Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation.
Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation.
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DOI：
10.1016/j.jaci.2013.01.042
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发表时间：
2013-06
影响因子：
14.2
通讯作者：
de Villartay, Jean-Pierre
中科院分区：
文献类型：
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作者：
Moshous, Despina;Martin, Emmanuel;Carpentier, Wassila;Lim, Annick;Callebaut, Isabelle;Canioni, Danielle;Hauck, Fabian;Majewski, Jacek;Schwartzentruber, Jeremy;Nitschke, Patrick;Sirvent, Nicolas;Frange, Pierre;Picard, Capucine;Blanche, Stephane;Revy, Patrick;Fischer, Alain;Latour, Sylvain;Jabado, Nada;de Villartay, Jean-Pierre
关键词：
颗粒依赖性细胞毒性的遗传缺陷导致危及生命的免疫病症噬血细胞性淋巴组织细胞增多症（HLH），其特征在于不受控制的CD 8 T细胞和巨噬细胞活化。在一组遗传异常的HLH患者中，预期会导致穿孔素、Rab 27 a或突触融合蛋白-11完全缺失，我们发现根据HLH发作时的年龄确定的疾病严重程度存在显著差异，严重程度梯度为穿孔素（早发）> Rab 27 a>突触融合蛋白-11（晚发）。与此同时，我们已经产生了一个syntaxin-11缺陷（Stx 11 −/−）小鼠模型，忠实地再现了淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后HLH的表现。Stx 11 −/−小鼠淋巴细胞表现出脱颗粒缺陷，可以通过表达人syntaxin-11而不是表达C-末端截短突变体来挽救。在3种人类疾病的小鼠对应物中，LCMV感染诱导的HLH特征的比较揭示了HLH表现的表型严重程度的相似梯度。值得注意的是，HLH的严重程度与LCMV载量无关，也不完全与细胞毒活性强度的差异相关。Rab 27 a-和Syntaxin-11-缺陷突变体之间的抗原呈递能力在体内不同。我们的数据表明，细胞毒性效应可能有其他的免疫调节作用，除了他们在控制病毒复制的作用。
Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.
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影响因子：
2.2
作者：
Lim, A;Baron, V;Pannetier, C
通讯作者：
Pannetier, C
影响因子：
11.4
作者：
Linka, R. M.;Risse, S. L.;Borkhardt, A.
通讯作者：
Borkhardt, A.
DOI：
10.4049/jimmunol.0804256
发表时间：
2009-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Astrakhan A;Ochs HD;Rawlings DJ
通讯作者：
Rawlings DJ
DOI：
10.1084/jem.20111692
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mou F;Praskova M;Xia F;Van Buren D;Hock H;Avruch J;Zhou D
通讯作者：
Zhou D
影响因子：
3.9
作者：
Lalonde, Emilie;Albrecht, Steffen;Jabado, Nada
通讯作者：
Jabado, Nada