Fas(lpr) gene 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 the 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 ANA 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-1⍺, IL-2, and IL-27. Taken together, Sle1(homo).lpr(het) strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.