Epigenetics and autoimmunity Wesley H. Brooks a , Christelle Le Dantec b , Jacques-Olivier Pers b, c , Pierre Youinou b, c , Yves Renaudineau b, c, * a Experimental HTS, Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA b EA2216 Immunology and Pathology, IFR 148 ScInBioS, Université de Brest, Université Européenne de Bretagne, Brest, France c Laboratory of Immunology, CHU Brest, Hôpital Morvan, Brest, France Keywords: Autoimmune diseases Epigenetics DNA methylation Histone miRNA abstract Advances in genetics, such as sequencing of the human genome, have contributed to identification of susceptible genetic patterns in autoimmune diseases (AID). However, genetics is only one aspect of the diseases that does not reflect the influence of environment, sex or aging. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development, showing differences between AID patients and healthy controls but also showing how one disease differs from another. With regards to epigenetic abnormalities, DNA methylation and histone modifications could be affected leading to large spatial and temporal changes in gene regulation. Other epigenetic processes, such as the influence of the ionic milieu around chromatin and DNA supercoiling stresses may be suspected also. The newly described role of microRNAs in control of gene expression is important by promoting or suppressing autoreactivity in AID. As a consequence control of cellular processes is affected becoming conducive, for example, to the development of autoreactive lymphocytes in systemic lupus erythematosus, synoviocyte proliferation in rheumatoid arthritis, or neural demyelination in multiple sclerosis. Application of epigenetics to AID is in its infancy and requires new hypotheses, techniques, tools, and collaborations between basic epigenetic researchers and autoimmune researchers in order to improve our compre- hension of AID. From this will arise new therapeutics, means for early intervention, and perhaps prevention. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Epigenetics has emerged to explain how cells with a limited number of genes (30,000) can differentiate into alternative cell types and how a phenotype can be passed from one cell to its daughter cells [1]. Epigenetics can be defined as stable and heri- table changes in gene expression that do not involve alterations in DNA sequence. Thus, the epigenetic process is important for controlling patterns of gene expression during the cell cycle, development, and in response to environmental or biological modifications. Of note, is the observation that epigenetic mecha- nisms may be reversed and these changes can be rapid, particularly during the cell cycle, in response to a stimulus or after exposure to environmental factors. Epigenetic states change with age and can become disrupted by environmental influences, providing an explanation for the empirical link observed between environmental factors, aging and the development of autoimmune diseases (AID) [2]. In addition, the predisposition of women to autoimmunity may be explained, in part, by the role of X chromosome inactivation, a major epigenetic event [3]. Unlike genetic alterations which are permanent and affect all cells when passed through the germline, AID related epigenetic modifications are reversible and cell type specific: primarily CD4 þ T cells, regulatory T cells (Treg) and B cells in SLE [4,5], lymphocytes and synovial fibroblasts in RA, and lymphocytes and skin fibro- blasts in patients with systemic sclerosis (SSc) [6,7]. Epigenetic alterations concern also organ-specific AID, like type 1 diabetes, multiple sclerosis (MS), idiopathic thrombocytopenic purpura (ITP) or celiac disease. Last but not least, epigenetic dysregulations are not limited to idiopathic AID since they are also present in chem- ical/drug-induced AID [8]. Abreviations: AID, autoimmune disease; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; SSc, systemic sclerosis; MS, multiple sclerosis. * Correspondence to: Yves Renaudineau, Laboratory of Immunology, Brest University Medical School Hospital, BP824, F-29609 Brest, France. Tel.: þ33 298 22 33 84; fax: þ33 298 22 38 47. E-mail address: yves.renaudineau@univ-brest.fr (Y. Renaudineau). Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm 0896-8411/$ e see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2009.12.006 Journal of Autoimmunity 34 (2010) J207eJ219