Chediak-Higashi Syndrome: Hereditary Gigantism of Cytoplasmic Organelles

Windhorst, Dorothy B.; Zelickson, Alvin S.; Good, Robert A.

doi:10.1126/science.151.3706.81

Cited by 74 publications

(25 citation statements)

References 15 publications

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“…[6][7][8] Other immunodeficiencies such as Chediak-Higashi syndrome (CHS) and Griscelli syndrome (GS) are characterized by the association of albinism with functional defects of neutrophils and NK cells. [21][22][23][24][25][26][27] Similar to melanocytes, certain hematopoietic cells such as NK cells and neutrophils display a well-organized array of cytoplasmic organelles and secretory lysosomes that require a complex machinery for lysosomal biogenesis and mobilization. Both CHS and GS are characterized by a generalized defect of biogenesis and/or mobilization of lysosomes that affect the intracellular trafficking of all lysosome-associated glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Because the processed form of NE interacts in vitro with the 3A subunit through a tyrosine-based sorting signal in its cytoplasmic tail, it was hypothesized that AP-3 directs NE docking to azurophil granules in a nonredundant fashion. 20 Neutropenia and impairment of cytotoxic activity have been reported in HPS2 patients 1,13,15 and in other inherited conditions characterized by partial albinism and immunodeficiency such as Chediak-Higashi and Griscelli syndromes, [21][22][23][24][25][26][27] but the mechanism involved in their pathogenesis in Hermansky-Pudlak type 2 has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Innate immunity defects in Hermansky-Pudlak type 2 syndrome

Fontana

Parolini

Vermi

et al. 2006

Blood

134

128

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Innate immunity defects in Hermansky-Pudlak type 2 syndrome

Fontana

Parolini

Vermi

et al. 2006

Blood

134

128

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“…CTL from CHS patients, however, show enlarged lysosomal compartments with ER-specific membrane proteins and autophagic inclusions, indicating a function of Lyst during lysosomal fission (151, 152). Why these enlarged lytic granules fail to fuse is still not fully understood.…”

Section: Contribution Of Fhl Patients To the Clarification Of The Cytmentioning

confidence: 99%

Familial Hemophagocytic Lymphohistiocytosis: When Rare Diseases Shed Light on Immune System Functioning

et al. 2014

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The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes.

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“…6 A cell biologic characteristic of CHS is the presence of giant lysosomes or lysosome-related organelles in several cell types. 7, 8 LYST is a 429 kDa protein with several distinct domains implicated in various aspects of vesicular trafficking: ARM/HEAT, PH, BEACH and WD-40, 2, 5, 9, 10 but its exact function remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Gil-Krzewska

Wood

Murakami

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Mutations in LYST cause Chediak-Higashi syndrome (CHS), a rare immunodeficiency with impaired cytotoxic lymphocyte function, mainly that of natural killer (NK) cells. Our understanding of NK cell function deficiency in CHS, and how LYST regulates lytic granule exocytosis is very limited. Objective We sought to delineate cellular defects, associated with LYST mutations, responsible for the impaired NK cell function in CHS. Methods We analyzed NK cells from CHS patients with missense mutations in the LYST ARM/HEAT or BEACH domains. Results CHS NK cells displayed severely reduced cytotoxicity. Mutations in the ARM/HEAT domain led to a reduced number of perforin-containing granules, which were significantly increased in size, but able to polarize to the immunological synapse (IS); however, they were unable to properly fuse with the plasma membrane. Mutations in the BEACH domain resulted in the formation of normal or slightly enlarged granules that had markedly impaired polarization to the immunological synapse, but could be exocytosed upon reaching the IS. Perforin-containing granules in CHS NK cells did not acquire certain lysosomal markers (LAMP1/2), but were positive for markers of transport vesicles (CI-MPR), late endosomes (Rab27a), and to some extent, early endosomes (EEA-1), indicating a lack of integrity in the endo-lysosomal compartments. CHS NK cells had normal cytokine compartments and cytokine secretion. Conclusion LYST is involved in regulation of multiple aspects of NK cell lytic activity ranging from governance of lytic granule size to control of their polarization and exocytosis, as well as the regulation of endo-lysosomal compartment identity. LYST functions in the regulated exocytosis, but not in the constitutive secretion pathway.

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Chediak-Higashi Syndrome: Hereditary Gigantism of Cytoplasmic Organelles

Cited by 74 publications

References 15 publications

Innate immunity defects in Hermansky-Pudlak type 2 syndrome

Innate immunity defects in Hermansky-Pudlak type 2 syndrome

Familial Hemophagocytic Lymphohistiocytosis: When Rare Diseases Shed Light on Immune System Functioning

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

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