Department of Pathophysiology, School of Medicine, University of Athens, Mikras Asias Str 75, 115 27, Athens, Greece.
Department of Pathophysiology, School of Medicine, University of Athens, Mikras Asias Str 75, 115 27, Athens, Greece.
J Autoimmun. 2019 Nov;104:102315. doi: 10.1016/j.jaut.2019.102315. Epub 2019 Aug 15.
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.
自身免疫性疾病的特征是免疫系统对自身抗原的反应性增加，导致组织损伤。尽管其病因在很大程度上仍然未知，但遗传、微生物、环境和心理因素被认为是促成因素。表观遗传变化，包括 DNA 和组蛋白的共价修饰，是基因组与环境之间的关键信号转导介质，因此是细胞功能的有力调节剂。研究最多的表观遗传修饰是胞嘧啶 DNA 甲基化和各种残基上的组蛋白乙酰化和甲基化。这些修饰被认为会影响染色质结构和特定效应因子的结合，从而调节转录、复制和其他过程。最近的研究发现，与健康个体的样本相比，自身免疫性疾病患者来源的细胞或组织中存在显著的表观遗传改变，并将其与疾病表型联系起来。特定基因中的表观遗传变化与转录的上调或下调相关。例如，在许多系统中，干扰素诱导基因的 DNA 甲基化减少和组蛋白乙酰化增加与它们在自身免疫性疾病患者中的表达增加相关。此外，反转录元件的 DNA 甲基化减少被提出作为一种激活机制，并与免疫反应性增加相关，而 X 染色体上的表观遗传差异可能表明不完全的剂量补偿，并在一定程度上解释了女性比男性更容易患上大多数自身免疫性疾病的原因。除了表观遗传修饰的变化外，在自身免疫患者中还检测到催化这些标记添加或去除的许多酶以及识别它们并作为效应分子发挥功能的蛋白质的水平存在差异。尽管现有知识尚不能完全解释表观遗传改变是导致免疫激活增加的原因还是结果，但对其进行特征描述对于理解发病机制非常有用，并补充了遗传和临床研究。此外，特定的表观遗传标记有可能作为疾病状态、预后和对治疗反应的生物标志物。最后，表观遗传因素目前正在被作为候选治疗靶点进行研究。
