Key Points• Syntaxin-11-deficient mice as the first animal model for human familial hemophagocytic lymphohistiocytosis type 4 (FHL4).• T-cell exhaustion limits HLH progression in syntaxin-11-deficient mice. IntroductionCytolytic activity is a key function of cytotoxic T lymphocytes (CTLs) and NK cells to eliminate infected and malignant cells. Thereby, cytotoxicity is mediated by polarized exocytosis of lytic granules at the immunological synapse. Lytic granules are secretory lysosomes containing effector molecules, such as perforin and granzymes. On interaction with target cells, CTLs undergo polarization, characterized by Ca 2ϩ mobilization, reorientation of the microtubule organization center, and directed movement of lytic granules. The docking-priming-fusion steps of lytic granules are tightly controlled and result in the release of effector molecules at the immunological synapse. Synaptogamin-like proteins, members of the Rab and the Sec1/Munc18 protein families, as well as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins are involved in this process. SNARE proteins are helical transmembrane molecules expressed on the vesicle and target membranes. On association, they build a trans-SNARE complex, which leads to the fusion of docked lipid bilayers. 1 Syntaxin-11 (Stx11) is an atypical member of the Q-SNARE family and expressed in various cells of the immune system. 2-8 Stx11 associates with Vti1b, 7,9 SNAP23, 10 and syntaxin binding protein 2 (STXBP2/Munc18-2), 11,12 regulating the fusion of lytic granules with the plasma membrane at the immunological synapse. Consistent with this, CTLs and NK cells from patients with mutated STX11 gene or with experimentally reduced Stx11 expression levels displayed defects in degranulation and cytolytic activities. 5,6 In addition, it was described recently that Stx11 plays a role in platelet exocytosis. 13 Patients with mutations in the STX11 gene develop hemophagocytic lymphohistiocytosis (HLH), a lifethreatening disorder of severe hyperinflammation resulting from immune dysregulation. 4,6,14 HLH is associated with defects in components of the cytolytic machinery of T and NK cells [15][16][17][18] and characterized by inflammatory processes in various tissues as a result of infiltrating, hyperactive T cells, NK cells and macrophages, accompanied by massive cytokine production (IFN-␥, TNF-␣, . 19 Because of this loss in immune There is an Inside Blood commentary on this article in this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From homeostasis, patients present with prolonged fever, hepatosplenomegaly, neurologic manifestations, hypercytokinemia, and hemophagocytosis. The diagnostic criteria for HLH according to the Histiocyt...

Key Points Hermansky-Pudlak syndrome type 2 confers a moderate risk for hemophagocytic lymphohistiocytosis.

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.