浆细胞样树突状细胞通过信号素4a介导的调节性T细胞增殖在病毒性细支气管炎和哮喘中起保护作用
2018/05/30
摘要
呼吸道合胞体病毒 - 细支气管炎是引起后继哮喘的主要独立危险因素，但其原因机制仍不清楚。我们发现在初发肺炎病毒感染期间短暂的浆细胞样树突状细胞（pDC）耗竭易于在早期生活中患严重细支气管炎，在后期生活中再次感染后患后继哮喘。pDC消耗消除干扰素产生，增加病毒载量；然而，后继哮喘的免疫病理学和易感性的提高是由于pDC来源的信号素4a（Sema4a）的缺乏导致的功能性神经毡蛋白-1阳性调节性T（T reg）细胞增殖调节失败。在成年小鼠中，只有在抗生素治疗后，pDC缺失才易患严重细支气管炎。与微生物组的保护作用一致，用微生物来源的丙酸盐代谢物治疗pDC耗尽的新生儿促进了Sema4a依赖性T reg细胞的增殖，治疗也改善了这两种疾病。在病毒性细支气管炎患儿中，鼻腔丙酸酯水平降低，并与IL-6高/ IL-10低微环境相关。我们强调，pDC和微生物定植有一个共同的、与年龄有关的、Sema4a介导的通路，通过该通路诱导了T reg细胞增殖，进而在严重细支气管炎和后继哮喘中起保护作用。
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.
Lynch JP, Werder RB, Loh Z, Sikder MAA, Curren B, Zhang V, Rogers MJ, Lane K,Simpson J, Mazzone SB, Spann K, Hayball J, Diener K, Everard ML, Blyth CC,Forstner C, Dennis PG, Murtaza N, Morrison M, Ó Cuív P, Zhang P, Haque A, Hill GR, Sly PD, Upham JW, Phipps S.
Abstract
Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1 + regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6 high/IL-10 low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
呼吸道合胞体病毒 - 细支气管炎是引起后继哮喘的主要独立危险因素，但其原因机制仍不清楚。我们发现在初发肺炎病毒感染期间短暂的浆细胞样树突状细胞（pDC）耗竭易于在早期生活中患严重细支气管炎，在后期生活中再次感染后患后继哮喘。pDC消耗消除干扰素产生，增加病毒载量；然而，后继哮喘的免疫病理学和易感性的提高是由于pDC来源的信号素4a（Sema4a）的缺乏导致的功能性神经毡蛋白-1阳性调节性T（T reg）细胞增殖调节失败。在成年小鼠中，只有在抗生素治疗后，pDC缺失才易患严重细支气管炎。与微生物组的保护作用一致，用微生物来源的丙酸盐代谢物治疗pDC耗尽的新生儿促进了Sema4a依赖性T reg细胞的增殖，治疗也改善了这两种疾病。在病毒性细支气管炎患儿中，鼻腔丙酸酯水平降低，并与IL-6高/ IL-10低微环境相关。我们强调，pDC和微生物定植有一个共同的、与年龄有关的、Sema4a介导的通路，通过该通路诱导了T reg细胞增殖，进而在严重细支气管炎和后继哮喘中起保护作用。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Exp Med. 2017 Dec 22. pii: jem.20170298. )
(J Exp Med. 2017 Dec 22. pii: jem.20170298. )
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.
Lynch JP, Werder RB, Loh Z, Sikder MAA, Curren B, Zhang V, Rogers MJ, Lane K,Simpson J, Mazzone SB, Spann K, Hayball J, Diener K, Everard ML, Blyth CC,Forstner C, Dennis PG, Murtaza N, Morrison M, Ó Cuív P, Zhang P, Haque A, Hill GR, Sly PD, Upham JW, Phipps S.
Abstract
Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1 + regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6 high/IL-10 low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
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在使用吸入性糖皮质激素治疗的哮喘患者中的大型亚组中的难治性2型气道炎症
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过敏原诱导的NK细胞活化代表过敏性哮喘发展过程中的早期免疫应答
