biostudies-literatureBohat RNIDDK NIH HHS109874https://www.ebi.ac.uk/biostudies/studies/S-EPMC12374782biostudies-literatureUnknown258Sle1 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.Clinical immunology (Orlando, Fla.)Fas<sup>lpr</sup> gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus.PMC12374782K08 DK119466Guerrero AUnsal EPeng WLiang XRobles AMohan CXu CDu YBohat RJaffery RHou JLi YLin JSZheng NLiang HChung SHHicks MJChen YMajor AMElldakli HChen XChen SEgan NATang YfalseFas<sup>lpr</sup> 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.2024-01-01T00:00:00Z2024 Jan2026-05-08T10:47:29.387Z2026-04-07T23:47:29.201ZS-EPMC123747823811396210.1016/j.clim.2023.109874