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X Chromosome Monosomy: A Common Mechanism for Autoimmune Diseases¹

Pietro Invernizzi^2,*, Monica Miozzo, Carlo Selmi^*,#, Luca Persani^,, Pier Maria Battezzati^*, Massimo Zuin^*, Simona Lucchi, Pier Luigi Meroni^¶, Bianca Marasini^*, Silvana Zeni^||, Mitchell Watnik^**, Francesca R. Grati, Giuseppe Simoni, M. Eric Gershwin^# and Mauro Podda^*

^* Division of Internal Medicine and Laboratory of Human Genetics, Department of Medicine, Surgery and Dentistry, San Paolo School of Medicine, Institute of Endocrine Sciences, Laboratory of Experimental Endocrinology and ^¶ Clinical Immunology Unit, Department of Internal Medicine, Institute for Research and Treatment, Istituto Auxologico Italiano, and ^|| Department of Rheumatology, Gaetano Pini Orthopedics Institute, University of Milan, Milan, Italy; and ^# Division of Rheumatology, Allergy and Clinical Immunology and^** Statistical Laboratory, University of California, Davis, CA 95616

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y -satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs 2.9 ± 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

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The JI 2005 175: 1-2. [Full Text]  

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