Natural Killer Deficiency: A Minor or Major Factor in the Manifestation of Hemophagocytic Lymphohistiocytosis?

Em, Schneider; Lorenz, I.; Walther, Phillip J; Ge, Janka-Schaub

doi:10.1097/00043426-200309000-00002

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…13,14 Defective CTL activity was subsequently reported as another hallmark of FHL. 7,8,16,28 However, NK-cell activity is also decreased in some cases of secondary HLH, 15,[17][18][19][20] and the CTL cytotoxicity assay is not readily accessible to most clinicians. The NK-cell lysosomal exocytosis assay is a comprehensive method to identify patients with a degranulation defect.…”

Section: Discussionmentioning

confidence: 99%

“…1,12 Consequently, defective cytotoxic activity of CTLs and NK cells is one of the hallmark findings of FHL, 7,8,[13][14][15][16] although NK cell activity is also decreased in some cases of secondary HLH. 15,[17][18][19][20] Prompt and accurate diagnosis of FHL is mandatory to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. Detection of perforin expression in NK cells with flow cytometry is a reliable method to screen for FHL2.…”

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confidence: 99%

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Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein

Murata

Yasumi

Shirakawa

et al. 2011

Blood

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Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially lethal genetic disorder of immune dysregulation that requires prompt and accurate diagnosis to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. In the present study, 85 patients with hemophagocytic lymphohistiocytosis were screened for FHL3 by Western blotting using platelets and by natural killer cell lysosomal exocytosis assay. Six of these patients were diagnosed with FHL3. In the acute disease phase requiring platelet transfusion, it was difficult to diagnose FHL3 by Western blot analysis or by lysosomal exocytosis assay. In contrast, the newly established flow cytometric analysis of IntroductionThe granule-dependent cytotoxic pathway is a major immune effector mechanism used by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. 1 The pathway involves a series of steps, including cell activation, polarization of the lysosomal granules to the immunologic synapse, exocytosis of lytic proteins such as perforin and granzymes, and induction of apoptosis in the target cells. 2 In addition to its central role in the defense against intracellular infections and in tumor immunity, this pathway also plays an important role in the regulation of immune homeostasis. Defects in the granule-dependent cytotoxic pathway result in a catastrophic hyperinflammatory condition known as hemophagocytic lymphohistiocytosis (HLH). 1,3 HLH is a life-threatening syndrome of immune dysregulation resulting from the uncontrolled activation and proliferation of CTLs, which leads to macrophage activation and the excessive release of inflammatory cytokines. 4,5 Clinical diagnosis of HLH is made on the basis of cardinal signs and symptoms including prolonged fever and hepatosplenomegaly, and by characteristic laboratory findings such as pancytopenia, hyperferritinemia, hypofibrinogenemia, increased levels of soluble IL-2 receptor, and low or absent NK cell activity. 5,6 HLH can be classified into primary (genetic) or secondary (acquired) forms according to the underlying etiology, although this distinction is difficult to make in clinical practice. 4,5 Familial hemophagocytic lymphohistiocytosis (FHL) encompasses major forms of primary HLH for which mutations in the genes encoding perforin (PRF1; FHL2), 7 Munc13-4 (UNC13D; FHL3), 8 syntaxin-11 (STX11; FHL4), 9 and syntaxinbinding protein 2 (also known as Munc18-2) (STXBP2; FHL5) 10,11 have been identified to date. Perforin is a cytolytic effector that forms a pore-like structure in the target cell membrane. Munc13-4, syntaxin-11, and Munc18-2 are involved in intracellular trafficking or the fusion of cytolytic granules to the plasma membrane and the subsequent delivery of their contents into target cells. 1,12 Consequently, defective cytotoxic activity of CTLs and NK cells is one of the hallmark findings of FHL, 7,8,[13][14][15][16] although NK cell activity is also decreased in some cases of secondary HLH. 15,[17][18][19][20] Prompt and accurate diagnosis o...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein

Murata

Yasumi

Shirakawa

et al. 2011

Blood

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“…Patients with FHL present with an increased inflammatory response involving hypersecretion of proinflammatory cytokines. However, despite this global hyperstimulation, impaired function of NK cells and CTLs is a hallmark feature of FHL (1,2).…”

Section: F Amilial Hemophagocytic Lymphohistiocytosis (Fhl)mentioning

confidence: 99%

Cutting Edge: Syntaxin 11 Regulates Lymphocyte-Mediated Secretion and Cytotoxicity

Arneson

Brickshawana

Segovis

et al. 2007

The Journal of Immunology

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Little is known about the regulatory roles of specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in cytotoxic lymphocytes. Recent information suggests that mutations in the SNARE protein syntaxin 11 result in a form of familial hemophagocytic lymphohistiocytosis (FHL). Because genetic abnormalities in key granule components (e.g., perforin) or in regulators of secretion (e.g., Munc13–4) underlie the other identified forms of FHL, we assessed whether syntaxin 11 might also serve a related regulatory role. We determined that syntaxin 11 is expressed in NK cells and activated CTLs and is located in discrete membrane-associated structures in the cytoplasm. Enhanced expression of syntaxin 11 augments the secretion and killing of tumor targets, and suppression of syntaxin 11 expression inhibits these functions. Our data identify and characterize a role for syntaxin 11 in granule exocytosis and in the generation of cell-mediated killing. These results also provide new insights on the mechanisms of hemopoietic dysregulation in FHL.

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“…Indicadores de hipercitocinemia, específi-camente niveles elevados de IL-2Rα soluble (marcador de las células T activadas), también han demostrado ser útiles en el diagnóstico (1,29,30) .…”

Section: Datos De Laboratoriounclassified

Linfohistiocitosis hemofagocítica

Rojas

Macías

Salgado

2012

RFS

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Natural Killer Deficiency: A Minor or Major Factor in the Manifestation of Hemophagocytic Lymphohistiocytosis?

Cited by 19 publications

References 28 publications

Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein

Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein

Cutting Edge: Syntaxin 11 Regulates Lymphocyte-Mediated Secretion and Cytotoxicity

Linfohistiocitosis hemofagocítica

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