HDAC Inhibition in Lupus Models
HDAC Inhibition in Lupus Models
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DOI：
10.2119/molmed.2011.00055
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发表时间：
2011-05-01
影响因子：
5.7
通讯作者：
Mishra, Nilamadhab
中科院分区：
文献类型：
--
作者：
Reilly, Christopher M.;Regna, Nicole;Mishra, Nilamadhab
系统性红斑狼疮（SLE）是一种典型的自身免疫性炎症性疾病，其特征在于产生针对核抗原的自身抗体，所述核抗原例如在身体细胞和血浆中发现的核小体、DNA和组蛋白。自身抗体可通过形成免疫复合物而诱发疾病，该免疫复合物驻留在靶器官中或通过与靶抗原发生交叉反应并损伤组织。除了自身抗体产生之外，凋亡缺陷和凋亡细胞的受损去除有助于引发自身免疫应答的自身抗原的过载。除了公认的SLE遗传易感性外，环境和表观遗传因素在疾病发病机制中起着至关重要的作用，单卵双胞胎通常对疾病不一致。DNA甲基化和组蛋白乙酰化的变化改变基因表达，并被认为有助于疾病中的表观遗传失调。在SLE中，已经证明发生了全局和基因特异性DNA甲基化变化。此外，异常组蛋白乙酰化在SLE患者中是明显的。此外，组蛋白去乙酰化酶抑制剂（HDACi）已被证明可以逆转SLE中涉及的多个基因的偏斜表达。在这篇综述中，我们讨论了表观遗传学改变在SLE的发展和进展中的意义，以及旨在改变组蛋白乙酰化状态的治疗方法如何可能成为靶向疾病的一种有前途的途径。(C)2011 Feinstein医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00055
Systemic lupus erythematosus (SLE) is a prototypic autoimmune inflammatory disease characterized by the production of autoantibodies directed against nuclear antigens such as nucleosomes, DNA and histone proteins found within the body's cells and plasma. Autoantibodies may induce disease by forming immune complexes that lodge in target organs or by crossreacting with targeted antigens and damaging tissue. In addition to autoantibody production, apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, environmental and epigenetic factors play a crucial role in disease pathogenesis as evidenced by monozygotic twins typically being discordant for disease. Changes in DNA methylation and histone acetylation alter gene expression and are thought to contribute to the epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Additionally, aberrant histone acetylation is evident in individuals with SLE. Moreover, histone deacetylase inhibitors (HDACi) have been shown to reverse the skewed expression of multiple genes involved in SLE. In this review, we discuss the implications of epigenetic alterations in the development and progression of SLE, and how therapeutics designed to alter histone acetylation status may constitute a promising avenue to target disease. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00055