animals congenic for this region (B6. MRLc7 animals).; When B6.MRLc7-Faslpr animals were examined for their lupus disease phenotype, we found that they exhibited accelerated and exaggerated disease, including increased splenomegaly, lymphadenopathy, autoantibody production, and kidney disease, over B6-Faslpr control animals. This confirms the role of this locus as a lupus susceptibility locus and its capacity in promoting disease. The MRLc7 locus acts as a modifier of Faslpr for disease expression, as Fas-intact B6.MRLc7 animals did not develop overt disease.; These disease traits were accompanied by changes in cells of the adaptive immune system, including B cell hyperactivity indicated by hyperglobulinemia, and increased T cell activation status. When isolated and in culture, B6. MRLc7-Faslpr B cells displayed a heightened responsiveness to various stimuli, leading to increased cell recovery and elevated immunoglobulin secretion. These were attributed to increased survival in culture, and to increased differentiation into antibody-forming cells, by B6.MRLc7-Fas lpr B cells. By contrast, detailed analysis revealed that B6.MRLc7 T cells are intrinsically normal, suggesting that the T cell defect seen in the whole animal is cell nonautonomous.; The MRLc7 locus also bestowed a hypo-responsiveness phenotype on the innate immune cells in the congenic animals leading to reduced inflammation in multiple challenges. This may be linked to the wound-healing phenotype that is uniquely found in the MRL strain.; In summary, this study presents evidence to suggest that MRLc7 carries genes that lead to lupus susceptibility through altering B cell responsiveness in Faslpr animals. The phenotypic characterization described here provides novel insight into the action of a chromosomal region important in lupus susceptibility, and should help in future gene identification efforts. |
