Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis.
Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis.
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DOI：
10.1084/jem.20062447
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发表时间：
2007-04-16
期刊：
影响因子：
--
通讯作者：
Beutler B
中科院分区：
文献类型：
--
作者：
Crozat K;Hoebe K;Ugolini S;Hong NA;Janssen E;Rutschmann S;Mudd S;Sovath S;Vivier E;Beutler B
小鼠巨细胞病毒（MCMV）的易感性通常是由自然杀伤细胞（NK）功能缺陷引起的。在这里，我们描述了Jinx，一种n -乙基-n -亚硝基源诱导的MCMV易感性突变，它允许病毒不受控制的增殖，导致死亡。在Jinx纯合子中，活化的NK细胞和细胞毒性T淋巴细胞（ctl）不能脱颗粒，尽管它们保留产生细胞因子的能力，并且在感染突变小鼠的血液中细胞因子水平显着升高。Jinx被定位到小鼠第11染色体上共246个减数分裂上，局限于包含122个注释基因的460万个碱基对关键区域。该表型归因于在Unc13d中创建了一个新的供体剪接位点，Unc13d是人类MUNC13-4的小鼠同源物，其突变导致3型家族性噬血细胞淋巴组织细胞病（FHL3），这是一种致命的疾病，其特征是大量肝脾肥大、贫血和血小板减少。Jinx小鼠不会自发出现噬血细胞性淋巴组织细胞增多症（HLH）的临床特征，但当感染淋巴细胞性脉络丛脑膜炎病毒时，会出现这种症状，表现为ctl和抗原呈递细胞的过度活化，以及对病毒增殖的限制不足。相比之下，单核细胞增生李斯特菌和MCMV都不会引起这种综合征。在小鼠中，HLH表型是有条件的，这表明在人类中存在特定的感染触发FHL3。
Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.
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