DNA methylation and silencing of gene expression role in pathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies against a wide array of host nuclear antigens. Though the causes and etiology of the disease is not clearly understood, some genetic, epigenetic and environmental issues have been found responsible as risk factors. The impact of environment, which is majorly reflected by the epigenetic mechanisms, especially DNA methylation and epigenetic regulation of gene expressions are generally considered as key players in the due course of SLE pathogenesis. The repertoire of the evidences has indicated that DNA hypomethylation in T cells is an important characteristic of SLE. DNA hypomethylation mechanisms in the genes like CD11a (ITGL), perforin (PRF1), CD70 (TNFSF7), CD40LG (CD40), IFN-Ɣ, IL-4, have been designated them as classic methylation-sensitive autoimmunity related genes. In addition to these, the genome wide analyses have reported the hypomethylation in IL10 and IL-1R2 genes in SLE. On the other hand, certain drugs such as procainamide, hydralazine, 5-azacytidine (5-azaC) which are competitive DNA methyltransferases inhibitors, have been proposed as potential agents causing DNA hypomethylation in lupus. In this review, we summerise the current understanding of aberrant DNA methylation in T cells and consequently altered gene expression in SLE. Based on DBA 2 and AKR mice models, we have summarized the alterations in ERK (Ras-MAPK) signaling pathway and overexpression of LFA-1 caused by certain drugs contributing to the development of manifestations of the disease.