Epigenetic perspectives on systemic autoimmune disease

J Autoimmun. 2019 Nov;104:102315. doi: 10.1016/j.jaut.2019.102315. Epub 2019 Aug 15.

Abstract

Autoimmune diseases are characterized by increased reactivity of the immune system towards self-antigens, causing tissue damage. Although their etiology remains largely unknown, genetic, microbial, environmental and psychological factors are recognized as contributing elements. Epigenetic changes, including covalent modifications of the DNA and histones, are critical signaling mediators between the genome and the environment, and thus potent regulators of cellular functions. The most extensively studied epigenetic modifications are Cytosine DNA methylation and histone acetylation and methylation on various residues. These are thought to affect chromatin structure and binding of specific effectors that regulate transcription, replication, and other processes. Recent studies have uncovered significant epigenetic alterations in cells or tissues derived from autoimmune disease patients compared to samples from healthy individuals and have linked them with disease phenotypes. Epigenetic changes in specific genes correlate with upregulated or downregulated transcription. For instance, in many systems, reduced DNA methylation and increased histone acetylation of interferon-inducible genes correlate with their increased expression in autoimmune disease patients. Also, reduced DNA methylation of retroelements has been proposed as an activating mechanism and has been linked with increased immune reactivity, while epigenetic differences on the X chromosome could indicate incomplete dosage compensation and explain to some extent the increased susceptibility of females over males towards the development of most autoimmune diseases. Besides changes in epigenetic modifications, differences in the levels of many enzymes catalyzing the addition or removal of these marks as well as proteins that recognize them and function as effector molecules have also been detected in autoimmune patients. Although the existing knowledge cannot fully explain whether epigenetic alterations cause or follow the increased immune activation, their characterization is very useful for understanding the pathogenetic mechanisms and complements genetic and clinical studies. Furthermore, specific epigenetic marks have the potential to serve as biomarkers for disease status, prognosis, and response to treatment. Finally, epigenetic factors are currently being examined as candidate therapeutic targets.

Keywords: Autoimmune; Epigenetic; RA; SLE; Sjögren's syndrome.

Publication types

  • Review

MeSH terms

  • Acetylation
  • Animals
  • Autoimmune Diseases* / genetics
  • Autoimmune Diseases* / immunology
  • DNA Methylation / immunology*
  • Epigenesis, Genetic / immunology*
  • Histones / immunology*
  • Humans

Substances

  • Histones