Cytotoxic granule secretion by lymphocytes and its link to immune homeostasis.
Cytotoxic granule secretion by lymphocytes and its link to immune homeostasis.
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DOI：
10.12688/f1000research.6754.1
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Fischer, Alain
中科院分区：
文献类型：
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作者：
de Saint Basile, Genevieve;Sepulveda, Fernando E;Fischer, Alain
T和自然杀伤淋巴细胞的颗粒依赖性细胞毒活性已逐渐成为不仅用于宿主防御而且用于免疫调节的重要效应途径。对一种称为噬血细胞性淋巴组织细胞增多症（HLH）的早发性、严重的原发性免疫失调综合征的分析，在强调后者的作用和根据基因突变分析和细胞毒性颗粒成熟和分泌中的介质确定关键效应物方面具有决定性意义。对缺乏细胞毒性的小鼠对应物的研究有助于将原发性HLH定义为一种综合征，其中响应于淋巴细胞性脉络丛脑膜炎病毒感染的不受控制的T细胞活化导致过度的巨噬细胞活化和炎症相关的血细胞减少。最近认识到迟发性HLH，发生在各种设置，与亚型，单等位基因突变的基因编码的颗粒依赖性细胞毒性途径的组件，甚至在没有这样的突变，拓宽了我们的看法的机制，免疫稳态的扰动。这些发现导致了一种模型的发展，在这种模型中，当通过遗传和环境风险因素的积累达到阈值时，疾病就会发生。然而，这一模式的验证将需要进一步的调查。
The granule-dependent cytotoxic activity of T and natural killer lymphocytes has progressively emerged as an important effector pathway not only for host defence but also for immune regulation. The analysis of an early-onset, severe, primary immune dysregulatory syndrome known as hemophagocytic lymphohistiocytosis (HLH) has been decisive in highlighting this latter role and identifying key effectors on the basis of gene mutation analyses and mediators in the maturation and secretion of cytotoxic granules. Studies of cytotoxicity-deficient murine counterparts have helped to define primary HLH as a syndrome in which uncontrolled T-cell activation in response to lymphocytic choriomeningitis virus infection results in excessive macrophage activation and inflammation-associated cytopenia. Recent recognition of late-onset HLH, which occurs in a variety of settings, in association with hypomorphic, monoallelic mutations in genes encoding components of the granule-dependent cytotoxic pathway or even in the absence of such mutations has broadened our view about the mechanisms that underlie the perturbation of immune homeostasis. These findings have led to the development of a model in which disease occurs when a threshold is reached through the accumulation of genetic and environmental risk factors. Nevertheless, validation of this model will require further investigations.