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

521-528Systemic 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

Effect of Proinflammatory Cytokines (IL-6, TNF-α, and IL-1β) on Clinical Manifestations in Indian SLE Patients

Systemic lupus erythematosus (SLE) is an inflammatory rheumatic disease characterized by production of autoantibodies and organ damage. Elevated levels of cytokines have been reported in SLE patients. In this study we have investigated the effect of proinflammatory cytokines (IL-6, TNF-α, and IL-1β) on clinical manifestations in 145 Indian SLE patients. One hundred and forty-five healthy controls of the same ethnicity served as a control group. Clinical disease activity was scored according to SLEDAI score. Accordingly, 110 patients had active disease and 35 patients had inactive disease. Mean levels of IL-6, TNF-α, and IL-1β were found to be significantly higher in SLE patients than healthy controls (P<0.001). Mean level of IL-6 for patients with active disease (70.45±68.32 pg/mL) was significantly higher (P=0.0430) than those of inactive disease patients (43.85±63.36 pg/mL). Mean level of TNF-α was 44.76±68.32 pg/mL for patients with active disease while it was 25.97±22.03 pg/mL for those with inactive disease and this difference was statistically significant (P=0.0161). Similar results were obtained for IL-1β (P=0.0002). Correlation between IL-6, TNF-α, and IL-1β serum levels and SLEDAI score was observed (r=0.20, r=0.27, and r=0.38, resp.). This study supports the role of these proinflammatory cytokines as inflammatory mediators in active stage of disease