Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RA...

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Autores principales:	Erica A. Steen, Michelle L. Hermiston, Kim E. Nichols, Lauren K. Meyer
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	hemophagocytic lymphohistiocytosis digenic degranulation variants cytotoxic lymphocyte natural killer cell Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/a1bf01ecb2e847d28c69fed45a4347ff
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spelling	oai:doaj.org-article:a1bf01ecb2e847d28c69fed45a4347ff2021-11-17T04:46:33ZDigenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis1664-322410.3389/fimmu.2021.777851https://doaj.org/article/a1bf01ecb2e847d28c69fed45a4347ff2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.777851/fullhttps://doaj.org/toc/1664-3224Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.Erica A. SteenMichelle L. HermistonKim E. NicholsLauren K. MeyerFrontiers Media S.A.articlehemophagocytic lymphohistiocytosisdigenicdegranulationvariantscytotoxic lymphocytenatural killer cellImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hemophagocytic lymphohistiocytosis digenic degranulation variants cytotoxic lymphocyte natural killer cell Immunologic diseases. Allergy RC581-607
spellingShingle	hemophagocytic lymphohistiocytosis digenic degranulation variants cytotoxic lymphocyte natural killer cell Immunologic diseases. Allergy RC581-607 Erica A. Steen Michelle L. Hermiston Kim E. Nichols Lauren K. Meyer Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
description	Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.
format	article
author	Erica A. Steen Michelle L. Hermiston Kim E. Nichols Lauren K. Meyer
author_facet	Erica A. Steen Michelle L. Hermiston Kim E. Nichols Lauren K. Meyer
author_sort	Erica A. Steen
title	Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
title_short	Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
title_full	Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
title_fullStr	Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
title_full_unstemmed	Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
title_sort	digenic inheritance: evidence and gaps in hemophagocytic lymphohistiocytosis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a1bf01ecb2e847d28c69fed45a4347ff
work_keys_str_mv	AT ericaasteen digenicinheritanceevidenceandgapsinhemophagocyticlymphohistiocytosis AT michellelhermiston digenicinheritanceevidenceandgapsinhemophagocyticlymphohistiocytosis AT kimenichols digenicinheritanceevidenceandgapsinhemophagocyticlymphohistiocytosis AT laurenkmeyer digenicinheritanceevidenceandgapsinhemophagocyticlymphohistiocytosis
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Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis

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