Increased X-inactivation skewing in SLE?

In a recent Viewpoint, Stewart1xStewart, J. Immunol. Today. 1998; 19: 352–357Abstract | Full Text | Full Text PDF | Scopus (55)See all References1 beautifully makes the case for skewed X-chromosome inactivation as a risk factor for autoimmune disease in females. The proposed mechanism involves a lack of T-cell tolerance to polymorphic X-linked antigens, through inadequate thymic negative selection. This hypothesis predicts that bone-marrow-derived elements will exhibit increased skewing in systemic lupus erythematosus (SLE) patients.We have addressed this hypothesis by comparing the pattern of X-chromosome inactivation in a population of 46 SLE patients, with normal control females (2xGregersen, P.K. Arthritis Rheum. 1993; 36: 1185–1192Crossref | Scopus (39)See all References, 3xTrejo, V., Derom, C., Vlietinck, R. et al. Mol. Med. 1994; 1: 62–70See all References, 4xMonteiro, J., Derom, C., Vlietink, R., Kohn, N., Lesser, M., and Gregersen, P.K. Am. J. Hum. Genet. 1998; 63: 339–346Abstract | Full Text | Full Text PDF | Scopus (95)See all References; author, unpublished). The degree of X-inactivation was determined using an HpaII polymerase chain reaction (PCR) assay of the androgen receptor (AR) gene on the human X chromosome5xAllen, R.C., Zoghbi, H.Y., Moseley, A.B., Rosenblatt, H.M., and Belmont, J.W. Am. J. Hum. Genet. 1992; 51: 1229–1239PubMedSee all References5. This assay distinguishes the methylated (inactivated) X chromosome from the unmethylated AR allele (active), and distinguishes the two parental alleles by virtue of a highly polymorphic CAG repeat within the AR gene. This assay is highly reproducible with standard errors of <5% (Ref. 4xMonteiro, J., Derom, C., Vlietink, R., Kohn, N., Lesser, M., and Gregersen, P.K. Am. J. Hum. Genet. 1998; 63: 339–346Abstract | Full Text | Full Text PDF | Scopus (95)See all ReferencesRef. 4).It is apparent that there is no difference in the degree of X-inactivation skewing in the lupus patients compared with normal controls (Fig. 1Fig. 1). Although some individuals show extreme preferential inactivation of one X chromosome, there is no difference in the number of these individuals in the two groups, nor is the mean degree of skewing significantly different between lupus patients and controls. This result argues against the hypothesis that skewed X-chromosomal usage by thymic bone-marrow-derived elements is a risk factor for SLE.Fig. 1Comparison of X-inactivation patterns in PBMCs of normal females and systemic lupus erythematosus patients. The degree of skewing of X-inactivation (away from 50% for each X chromosome) was performed using an HpaII (methylation sensitive) polymerase chain reaction (PCR) assay based on the X-linked androgen receptor locus. Each dot represents the result for an individual. The mean degree of skewed X-chromosome inactivation for each population is shown by the bars.View Large Image | Download PowerPoint SlideThe data shown in Fig. 1Fig. 1 are based upon an analysis of X-inactivation in peripheral blood mononuclear cells. It is likely that this reflects the patterns of X-skewing in dendritic cells, since all bone-marrow-derived elements are mesodermal in origin and X-chromosome inactivation patterns are established very early in development. Except in very unusual circumstances (such as carrier status for X-linked immunodeficiencies), mononuclear cell subsets exhibit identical patterns of X-chromosome usage. However, it is possible that the dendritic cells that colonize the thymus are derived from very few clones, and this could result in local tissue skewing of X-inactivation. This will require direct analysis of X-inactivation patterns in the thymic dendritic cells of females.