Unexpected link between mitochondrial DNA and T cell help in systemic lupus erythematosus.
Unexpected link between mitochondrial DNA and T cell help in systemic lupus erythematosus.
复制标题
线粒体 DNA 和 T 细胞之间的意外联系有助于治疗系统性红斑狼疮。
DOI：
10.1136/annrheumdis-2019-215597
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发表时间：
2019
影响因子：
27.4
通讯作者：
Pisetsky,DavidS
中科院分区：
文献类型：
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作者：
Pisetsky,DavidS
自从发现抗 DNA 抗体以来，DNA 作为系统性红斑狼疮 (SLE) 自身免疫的靶点一直备受关注。 1 作为遗传物质，DNA 通常隐藏在细胞核的安全范围内，不被免疫系统发现。那么DNA如何成为自身抗原呢？答案在于 DNA 的地理易位能力。与许多分子一样，DNA 可以在细胞周围移动，甚至逃逸到细胞外，尤其是在细胞死亡期间。 2 根据机制，细胞死亡可诱发炎症，提供佐剂活性以诱导抗 DNA 产生。抗体诱导的另一种机制是在感染过程中与另一种外来抗原甚至自身抗原的交叉反应，这是强烈的免疫激活的环境。个体的遗传背景可能会影响这些反应。 3 一旦离开细胞，DNA 就可以通过与抗 DNA 抗体形成免疫复合物来显示免疫特性。这些复合物在疾病中具有两个关键作用：沉积在肾脏中以引发肾炎，以及通过与在各种亚细胞区室中运行的 Toll 样受体 (TLR) 和非 TLR 内部核酸传感器相互作用来刺激细胞因子的产生。 4 这些传感器的位置与细胞膜上的 TLR 受体（例如 TLR4）的位置形成对比。虽然对感染的反应通常被概念化为从血液或组织的细胞外空间开始，但细胞内空间也是宿主防御的重要部位，内部核酸传感器是激活先天免疫的关键。在感染过程中，这些内部传感器可以结合来自细胞内细菌或病毒感染的DNA（以及RNA），并触发与细胞外病原体相关分子模式激活的系统相同的系统。 5–7 线粒体 DNA (mtDNA) 也可以在细胞应激期间触发这些传感器，因为线粒体会泄漏或释放其 DNA。 8 9 mtDNA 在遗传上与染色体 DNA 分离，编码多种线粒体蛋白，但其具有免疫刺激作用的未甲基化 CpG 碱基序列（CpG 基序）的含量与染色体 DNA 不同。 mtDNA 与其他线粒体结构一起，具有免疫学潜力，反映了线粒体作为共生细菌的假定起源。 10 虽然含 DNA 的免疫复合物在被树突细胞吸收后可以触发内部传感器，但 mtDNA 也可以单独发挥作用，触发先天免疫反应。正如 Caielli 及其同事在《自然医学》杂志上进行的一项优雅且具有挑战性的研究所示，游离或“裸露”mtDNA 的免疫活性非常重要。 11 事实上，正如本文中令人信服的实验所表明的，细胞外氧化 mtDNA 可以启动树突细胞激活的独特模式，进而导致 CD4+ 辅助 T 细胞的激活，从而通过白细胞介素 (IL)-10 和琥珀酸为 B 细胞提供帮助。树突状细胞的 DNA 刺激、辅助 T 细胞的诱导以及信号代谢物的表达之间的联系是新颖且出乎意料的，并提出了可能进行治疗干预的新步骤。关于 mtDNA 在 SLE 中的作用的故事始于重要的研究，这些研究表明中性粒细胞可以释放诱导 1 型干扰素 (IFN) 的 DNA，即所谓的干扰性 DNA；这种释放主要发生在 NETosis 期间。 12 13 释放的 DNA 部分来自线粒体，根据细胞的状态，线粒体 DNA 可能会因靠近电子传输系统而发生氧化。 10 通常情况下，
Since the discovery of anti-DNA antibodies, DNA has been the subject of fascination as a target of autoimmunity in systemic lupus erythematosus (SLE). 1 As the material of heredity, DNA is usually hidden from the immune system in the safe confines of the cell nucleus. How then can DNA become an autoantigen? The answer lies in DNA’s capacity for geographic translocation. Like many molecules, DNA can move around the cell and even escape outside, especially during cell death. 2 Depending on the mechanism, cell death can induce inflammation, providing adjuvant activity to induce anti-DNA production. Another mechanism for antibody induction is cross-reactivity with another foreign or even self-antigen during infection, a setting for intense immune activation. The genetic background of the individual may influence these responses. 3 Once outside the cell, DNA can display immunological properties by forming immune complexes with anti-DNA antibodies. These complexes have two key roles in disease: deposition in the kidney to incite nephritis and stimulation of cytokine production via interaction with both Toll-like receptor (TLR) and non-TLR internal nucleic acid sensors that operate in various subcellular compartments. 4 The location of these sensors contrasts with that of TLR receptors such as TLR4, which are found on the cell membrane. While the response to infection is usually conceptualised as beginning in the extracellular space in the blood or tissue, the intracellular space is also an important site of host defence, with internal nucleic acid sensors key to activation of innate immunityDuring infection, these internal sensors can bind DNA (as well as RNA) from intracellular bacterial or viral infection and trigger the same systems as those activated by extracellular pathogen associated molecular patterns. 5–7 Mitochondrial DNA (mtDNA) can also trigger these sensors during cell stress since mitochondria can leak or release their DNA. 8 9 Genetically separate from chromosomal DNA, mtDNA encodes several mitochondrial proteins but differs from chromosomal DNA in terms of its content of unmethylated CpG base sequences (CpG motifs) that are immunostimulatory. Reflecting the presumed origin of mitochondria as symbiotic bacteria, mtDNA, along with other mitochondrial structures, has immunological potential. 10 While DNA-containing immune complexes can trigger the internal sensors following uptake into dendritic cells, mtDNA can also act alone to trigger innate immune responses. As shown in an elegant and provocative study by Caielli and colleagues in Nature Medicine, the immune activity of free or ‘naked’mtDNA is significant. 11 Indeed, as compelling experiments in this paper show, extracellular oxidised mtDNA can initiate a unique pattern of dendritic cell activation that in turn leads to the activation of CD4+ helper T cells that provide help to B cells via interleukin (IL)-10 and succinate. The link between DNA stimulation of dendritic cells, the induction of helper T cells and the expression of metabolites that signal is novel and unexpected and suggests new steps in which therapeutic intervention is possible. The story on the role of mtDNA in SLE begins with important studies demonstrating that neutrophils can release DNA that induces type 1 interferon (IFN), so-called interferogenic DNA; this release occurs prominently during NETosis. 12 13 The DNA released derives in part from mitochondria, and depending on the state of the cell, mtDNA can undergo oxidation because of the proximity to the electron transport system. 10 Ordinarily,