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Deletion of the Antiphospholipid Syndrome Autoantigen β 2 ‐Glycoprotein I Potentiates the Lupus Autoimmune Phenotype in a Toll‐like Receptor 7–Mediated Murine Model
Author(s) -
Giannakopoulos Bill,
Mirarabshahi Peyman,
Qi Miao,
Weatherall Chris,
Qi Jian Cheng,
Tanaka Kumiko,
Millar Ewan,
Vonthethoff Leon,
Gatto Dominique,
Spielman Derek,
Krilis Steven A.
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38646
Subject(s) - autoantibody , immunology , systemic lupus erythematosus , biology , b cell activating factor , glomerulonephritis , tumor necrosis factor alpha , endocrinology , b cell , medicine , antibody , kidney , disease
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 β 2 ‐glycoprotein I (β 2 GPI) gene was deleted in male BXSB. Yaa mice. Methods We generated BXSB. Yaa and NZW mouse strains in which the β 2 GPI gene had been knocked out by backcrossing the wild‐type strains with C57BL/6 β 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 β 2 GPI −/− mice developed significant lymphadenopathy and splenomegaly compared with age‐matched controls. Male BXSB. Yaa β 2 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 β 2 GPI −/− mice was significantly higher than that in control mice. Male BXSB. Yaa β 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 β 2 GPI accelerates and potentiates the autoimmune phenotype in male BXSB. Yaa mice.