title: The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY.
abstract: OBJECTIVE
  Many autoimmune diseases are characterised by a female predominance. This may be caused by sex hormones, sex chromosomes or both. This report uses a transgenic mouse model to investigate how sex chromosome complement, not confounded by differences in gonadal type, might contribute to lupus pathogenesis.
  
  
  METHODS
  Transgenic NZM2328 mice were created by deletion of the Sry gene from the Y chromosome, thereby separating genetic from gonadal sex. Survival, renal histopathology and markers of immune activation were compared in mice carrying the XX versus the XY(-) sex chromosome complement, with each genotype being ovary bearing.
  
  
  RESULTS
  Mice with XX sex chromosome complement compared with XY(-) exhibited poorer survival rates and increased kidney pathology. Splenic T lymphocytes from XX mice demonstrated upregulated X-linked CD40 ligand expression and higher levels of activation markers ex vivo. Increased MMP, TGF and IL-13 production was found, while IL-2 was lower in XX mice. An accumulation of splenic follicular B cells and peritoneal marginal zone B cells was observed, coupled with upregulated costimulatory marker expression on B cells in XX mice.
  
  
  CONCLUSIONS
  These data show that the XX sex chromosome complement, compared with XY(-), is associated with accelerated spontaneous lupus.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Manda V
authors.initials: MV
authors.lastname: Sasidhar
authors.forename: Noriko
authors.initials: N
authors.lastname: Itoh
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gold
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Lawson
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism; D058674:Chromosome Duplication; D005260:Female; D007668:Kidney; D007674:Kidney Diseases; D008136:Longevity; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012729:Sex Chromosome Aberrations; D025064:Sex Chromosome Disorders / Q000235:genetics*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation; D014960:X Chromosome / Q000235:genetics*; D014998:Y Chromosome / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018106:CD28 Antigens; D017252:CD3 Complex; D023201:CD40 Ligand