FASlprgene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Sle1 and Fas lpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate dosage effects of FAS lpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6. Sle1/Sle1.Fas lpr /+ (sle1 homo .lpr het ) and compared it with B6. Fas lpr/lpr (lpr homo ), B6. Sle1/Sle1 (sle1 homo ), and B6. Sle1/Sle1.Fas lpr/lpr (sle1 homo .lpr homo ) strains. Whereas Sle1 homo .lpr homo mice exhibited profound lymphoproliferation and early mortality, sle1 homo .lpr het mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, sle1 homo .lpr het mice exhibited significantly elevated serum anti-dsDNA antibodies and increased proteinuria. Additionally, Sle1 homo .lpr het T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Fas lpr were noted in upregulating serum IL-1α, IL-2, and IL-27. Taken together, sle1 homo .lpr het mice emerge as a more faithful model of human SLE, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing.