The key culprit in the pathogenesis of systemic lupus erythematosus: Aberrant DNA methylation

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement. It is characterized by abundant autoantibodies that form immune complex with autoantigens and deposit in organs and cause tissue damage by inducing inflammation. The pathogenesis of SLE has been intensively studied but remains unclear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are believed to contribute to the initiation and development of SLE. The up-to-date research findings point to the relationship between abnormal DNA methylation and SLE, which has attracted considerable interest worldwide. Besides the global hypomethylation on lupus T and B cells, the gene specific and site-specific methylation has been identified and documented to be responsible for SLE. The purpose of this review was to present and summarize the association between aberrant DNA methylation of immune cells and SLE, the possible mechanisms of immune dysfunction caused by DNA methylation, and to better understand the roles of aberrant DNA methylation in the initiation and development of SLE and to provide an insight into the related diagnosis biomarkers and therapeutic options in SLE.

Introduction

SLE is a multi-systemic, autoimmune disorder that predominately affects women during their reproductive years [1], [2]. The prevalence and the incidence of SLE have been shown to vary across geographic regions around the world. It has been found more frequently in non-white populations compared to Caucasians, and the highest prevalence is reported among Afro-Caribbeans [3], [4].

SLE is characterized by autoreactive T and B lymphocytes [5], [6], together with a presence of a diverse set of autoantibodies in the circulation of affected patients [7], such as antinuclear antibodies (ANAs), anti-double-strand DNA (dsDNA) antibody, and anti-Smith (Anti-Sm) antibody, which have been used as conventional serological markers in patients with SLE [8]. Although the direct cause of SLE remains unclear, many factors are revealed to contribute to the pathogenesis of SLE, including genetic susceptibility, epigenetics, hormones, and environmental factors [9]. SLE occurs when an individual with genetic susceptibility to lupus encounters environmental triggers such as sunlight, drugs, or infection. Immune tolerance is broken down such that T cells recognize self-antigens and provide help to autoreactive B cells, which produce abundant autoantibodies. These autoantibodies bind to self-antigens and reside in multiple organs, leading to organ inflammation, dysfunction, and failure. SLE can affect various organ systems, including skin, joint, kidney, central nervous system, and bone marrow [10], [11], [12], [13].

Epigenetics is a study of the reversible and potentially heritable changes in gene expression without genetic code alterations, including DNA methylation, histone modification, and microRNA (miRNA). Recently, epigenetics becomes a new area of investigation into the pathogenesis of SLE [14]. Even before DNA was identified as the inheritable molecules, it was known that not every gene in an organism can be active in each cell at all times. Indeed, epigenetics provides an additional explanation for how genetics can contribute to health and disease and is being increasingly recognized as an important factor contributing to SLE. For example, only 20% of concordance for SLE has been found in homozygotic twins, suggesting that there are roles of environmental and epigenetic factors in the onset of disease [15]. Further indirect evidence of the role of epigenetics is that SLE is found predominantly in females and that it can be accelerated by environmental triggers (e.g., infection, UV, drugs) and/or internal factors (hormones and stress). In addition, certain types of drugs, which have been reported to induce SLE, are also known to cause epigenetic modifications, including 5-azacytidine and procainamide [16]. However, the precise mechanism by which these and many other environmental agents initiate lupus flares in genetically predisposed individuals has not been elucidated. Among these epigenetic modifications, DNA methylation received global attention and has been intensively studied by our group and others. Thus, this review summarizes up-to-date data showing the immune abnormalities induced by DNA methylation in SLE patients and provides insight into the possibility of relevant diagnosis biomarkers and therapies.