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

Abstract

AbstractSle1andFaslprare two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate dosage effects ofFASlprin determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+(sle1homo.lprhet) and compared it with B6.Faslpr/lpr(lprhomo), B6.Sle1/Sle1(sle1homo), and B6.Sle1/Sle1.Faslpr/lpr(sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomomice exhibited profound lymphoproliferation and early mortality, sle1homo.lprhetmice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, sle1homo.lprhetmice exhibited significantly elevated serum anti-dsDNA antibodies and increased proteinuria. Additionally, Sle1homo.lprhetT cells had an increased propensity to differentiate into Th1 cells. Gene dose effects ofFaslprwere noted in upregulating serum IL-1α, IL-2, and IL-27. Taken together, sle1homo.lprhetmice emerge as a more faithful model of human SLE, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing.