Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.
Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.
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DOI：
10.1016/j.jaci.2017.11.063
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Benvenuti F
中科院分区：
文献类型：
--
作者：
Cervantes-Luevano KE;Caronni N;Castiello MC;Fontana E;Piperno GM;Naseem A;Uva P;Bosticardo M;Marcovecchio GE;Notarangelo LD;Cicalese MP;Aiuti A;Villa A;Benvenuti F
Wiskott-Aldrich综合征（WAS）是一种罕见的原发性免疫缺陷，由Wiskott-Aldrich综合征蛋白（WASp）突变引起，WASp是造血细胞中细胞骨架动力学的关键调节因子。高比例的患者经历由T细胞和B细胞耐受性破坏引起的自身免疫。此外，浆细胞样树突状细胞（pDC）过度产生I型干扰素（IFN-I）有助于自身免疫性体征;然而，触发过度先天激活的因素尚未确定。神经细胞外陷阱（NET）成为系统性红斑狼疮和类风湿关节炎等疾病患者的主要启动因素。在这项研究中，我们探讨了异常的中性粒细胞功能在WAS患者的可能参与。我们评估了一组WAS患者中与NET相关的粒细胞基因的表达以及血清中NET诱导剂的存在。使用WAS的小鼠模型，我们分析了WASP无效中性粒细胞的NET释放，并评估了体内中性粒细胞的组成和稳态。通过消耗实验，我们评估了中性粒细胞在促进炎症和对自身抗原的反应性中的作用。WAS患者粒细胞中编码中性粒细胞酶和抗菌肽的基因转录物增加，血清可溶性因子触发NET释放。WASp缺失的中性粒细胞表现出自发性NETosis增加，诱导pDC产生IFN-I，并通过B细胞活化因子活化B细胞。一致地，它们的消耗消除了组成型pDC活化，使循环IFN-I水平正常化，并且重要的是，消除了针对双链DNA、核小体和髓过氧化物酶的自身抗体的产生。这些发现揭示了中性粒细胞参与了导致先天性细胞和自身反应性B细胞过度活化的致病循环，从而确定了导致WAS自身免疫的新机制。
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.
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发表时间：
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期刊：
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影响因子：
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作者：
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