The central role of nucleic acids in the pathogenesis of systemic lupus erythematosus.
The central role of nucleic acids in the pathogenesis of systemic lupus erythematosus.
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DOI：
10.12688/f1000research.17959.1
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Pisetsky, David S
中科院分区：
文献类型：
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作者：
Pisetsky, David S
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其发病机制可以通过基于抗核抗体和核酸之间的免疫复合物（IC）的中心作用的模型来概念化。根据该模型，IC可以通过两种主要机制促进发病机制：沉积在组织中以煽动局部炎症和与先天免疫系统的细胞相互作用以刺激细胞因子的产生，最突出的是1型干扰素。后一种刺激是由IC形式的DNA和RNA摄取到细胞中以及随后由DNA和RNA的内部核酸传感器发出信号引起的。这些传感器可能对细胞内感染的反应很重要，尽管它们也可能在细胞应激或损伤期间被细胞质中异常存在的DNA或RNA触发。对于IC的形成，细胞外DNA和RNA的来源是必不可少的。目前的SLE模型假定细胞死亡是IC中核酸的起源，清除机制的损伤增加了细胞外间隙中核物质的量。这种SLE模型很重要，因为它指出了新的治疗方法;靶向干扰素或干扰素受体的药物是源自这种模型的治疗方法的例子。未来的研究将探索新的生物标志物，以监测这些机制的运作，并阐明其他步骤的发病机制，可以有针对性的治疗。
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease whose pathogenesis can be conceptualized by a model based on a central role for immune complexes (ICs) between antinuclear antibodies and nucleic acids. According to this model, ICs can promote pathogenesis by two main mechanisms: deposition in the tissue to incite local inflammation and interaction with cells of the innate immune system to stimulate the production of cytokines, most prominently type 1 interferon. The latter stimulation results from the uptake of DNA and RNA in the form of ICs into cells and subsequent signaling by internal nucleic acid sensors for DNA and RNA. These sensors are likely important for the response to intracellular infection, although they may also be triggered during cell stress or injury by DNA or RNA aberrantly present in the cytoplasm. For IC formation, a source of extracellular DNA and RNA is essential. The current model of SLE posits that cell death is the origin of the nucleic acids in the ICs and that impairment of clearance mechanisms increases the amount of nuclear material in the extracellular space. This model of SLE is important since it points to new approaches to therapy; agents targeting interferon or the interferon receptor are examples of therapeutic approaches derived from this model. Future studies will explore novel biomarkers to monitor the operation of these mechanisms and to elucidate other steps in pathogenesis that can be targeted for therapy.