Abstract
The pathogenesis of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications, such as DNA methylation, histone modifications and microRNAs, influence gene expression and impact cell function without modifying the genomic sequence. Epigenetic dysregulation is associated with autoimmune diseases, including systemic lupus erythematosus. Understanding the molecular mechanisms, including epigenetic regulation of immune response, that are involved in the pathophysiology of lupus is essential for the introduction of effective, target-directed and tolerated therapies. In this monographic issue, the role of epigenetic mechanisms in lupus is discussed from different perspectives.
Liu and La Cava [Citation1] present an overview of the role of epigenetics in systemic lupus, and the investigations aimed at possibly targeting epigenetic mechanisms and/or related biomarkers to improve the monitoring, management and the prognosis of lupus.
Doyle et al. [Citation2] address several specific areas that fall among the non-genetic factors that contribute to lupus autoimmunity and related syndromes. In particular, the importance of understanding various protein post-translational modifications (PTMs), mechanisms that mediate the ability of “modified self” to trigger autoimmunity, and how these PTMs influence lupus diagnosis. They also discuss altered pathways of autoantigen presentation that contribute to the perpetuation of chronic autoimmune disease.
Epigenetic alterations of cytokine genes have been associated with various autoimmune/inflammatory disorders. Hedrich et al. [Citation3] discuss epigenetic regulation of cytokine expression in lupus, including compelling evidence from their laboratory that suggest epigenetic patterns of cytokine genes follow disease activity in lupus. These investigators also suggest that the transcription factor CREMα reciprocally mediates trans repression and epigenetic silencing of IL-2 while trans-activating IL-17A.
In addition to sequence-specific DNA binding factors, the chromatin landscape can play a pivotal role in controlling activation and differentiation of immune cells and in preventing the onset of autoimmunity. Interferon regulatory factors (IRFs) are emerging as critical regulators of the activation and differentiation of immune cells and deregulation in the expression and/or function of members of the IRF family has increasingly been linked to the pathogenesis of lupus. Rogatsky et al. [Citation4] address the role of different IRFs in immune responses and lupus development and discuss studies, which highlight the intricate relationship of this family of transcription factors with the epigenetic machinery.
Modifications of DNA and histones require substrates derived from diet and intermediary metabolism. Zachary Oaks and Andras Perl [Citation5] discuss comprehensively the sources of metabolites required for epigenetic regulation and how the flux of the underlying metabolic pathways affects gene expression.
T cells and B cells from systemic lupus patients are defective in their ability to methylate their DNA upon antigen stimulation, leading to the overexpression of DNA methylation sensitive genes. Falli et al. [Citation6] investigate whether DNA demethylation affects the transcription of HRES-1, the prototype of human endogenous retrovirus (HERV) overexpressed in lupus B cells. In this issue, these investigators provide experimental evidence that ErK/DNMT1-mediated HRES-1 promoter DNA methylation, which regulates HRES-1/p28 expression, is reduced in resting and anti-IgM antibody stimulated lupus B cells. The reduction of DNA methylation can be reversed by blocking IL-6 autocrine loop.
microRNAs play key roles in the post-transcriptional regulation of almost every gene-regulatory pathway. They regulate both the innate and the adaptive immune responses. Altered microRNA expression is associated with lupus. The regulation of microRNA and the role of microRNAs in pathogenesis, diagnosis and treatment of lupus are also extensively discussed in this issue [Citation7].
Declaration of interest
Hong Zan is supported by an Arthritis National Research Foundation grant.
References
- Liu, A., and A. La Cava. 2014. Epigenetic dysregulation in systemic lupus erythematosus. Autoimmunity 47: 215–219
- Doyle, H. A., M.-L. Yang, M. T. Raycroft, et al. 2014. Autoantigens: novel forms and presentation to the immune system. Autoimmunity 47: 220–233
- Hedrich, C. M., J. C. Crispin, and G. C. Tsokos. 2014. Epigenetic regulation of cytokine expression in systemic lupus erythematosus. Autoimmunity 47: 234–241
- Rogatsky, I., U. Chandrasekaran, M. Manni, et al. 2014. Epigenetics and the IRFs: a complex interplay in the control of immunity and autoimmunity. Autoimmunity 47: 242–255
- Oaks, Z., and A. Perl. 2014. Metabolic control of the epigenome in systemic lupus erythematosus. Autoimmunity 47: 256–264
- Falli, T., C. Le Dantec, Y. Thabet, et al. 2014. DNA methylation modulates HRES1/p28 expression in B cells from patients with lupus. Autoimmunity 47: 265–271
- Zan, H., C. Tat, and P. Casali. 2014. microRNAs in lupus. Autoimmunity 47: 272–285