三篇Nature子刊发布免疫学里程碑成果 - 中国病毒学论坛|我们一直在坚持！

导读：阿斯利康旗下MedImmune日前公布了免疫学研究的重要里程碑。他们在Nature Immunology杂志上连发三篇文章，揭示了慢性阻塞性肺病COPD和系统性红斑狼疮SLE病背后鲜为人知的分子机制。

此前人们发现，吸烟会改变肺部免疫系统的活性，对2型固有淋巴细胞（ILC2）有明显影响。这项研究显示，吸烟或感染会使小鼠肺部的组织保护性ILC2发生变化。这些细胞在白介素IL-12和IL-18的作用下，获得了与炎症性ILC1类似的特性。研究人员认为，上述ILC2转变存在于慢性阻塞性肺病COPD中。因为循环ILC1在血液中的比例越高，COPD患者的病情就更严重。

COPD是一种常见的呼吸系统疾病，严重危害着人类健康。这项研究表明，循环ILC的变化可以用来预测患者的疾病风险。人们还可以想办法让ILC1变回ILC2，以此治疗COPD恶化。“我们展示了免疫系统的强大可塑性，”MedImmune的Alison Humbles博士说。“通过细胞类型的简单转化，免疫系统实现了组织保护与炎症之间的切换。”

固有淋巴细胞ILC是近几年发现的新型免疫细胞，不仅在先天免疫抵御病原体的过程中起到了核心作用，也在炎症类疾病中扮演着重要的角色。一些研究者把这些细胞比作是保护边界组织的步兵，因为它们能够帮助皮肤、肺壁、和肠道壁抵御微生物的侵袭。Mainz大学和Freiburg大学的科学家们在Cell杂志上发表文章，为人们揭示了ILC的关键前体细胞，以及一个此前未知的新型ILC。

Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.

这篇文章进一步探索了ILC1与ILC2之间的转变，鉴定了ILC2可塑性的关键调控子——IL-1。研究人员发现，细胞因子IL-1提供的信号会显著增加ILC2的数量，使其成为功能完全的成熟细胞。在IL-12存在的情况下，IL-1能刺激ILC2转变为ILC1。此外，IL-1还是上皮源性细胞因子（IL-33、IL-25和TSLP）的上游调控子，这些细胞因子在ILC2活化中起到了重要作用。

“这项研究开辟了全新的ILC2研究线路，”MedImmune的Yoichiro Ohne博士说。“我们现在进一步了解了ILC2的活性调控以及关键的触发因子，在疾病中靶标这些细胞有了更多的选择。这是开发新疗法限制有害炎症的重要一步。”

去年年底Nature Immunology杂志发表的一项研究指出，阑尾在固有淋巴细胞（ILC）的帮助下对消化系统健康起到了关键作用。阑尾并不是多余的退化器官，而是默默做出贡献的无名英雄。研究人员发现，对于免疫系统存在缺陷的人来说固有淋巴细胞是非常重要的。这些细胞保护阑尾避免细菌感染，帮助阑尾成为好细菌的天然“水库”，对机体健康产生重要影响。

Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1β was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1β also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rβ2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-α(IFN-α) and the loci encoding IL-5 and IL-13. Finally, IL-1β potentiated ILC2 activation and plasticityin vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1β in facilitating ILC2 maturation and plasticity.

IgE是一种广为人知的抗体，在过敏中靶标过敏原并引起组胺反应。MedImmune的研究团队发现，IgE发生故障的时候也能靶标机体自身的DNA，触发免疫系统活化分子IFN-α的分泌，最终引起红斑狼疮相关的组织损伤。这项研究中54.4%的红斑狼疮患者具有DNA特异性IgE。

系统性红斑狼疮是一种自身免疫疾病，在世界上影响了至少数百万人。红斑狼疮的症状包括发疹、关节痛、贫血和肾脏损伤，若肾脏衰竭或血栓这样的并发症未得到有效治疗，患者就可能有生命危险。研究人员指出，患者血液中的DNA特异性IgE浓度与疾病的严重程度有关。这种IgE可以用来评估红斑狼疮治疗的有效性，也能成为治疗红斑狼疮的新靶标。

我们的免疫系统会对进入机体的外源物质展开攻击。严格来讲食物也算是外源物质，但机体却能够耐受它们以便吸取营养。这是因为免疫系统的内在机制会阻止它对有益抗原产生反应。如果这样的耐受机制出现问题，我们就会遭遇可能致命的食物过敏。近年来食物过敏发病率在不断升高，但科学家们还不清楚食物免疫耐受是如何建立的。前不久，韩国科学家们在Science杂志上发表文章阐明了这一过程中的关键机制。

Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcεRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.