The Histone Modification Code in the Pathogenesis of Autoimmune Diseases

Hindawi Mediators of Inflammation Volume 2017, Article ID 2608605, 12 pages https://doi.org/10.1155/2017/2608605 Review Article The Histone Modification Code in the Pathogenesis of Autoimmune Diseases Yasuto Araki1,2 and Toshihide Mimura1,2 1 Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan 2 Correspondence should be addressed to Yasuto Araki; Received 21 October 2016; Accepted 8 December 2016; Published 3 January 2017 Academic Editor: Jin-Wen Xu Copyright © 2017 Y. Araki and T. Mimura. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes. 1. Introduction A loss of self-tolerance causes autoimmunity in which the aberrant immune system attacks the healthy cells and tissues, leading to chronic inflammation. The immune system requires a strict balance of stable and reversible gene expression to maintain the normal function of immune cells and to ward off the development of autoimmune diseases. A gain of autoreactivity in immune cells as well as a loss of suppressive functions in regulatory T cells (Tregs) has been suggested to be implicated in the autoimmune pathogenesis. Recently, it has been demonstrated that not only genetic and environmental factors but also epigenetic changes are involved in the etiology of autoimmune diseases. Epigenetic mechanisms, such as histone modifications, DNA methylation, and microRNAs (miRNAs) signaling, contribute to the maintenance of the normal immune response through the dynamic regulation of chromatin structure as well as gene transcription. Epigenetic dysregulation may modulate the functions of immune cells, resulting in autoimmunity. Therefore, epigenetic regulation is at present focused on in the field of autoimmune diseases. However, a number of different histone modifications exist and their interactions are complex. Thus, the studies of histone modifications in autoimmune diseases are limited, compared with DNA methylation and miRNAs that have been extensively investigated. Histone modifications have a potential for biomarkers and therapeutic targets of autoimmune diseases. This review summarizes the recent advances in the studies of the roles of histone modifications in autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary biliary cirrhosis (PBC), and type 1 diabetes (T1D). 2. The Pathogenesis of Autoimmune Diseases Autoimmune diseases are multifactorial disorders characterized by the loss of immunological tolerance to self-antigens and the presence of autoantibodies and/or autoreactive T and B cells. The autoimmune inflammation can involve multiple 2 organs, resulting in systemic autoimmune diseases, such as RA, SLE, and SSc. On the other hand, organ-specific autoimmune diseases, including PBC and T1D, occur when the autoimmune responses are limited to specific organs. To date, more than 80 specific autoimmune diseases have been identified. In 1957, Witebsky et al. defined an autoantibody based on certain criteria, such as (1) the direct demonstration of circulating antibodies that are active at body temperature or of cell-bound antibodies by indirect means, (2) the recognition of the specific antigen against which this antibody is directed, (3) the production of antibodies against the same antigen in experimental animals, and (4) the appearance of pathological changes in the corresponding tissues of an actively sensitized experimental animal that are basically similar to those in human disease [1]. In 1963, Mackay and Burnet defined autoimmune diseases in their Autoimmune Diseases textbook as “a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against normal components of the body” that was induced by the emergence of “forbidden” (autoreactive) clones of lymphocytes [2]. In addition, they noted that the diseases were characterized by (1) autoantibodies, (2) hypergammaglobulinemia, (3) tissue deposition of immune complexes, (4) lymphocytic and plasma cell accumulation in the affected tissues, (5) the therapeutic benefit from corticosteroids, and (6) the overlap of differing autoimmune manifestations in the same patient. Previously, Burnet had proposed the clonal selection theory, in which antigen “C” selects “C”-specific lymphocytes and stimulates their proliferation, as either antibody-producing plasma cells or memory cells, and was awarded the Nobel Prize for discovery of acquired immunological tolerance in 1960 [3]. Based on this theory, immunological self-tolerance is caused by the deletion of self-reactive clones, whereas autoimmunity arises by the emergence of self-reactive clones [4]. In 1995, Sakaguchi et al. identified CD4+ CD25high Tregs that suppress the functions of CD4+ effector T cells [5]. At present, Tregs, which were later shown to be FOXP3+ cells, are thought to maintain immunological self-tolerance and prevent autoimmune diseases [6]. It is postulated that environmental elements trigger autoimmune diseases in genetically predisposed individuals [7]. A number of genome-wide association studies have demonstrated that the susceptibility to autoimmune diseases is affected by multiple risk genes, including human leukocyte antigen (HLA) genes as well as non-HLA genes that are related to cellular and humoral immune responses [8–13]. Several studies have shown high concordance rates in monozygotic twins compared with dizygotic twins or sibling pairs, indicating a strong contribution of a genetic component in autoimmune diseases [14]. However, the disease concordance in monozygotic twin (...truncated)