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Deletion of the antiphospholipid syndrome autoantigen beta2 -glycoprotein I potentiates the lupus autoimmune phenotype in a Toll-like receptor 7-mediated murine model

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 beta2 -glycoprotein I (beta2 GPI) gene was deleted in male BXSB.Yaa mice. METHODS: We generated BXSB.Yaa and NZW mouse strains in which the beta2 GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 beta2 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 beta2 GPI(-/-) mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB.Yaa beta2 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 beta2 GPI(-/-) mice was significantly higher than that in control mice. Male BXSB.Yaa beta2 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 beta2 GPI accelerates and potentiates the autoimmune phenotype in male BXSB.Yaa mice.

Type Journal
ISBN 2326-5205 (Electronic)
Authors Giannakopoulos, B.; Mirarabshahi, P.; Qi, M.; Weatherall, C.; Qi, J. C.; Tanaka, K.; Millar, E.; Vonthethoff, L.; Gatto, D.; Spielman, D.; Krilis, S. A.;
Garvan Authors Dr Dominique Hess (Gatto)
Publisher Name Arthritis & Rheumatology
Published Date 2014-01-01 00:00:00
Published Volume 66
Published Issue 8
Published Pages 2270-80
URL http://www.ncbi.nlm.nih.gov/pubmed/24692206
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12743_12959/15_Giannakopoulos_AR_.pdf