Deletion of the Antiphospholipid Syndrome Autoantigen β2-Glycoprotein I Potentiates the Lupus Autoimmune Phenotype in a Toll-like Receptor 7–Mediated Murine Model

Authors

  • Bill Giannakopoulos,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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    • Drs. Giannakopoulos and Mirarabshahi contributed equally to this work.

  • Peyman Mirarabshahi,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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    • Drs. Giannakopoulos and Mirarabshahi contributed equally to this work.

  • Miao Qi,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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  • Chris Weatherall,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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  • Jian Cheng Qi,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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  • Kumiko Tanaka,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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  • Ewan Millar,

    1. St. George Hospital, Kogarah, New South Wales, Australia, Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia, University of Western Sydney, Campbelltown Campus, Campbelltown, New South Wales, Australia, and University of New South Wales, Kensington, New South Wales, Australia
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  • Leon Vonthethoff,

    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
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  • Dominique Gatto,

    1. Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
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  • Derek Spielman,

    1. University of Sydney, Camperdown Campus, Camperdown, New South Wales, Australia
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  • Steven A. Krilis

    Corresponding author
    1. St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia
    • Department of Infectious Diseases, Immunology and Sexual Health, St. George Hospital, University of New South Wales, 2 South Street, Kogarah, Sydney NSW 2217, Australia. E-mail: s.krilis@unsw.edu.au

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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 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.

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