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Objective The BXSB. Yaa mouse strain is a model of systemic lupus erythematosus that is dependent on duplication of the Toll-like receptor 7 gene. The objective of this study was to systematically describe the amplified autoimmune phenotype observed when the soluble plasma protein β2-glycoprotein I (β2GPI) gene was deleted in male BXSB. Yaa mice. Methods We generated BXSB. Yaa and NZW mouse strains in which the β2GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 β2GPI−/− mice for 10 generations. Sex- and age-matched mice of the various strains were housed under identical conditions and were killed at fixed time intervals. Serum and tissue specimens were collected at various time points. Lupus-associated autoantibodies, inflammatory cytokines, and the type I interferon (IFN) gene signature were measured. Flow cytometric analyses of lymphocyte populations were performed. The severity of glomerulonephritis was graded by 2 independent renal histopathologists. Results Male BXSB. Yaa β2GPI−/− mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB. Yaa β2GPI−/− mice also had significantly higher levels of autoantibodies, increased levels of inflammatory cytokines including tumor necrosis factor α, interleukin-6, and BAFF, and more severe glomerulonephritis. The type I IFN gene signature in male BXSB. Yaa β2GPI−/− mice was significantly higher than that in control mice. Male BXSB. Yaa β2GPI−/− mice also had marked dysregulation of various B cell and T cell populations in the spleens and lymph nodes and a disturbance in apoptotic cell clearance. Conclusion Deletion of β2GPI accelerates and potentiates the autoimmune phenotype in male BXSB. Yaa mice. [ABSTRACT FROM AUTHOR]