title: Deletion of the antiphospholipid syndrome autoantigen β2 -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 β2 -glycoprotein I (β2 GPI) gene was deleted in male BXSB.Yaa mice.
  
  
  METHODS
  We generated BXSB.Yaa and NZW mouse strains in which the β2 GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 β2 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 β2 GPI(-/-) mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB.Yaa β2 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 β2 GPI(-/-) mice was significantly higher than that in control mice. Male BXSB.Yaa β2 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.
  
  
  CONCLUSIONS
  Deletion of β2 GPI accelerates and potentiates the autoimmune phenotype in male BXSB.Yaa mice.
authors.affiliation: St. George Hospital and University of New South Wales, Kogarah, New South Wales, Australia.
authors.forename: Bill
authors.initials: B
authors.lastname: Giannakopoulos
authors.forename: Peyman
authors.initials: P
authors.lastname: Mirarabshahi
authors.forename: Miao
authors.initials: M
authors.lastname: Qi
authors.forename: Chris
authors.initials: C
authors.lastname: Weatherall
authors.forename: Jian Cheng
authors.initials: JC
authors.lastname: Qi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ewan
authors.initials: E
authors.lastname: Millar
authors.forename: Leon
authors.initials: L
authors.lastname: Vonthethoff
authors.forename: Dominique
authors.initials: D
authors.lastname: Gatto
authors.forename: Derek
authors.initials: D
authors.lastname: Spielman
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
mesh_terms: D000818:Animals; D016736:Antiphospholipid Syndrome / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D004195:Disease Models, Animal; D017353:Gene Deletion; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D051199:Toll-Like Receptor 7 / Q000502:physiology; D053482:beta 2-Glycoprotein I / Q000235:genetics* / Q000276:immunology
chemical_list: D001324:Autoantigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D053482:beta 2-Glycoprotein I