NETs: the missing link between cell death and systemic autoimmune diseases?
NETs: the missing link between cell death and systemic autoimmune diseases?
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DOI：
10.3389/fimmu.2012.00428
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发表时间：
2012
影响因子：
7.3
通讯作者：
Andrade F
中科院分区：
文献类型：
--
作者：
Darrah E;Andrade F
近20年来，在系统性自身免疫性疾病的发病模型中，细胞凋亡和继发性坏死被认为是自身抗原和内源性佐剂的主要来源。这种关注是合理的，部分原因是系统性红斑狼疮(SLE)的初步证据引导研究人员转向细胞凋亡的研究，但也因为其他形式的细胞死亡尚不清楚。到目前为止，已知存在许多其他形式的细胞死亡，它们刺激和抑制免疫系统的能力各不相同。其中，NETsis(中性粒细胞死亡的一种抗菌素形式，核物质从细胞中挤出形成细胞外陷阱)正受到人们的主要关注，因为它可能引发SLE、伴多血管炎的肉芽肿(以前称为韦格纳肉芽肿)和Felty综合征的一些免疫特征。虽然已经发表了大量关于细胞死亡在自身免疫中的作用的令人信服的研究，但还没有采用统一的理论，也没有基于这一重要途径开发任何成功的治疗方法。最近将网织红细胞增多症纳入自身免疫性疾病的致病模型，无疑为这一范式增加了新的见解，但也揭示了以前未被认识到的复杂性水平，并提出了许多新的问题。本文讨论了细胞死亡在系统性自身免疫性疾病中的作用，重点讨论了细胞凋亡和网织红细胞增多症，突出了目前我们对细胞死亡的巨大复杂性的理解的不足，并考虑了自身免疫中细胞死亡范式的潜在转变。了解这种复杂性对于开发工具以明确定义活跃在系统性自身免疫性疾病中的死亡途径、识别疾病传播的驱动因素以及开发新的治疗方法至关重要。
For almost 20 years, apoptosis and secondary necrosis have been considered the major source of autoantigens and endogenous adjuvants in the pathogenic model of systemic autoimmune diseases. This focus is justified in part because initial evidence in systemic lupus erythematosus (SLE) guided investigators toward the study of apoptosis, but also because other forms of cell death were unknown. To date, it is known that many other forms of cell death occur, and that they vary in their capacity to stimulate as well as inhibit the immune system. Among these, NETosis (an antimicrobial form of death in neutrophils in which nuclear material is extruded from the cell forming extracellular traps), is gaining major interest as a process that may trigger some of the immune features found in SLE, granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) and Felty’s syndrome. Although there have been volumes of very compelling studies published on the role of cell death in autoimmunity, no unifying theory has been adopted nor have any successful therapeutics been developed based on this important pathway. The recent inclusion of NETosis into the pathogenic model of autoimmune diseases certainly adds novel insights into this paradigm, but also reveals a previously unappreciated level of complexity and raises many new questions. This review discusses the role of cell death in systemic autoimmune diseases with a focus on apoptosis and NETosis, highlights the current short comings in our understanding of the vast complexity of cell death, and considers the potential shift in the cell death paradigm in autoimmunity. Understanding this complexity is critical in order to develop tools to clearly define the death pathways that are active in systemic autoimmune diseases, identify drivers of disease propagation, and develop novel therapeutics.