nature20121129-8

长期以来白细胞被视作是免疫系统的英雄。当感染发生时,骨髓中生成的细胞通过血液循环到达感染位点对抗病原体。然而新研究表明个别的器官也能在免疫系统防御中发挥作用,本质上它们是自己的英雄。洛克菲勒大学的科学家们发现健康人的脑细胞有可能生成自己的免疫系统分子,显示了对于阻止感染至关重要的一种“内在免疫”。

 -2012年11月29日《自然》

中文翻译


【题目】人类iPSC来源的TLR3缺陷的CNS细胞中对HSV-1的先天性免疫受损

【译文】1-型单纯疱疹病毒(HSV-1)初次感染阶段,先天性缺陷toll样受体3 (TLR3)免疫的儿童易患HSV-1脑炎(HSE)。 我们验证了HSE的发病涉及到非造血性CNS固有细胞的假说。我们从TLR3-和UNC-93B缺陷患者及正常对照的皮肤成纤维细胞获得了可诱导多能性干细胞(iPSCs)。这些iPSC分化成神经元干细胞(NSCs)、神经元、星形胶质细胞和少突胶质细胞高度纯化的群体。在所有受检细胞中,应答dsRNA类似物聚肌苷酸聚胞苷酸(poly(I:C))时干扰素β(IFN-β)和/或IFN-λ1的诱导依赖于TLR3和UNC-93B。然而,对HSV-1感染应答的IFN-β和IFN-λ1的诱导在UNC-93B缺陷的神经元和少突胶质细胞中被选择性地损伤了。相比对照细胞,这些细胞也对HSV-1感染更加敏感,而UNC-93B缺陷的NSC和星形胶质细胞却不是如此。 我们也发现TLR3缺陷的神经元对HSV-1感染很敏感。具有相应野生型等位基因的UNC-93B-和TLR3-缺陷细胞的恢复表明遗传缺陷是引起poly(I:C) 和HSV-1表型的原因。通过用外源性IFN-α或IFN-β ( IFN-α/β)而非IFN-λ1处理,会更进一步恢复病毒感染表型。因此,CNS中对HSV-1的受损的TLR3-和UNC-93B依赖的IFN-α/β内在免疫,尤其是在神经元和少突胶质细胞中,可能是伴随TLR3通路缺陷的儿童HSE发病的原因。

英文原稿


[Title]: Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

[Authors]:Fabien G. Lafaille,1, 2, 16 Itai M. Pessach,3, 4, 16 Shen-Ying Zhang,5, 6, 16 Michael J. Ciancanelli,5 Melina Herman,5, 6 Avinash Abhyankar,5 Shui-Wang Ying,7 Sotirios Keros,8 Peter A. Goldstein,7 Gustavo Mostoslavsky,9 Jose Ordovas-Montanes,3 Emmanuelle Jouanguy,5, 6 Sabine Plancoulaine,6 Edmund Tu,1, 2 Yechiel Elkabetz,10 Saleh Al-Muhsen,11 Marc Tardieu,12 Thorsten M. Schlaeger,13 George Q. Daley,13 Laurent Abel,5, 6 Jean-Laurent Casanova,5, 6, 14 Lorenz Studer1, 2 & Luigi D. Notarangelo

[Abstract]In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-β (IFN-β) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-β ( IFN-α/β) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.

原文地址

http://www.nature.com/nature/journal/v491/n7426/full/nature11583.html

 

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