The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY
- 1Department of Neurology, David Geffen School of Medicine, University of California. Los Angeles, California, USA
- 2Center for Molecular Neurobiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
- 3Division of Laboratory Animal Medicine, David Geffen School of Medicine University of California, Los Angeles, California, USA
- Correspondence to Rhonda Voskuhl, Department of Neurology, University of California, Los Angeles, Neuroscience Research Building 1, Room 475D, 635 Charles Young Drive South, Los Angeles, California 90095, USA;
Contributors MVS, NI and GWL carried out the experiments. RRV designed and acquired funding for the study. MVS, SMG, GWL and RRV analysed the data. MVS, SMG and RRV wrote the manuscript.
- Accepted 9 April 2012
- Published Online First 12 May 2012
Objectives 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.
Conclusion These data show that the XX sex chromosome complement, compared with XY−, is associated with accelerated spontaneous lupus.
Funding Funding for this project was provided by National Institutes of Health (NIH) grant R21 NS071210 (RRV), an NIH-sponsored training grant through the UCLA Laboratory of Neuroendocrinology and the Jack H Skirball Foundation. MVS (FG-1857) and SMG (FG-1702-A1) were supported by fellowships from the National Multiple Sclerosis Society.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Any unpublished data are available to all on formal request.