ABSTRACT
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 ß2 -glycoprotein I (ß2 GPI) gene was deleted in male BXSB.Yaa mice. METHODS: We generated BXSB.Yaa and NZW mouse strains in which the ß2 GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 ß2 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 ß2 GPI(-/-) mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB.Yaa ß2 GPI(-/-) 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 ß2 GPI(-/-) mice was significantly higher than that in control mice. Male BXSB.Yaa ß2 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 ß2 GPI accelerates and potentiates the autoimmune phenotype in male BXSB.Yaa mice.
Subject(s)
Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , beta 2-Glycoprotein I/genetics , Animals , Antiphospholipid Syndrome/immunology , Autoantigens/immunology , Disease Models, Animal , Gene Deletion , Male , Membrane Glycoproteins/physiology , Mice , Mice, Inbred C57BL , Phenotype , Toll-Like Receptor 7/physiology , beta 2-Glycoprotein I/immunologyABSTRACT
Vascular thrombosis and/or recurrent miscarriages are the main characteristics defining Antiphospholipid Syndrome (APS). Currently there is no well-defined clinical features and/or laboratory tests that predicts the risk of adverse prognostic outcomes in APS. In this short review, we report the importance of posttranslational modification of beta2 glycoprotein I, the major autoantigen in the APS beta2 glycoprotein I that may, in part, explain possible mechanisms for the generation of auto antibodies to beta2 glycoprotein I. A specific ELISA measuring the level of oxidised beta2 glycoprotein I could be used as a potential new laboratory test - along with other laboratory tests - to more accurately predict the risk of having a clinical event in patients with APS.
Subject(s)
Antiphospholipid Syndrome/immunology , Antiphospholipid Syndrome/metabolism , Protein Processing, Post-Translational , beta 2-Glycoprotein I/immunology , beta 2-Glycoprotein I/metabolism , Animals , Autoantibodies/immunology , Humans , Oxidation-ReductionABSTRACT
ß2-glycoprotein I (ß2GPI) is the major autoantigen in the antiphospholipid syndrome. The central importance of understanding ß2GPI physiology from the perspective of the rheumatologist is that it forms the foundation for understanding the pathophysiology underlying autoantibody generation, and the diverse mechanisms by which anti-ß2GPI antibodies in complex with ß2GPI may predispose an individual to the antiphospholipid syndrome clinical phenotype. This review examines some of the latest novel findings in this area.
