INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
Cell Imaging Platform, INSERM US24 Centre National de la Recherche Scientifique Unité Mixte de Service 3633, Structure Fédérative de Recherche Necker, Paris Descartes Sorbonne Paris Cité University, Paris, France;
Blood. 2016 Apr 28;127(17):2113-21. doi: 10.1182/blood-2015-12-688960. Epub 2016 Feb 10.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disease. Inherited forms of HLH are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. A small proportion of patients with a so-called "secondary" form of HLH, which develops in the aftermath of infection, autoimmunity, or cancer, carry a monoallelic mutation in one or more HLH-associated genes. Although this observation suggests that HLH may have a polygenic mode of inheritance, the latter is very difficult to prove in humans. In order to determine whether the accumulation of partial genetic defects in lymphocyte-mediated cytotoxicity can contribute to the development of HLH, we generated mice that were doubly or triply heterozygous for mutations in HLH-associated genes, those coding for perforin, Rab27a, and syntaxin-11. We found that the accumulation of monoallelic mutations did indeed increase the risk of developing HLH immunopathology after lymphocytic choriomeningitis virus infection. In mechanistic terms, the accumulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the dynamics and secretion of cytotoxic granules at the immune synapse of T lymphocytes. In addition, the accumulation of heterozygous mutations within the three genes impaired natural killer lymphocyte cytotoxicity in vivo. The genetic defects can be ranked in terms of the severity of the resulting HLH manifestations. Our results form the basis of a polygenic model of the occurrence of secondary HLH.
噬血细胞性淋巴组织细胞增生症（HLH）是一种危及生命的过度炎症性疾病。HLH 的遗传性形式是由颗粒依赖性淋巴细胞介导的细胞毒性的几个效应子的双等位基因突变引起的。一小部分所谓的“继发性”HLH 患者，即在感染、自身免疫或癌症后发展，携带一个或多个 HLH 相关基因中的单等位基因突变。尽管这一观察结果表明 HLH 可能具有多基因遗传模式，但在人类中很难证明后者。为了确定淋巴细胞介导的细胞毒性中部分遗传缺陷的积累是否有助于 HLH 的发展，我们生成了双重或三重杂合突变的 HLH 相关基因、穿孔素、Rab27a 和 syntaxin-11 的小鼠。我们发现，单等位基因突变的积累确实增加了在淋巴细胞性脉络丛脑膜炎病毒感染后发生 HLH 免疫病理学的风险。从机制上讲，Rab27a 和 syntaxin-11 这两个脱颗粒基因中的杂合突变的积累，损害了 T 淋巴细胞免疫突触中细胞毒性颗粒的动力学和分泌。此外，三个基因中的杂合突变的积累损害了体内自然杀伤淋巴细胞的细胞毒性。可以根据导致 HLH 表现的严重程度对遗传缺陷进行排序。我们的研究结果为继发性 HLH 的多基因模型奠定了基础。
