Deletion Of The Antiphospholipid Syndrome Autoantigen Beta(2)-Glycoprotein I Potentiates The Lupus Autoimmune Phenotype In A Toll-Like Receptor 7-Mediated Murine Model

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 beta(2)-glycoprotein I (beta(2)GPI) gene was deleted in male BXSB.Yaa mice.Methods. We generated BXSB.Yaa and NZW mouse strains in which the beta(2)GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 beta(2)GPI(-/-) 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 beta(2)GPI(-/-) mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB. Yaa beta(2)GPI(-/-) mice also had significantly higher levels of autoantibodies, increased levels of inflammatory cytokines including tumor necrosis factor alpha, interleukin-6, and BAFF, and more severe glomerulonephritis. The type I IFN gene signature in male BXSB. Yaa beta(2)GPI(-/-) mice was significantly higher than that in control mice. Male BXSB. Yaa beta(2)GPI(-/-) 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 beta(2)GPI accelerates and potentiates the autoimmune phenotype in male BXSB. Yaa mice.