Wu Haijing, Zhao Ming, Yoshimura Akihiko, Chang Christopher, Lu Qianjin
Department of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Clin Rev Allergy Immunol. 2016 Jun;50(3):333-44. doi: 10.1007/s12016-016-8534-y.
Autoimmune diseases occur when the immune system loses tolerance to self-antigens, inducing inflammation and tissue damage. The pathogenesis of autoimmune diseases has not been elucidated. A growing mountain of evidence suggests the involvement of genetic and epigenetic factors in the development of these disorders. Genetic mapping has identified several candidate variants in autoimmune conditions. However, autoimmune diseases cannot be explained by genetic susceptibility alone. The fact that there is only 20 % of concordance for systemic lupus erythematosus (SLE) in homozygotic twins is an indication that epigenetics and environment may also play significant roles. Epigenetics refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. The primary mechanisms of epigenetic regulation include DNA methylation, histone modification, and non-coding RNA-mediated regulation. The regulation on gene expression by epigenetics is similar to that by transcription factors (TFs), and the normal execution of biological event is controlled by a combination of epigenetic modifications and TFs. These two mechanisms share similar regulatory logistics and cooperate in part by influencing activity of the binding sites of target genes. In addition, the promoters of TFs have been found themselves to be modified by epigenetic regulators and TFs can also induce epigenetic changes. There is a two-way street in which interplay between epigenetic regulation and TFs plays a role in the pathogenesis of SLE, rheumatoid arthritis, type 1 diabetes, systemic sclerosis, and multiple sclerosis. Understanding of pathogenesis of these autoimmune diseases will help define potential targets for therapeutic strategies.
当免疫系统对自身抗原失去耐受性，引发炎症和组织损伤时，自身免疫性疾病就会发生。自身免疫性疾病的发病机制尚未阐明。越来越多的证据表明，遗传和表观遗传因素参与了这些疾病的发生发展。基因定位已经在自身免疫性疾病中确定了几个候选变异体。然而，自身免疫性疾病不能仅用遗传易感性来解释。同卵双胞胎中系统性红斑狼疮（SLE）的一致性仅为20%这一事实表明，表观遗传学和环境也可能起重要作用。表观遗传学是指DNA和染色质中可遗传且可能可逆的变化，这些变化在不改变DNA序列的情况下调节基因表达。表观遗传调控的主要机制包括DNA甲基化、组蛋白修饰和非编码RNA介导的调控。表观遗传学对基因表达的调控类似于转录因子（TFs）的调控，生物事件的正常执行由表观遗传修饰和TFs共同控制。这两种机制具有相似的调控逻辑，部分通过影响靶基因结合位点的活性而协同作用。此外，已发现TFs的启动子本身会被表观遗传调节因子修饰，并且TFs也能诱导表观遗传变化。表观遗传调控与TFs之间的相互作用在SLE、类风湿性关节炎、1型糖尿病、系统性硬化症和多发性硬化症的发病机制中发挥作用，这是一条双向道路。了解这些自身免疫性疾病的发病机制将有助于确定治疗策略的潜在靶点。
