Skewed X chromosome inactivation in blood cells of women with scleroderma

Abstract

Objective. Scleroderma (SSc) is an autoimmune disease of unknown etiology. The disease is 3-8 times more frequent in women than in men. The role of X chromosome inactivation (XCI) in the predisposition of women to autoimmunity has been questioned. Until now this has not been illustrated experimentally. This study was undertaken to test the hypothesis that disturbances in XCI mosaicism may be involved in the pathogenesis of the disease in female patients with SSc.Methods. Seventy female SSc patients and 160 female controls were analyzed for the androgen receptor locus by the Hpa II/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. Furthermore, skin biopsy samples were obtained from 5 patients whose blood revealed an extremely skewed pattern of XCI, and the analysis repeated. Since microchimerism in SSc was reported, Y chromosome sequences were investigated in all samples.Results. Skewed XCI was observed in DNA from peripheral blood cells in 35 of 55 informative patients (64%), as compared with 10 of 124 informative controls (8%) (P < 0.0001). Extreme skewing was present in 27 of the patient group (49%), as compared with only 3 of the controls (2.4%) (P < 0.0001). However, XCI was random in all skin biopsy samples. The potential contribution of microchimerism to the random XCI pattern is highly unlikely based on the medical histories of the patients.Conclusion. Skewed XCI mosaicism may play a significant role in the pathogenesis of SSc.

Skewed X-Chromosome Inactivation in Scleroderma

“…Of these females, approximately 18% displayed extreme skewing (>90:10). This result is consistent with our previous study, ( 12 ) and indicates that skewed X-inactivation could be a common finding in different population groups.…”

“…Clinical characteristics of the patients and controls have been published elsewhere. ( 12,13 ) The ethics review boards at the participating institutions approved the study protocol. Informed consent was obtained from all subjects.…”

“…The X-chromosome inactivation status of the patients and controls was determined by genotyping a highly polymorphic CAG repeat in the first intron of the androgen receptor as previously described. ( 12,14 ) Depending on the definition and quantitative accuracy of the measurement method, a few percent to nearly one fifth of apparently healthy women display skewed (i.e., non-random) patterns of X-inactivation. Whereas, ratios in the range of 50-79 percent is usually regarded as normal variation, deviation from this range in 80-89 percent of cells is defined as skewed, and above 90 percent of cells as extremely skewed X-inactivation.…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…Other authors have suggested that women affected with specific female-preponderant autoimmune diseases, i.e., scleroderma, manifest a skewed XCI pattern in their peripheral white blood cells. 25 In PBC, however, we failed to demonstrate such preferential inactivation. 21 …”

Hvorfor er autoimmune sykdommer hyppigere hos kvinner?

“…The explanation is often that they have skewed X chromosome inactivation (8). Recent research has shown a higher prevalence of skewed X chromosome inactivation in some autoimmune diseases; this was first found for systemic sclerosis (10). Skewed X chromosome inactivation has been found in autoimmune thyroid disease, both Hashimoto's thyroiditis and Grave's disease (11) and in rheumatoid arthritis (12), but not in primary Sjögren's syndrome, systemic lupus erythematosus, primary biliary cirrhosis or multiple sclerosis (2, 13, 14) ( Table 1).…”