Centre of Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
Department for Medical Microbiology and Hygiene, Institute of Immunology, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
Front Immunol. 2013 Dec 16;4:448. doi: 10.3389/fimmu.2013.00448. eCollection 2013.
Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of hyperinflammation resulting from immune dysregulation due to inherited defects in the cytolytic machinery of natural killer and T cells. In humans, mutations in seven genes encoding proteins involved in cytolytic effector functions have so far been identified that predispose to HLH. However, although most affected patients develop HLH eventually, disease onset and severity are highly variable. Due to the genetic heterogeneity and variable time and nature of disease triggers, the immunological basis of these variations in HLH progression is incompletely understood. Several murine models of primary HLH have been established allowing to study HLH pathogenesis under more defined conditions. Here we directly compare the clinical HLH phenotype in six HLH-prone mouse strains with defects in the granule-dependent cytotoxic pathway. A severity gradient of HLH manifestations could be identified that is defined by the genetically determined residual lytic activity of cytotoxic T lymphocytes (CTL) and their ability to control lymphocytic choriomeningitis virus, which was used as a trigger for disease induction. Importantly, analysis of cohorts of HLH patients with severe bi-allelic mutations in the corresponding genes yielded a similar severity gradient in human HLH as reflected by the age at disease onset. Our findings define HLH as a threshold disease determined by subtle differences in the residual lytic activity of CTL.
原发性噬血细胞性淋巴组织细胞增生症（HLH）是一种危及生命的炎症过度活跃性疾病，是由于自然杀伤细胞和 T 细胞的细胞溶解机制的遗传性缺陷导致免疫失调引起的。在人类中，迄今为止已经鉴定出七个编码参与细胞溶解效应功能的蛋白的基因突变，这些突变易导致 HLH。然而，尽管大多数受影响的患者最终会发展为 HLH，但疾病的发作和严重程度差异很大。由于遗传异质性以及疾病触发的时间和性质的变化，这些 HLH 进展差异的免疫学基础尚不完全清楚。已经建立了几种原发性 HLH 的小鼠模型，允许在更明确的条件下研究 HLH 的发病机制。在这里，我们直接比较了六种依赖颗粒的细胞毒性途径缺陷的 HLH 易感小鼠品系的临床 HLH 表型。可以确定 HLH 表现的严重程度梯度，该梯度由细胞毒性 T 淋巴细胞（CTL）的遗传决定的残留溶解活性及其控制淋巴细胞性脉络丛脑膜炎病毒的能力定义，后者被用作疾病诱导的触发因素。重要的是，对具有相应基因的严重双等位基因突变的 HLH 患者队列的分析得出了与人类 HLH 相似的严重程度梯度，这反映在疾病发作的年龄上。我们的研究结果将 HLH 定义为一种由 CTL 的残留溶解活性的细微差异决定的阈值疾病。
