Analysis of X chromosome inactivation in primary and secondary Sjogren syndrome

Abstract

Sjogren Syndrome is an autoimmune disease with one of the highest prevalences and unknown etiology. The majority of the patients (~90%) are female similar to several other autoimmune diseases. Based on this observation, a hypothesis was proposed stating that X chromosome inactivation (XCI) could be involved in female predisposition to autoimmunity. XCI is a physiological mechanism which takes place early in development resulting in the transcriptional silencing of one of the pair of X chromosomes at random in each cell. A significant deviation from a random distribution of two cell populations with paternal and maternal X chromosome inactive is called skewed XCI. Skewing in the dendritic cell population involved in tolerance induction in the thymus was proposed to cause escape of autoreactive lymphocytes and result in autoimmunity (Immunol Today, 19, 352-7, 1998). Skewed XCI was observed in scleroderma (Arth Rheum 52, 1564-70, 2005) and autoimmune thyroiditis (Eur J Hum Genet 14, 791-7, 2006). But this observation is not true for all autoimmune diseases. For example, the XCI profiles of primary biliary cirrhosis patients are similar to normal controls (Hepatol Res 37, Suppl 3, 384-8, 2007). The aim of this study is to determine the XCI profiles of patients diagnosed with primary Sjogren Syndrome, manifesting exocrinopathy or secondary Sjogren Syndrome displaying additional systemic features. DNA was isolated from the peripheric blood samples of 78 Sjogren syndrome patients and 160 controls. XCI profile was determined by the genotyping of a polymorphism in the androgen receptor (AR) gene. For this analysis, restriction enzyme HpaII was used which does not cut methylated regions. Analysis was done with Genescan Abi Prism 310 or 8% polyacrylamide gel electrophoresis and densitometric analysis. Extreme skewing (>90%) of XCI was observed in 3 (5.9%) patients and 3 controls (2.4%) samples (P = 0.3651). Our findings do not support a role for skewed XCI in Sjogren Syndrome.