A Novel Complete Autosomal-Recessive STAT1 LOF Variant Causes Immunodeficiency with Hemophagocytic Lymphohistiocytosis-Like Hyperinflammation.
CXCL10
Hematopoietic stem cell transplantation
Hemophagocytic lymphohistiocytosis
Hyperinflammation
IL-18
LOF
PD-L1
Primary immune deficiency
STAT1
Journal
The journal of allergy and clinical immunology. In practice
ISSN: 2213-2201
Titre abrégé: J Allergy Clin Immunol Pract
Pays: United States
ID NLM: 101597220
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
27
03
2020
revised:
20
05
2020
accepted:
12
06
2020
pubmed:
1
7
2020
medline:
15
5
2021
entrez:
1
7
2020
Statut:
ppublish
Résumé
Complete signal transducer and activator of transcription 1 (STAT1) deficiency causes a rare primary immunodeficiency that is characterized by defective IFN-dependent gene expression leading to life-threatening viral and mycobacterial infections early in life. To characterize a novel STAT1 loss-of-function variant leading to pathological infection susceptibility and hyperinflammation. Clinical, immunologic, and genetic characterization of a patient with severe infections and hemophagocytic lymphohistiocytosis-like hyperinflammation was investigated. We reported a child of consanguineous parents who presented with multiple severe viral infections that ultimately triggered hemophagocytic lymphohistiocytosis and liver failure. Despite intensified therapy with antivirals and cytomegalovirus-specific donor cells, the child died after hematopoietic stem cell transplantation because of cytomegalovirus reactivation with acute respiratory distress syndrome. Exome sequencing revealed a homozygous STAT1 variant (p.Val339ProfsTer18), leading to loss of STAT1 protein expression. Upon type I and type II IFN stimulation, immune and nonimmune cells showed defective upregulation of IFN-stimulated genes and increased susceptibility to viral infection in vitro. Increased viral infection rates were paralleled by hyperinflammatory ex vivo cytokine responses with increased production of TNF, IL-6, and IL-18. Complete STAT1 deficiency is a devastating disorder characterized by severe viral infections and ensuing hyperinflammatory responses. Early diagnosis can be made by exome sequencing and variant validation by functional testing of STAT1-dependent programmed cell death 1 ligand 1 surface expression on monocytes. Furthermore, high awareness for hyperinflammatory complications and potential targeted treatment strategies such as IL-18 binding protein could be considered. Hematopoietic stem cell transplantation is the only definitive treatment strategy but remains challenging.
Sections du résumé
BACKGROUND
Complete signal transducer and activator of transcription 1 (STAT1) deficiency causes a rare primary immunodeficiency that is characterized by defective IFN-dependent gene expression leading to life-threatening viral and mycobacterial infections early in life.
OBJECTIVE
To characterize a novel STAT1 loss-of-function variant leading to pathological infection susceptibility and hyperinflammation.
METHODS
Clinical, immunologic, and genetic characterization of a patient with severe infections and hemophagocytic lymphohistiocytosis-like hyperinflammation was investigated.
RESULTS
We reported a child of consanguineous parents who presented with multiple severe viral infections that ultimately triggered hemophagocytic lymphohistiocytosis and liver failure. Despite intensified therapy with antivirals and cytomegalovirus-specific donor cells, the child died after hematopoietic stem cell transplantation because of cytomegalovirus reactivation with acute respiratory distress syndrome. Exome sequencing revealed a homozygous STAT1 variant (p.Val339ProfsTer18), leading to loss of STAT1 protein expression. Upon type I and type II IFN stimulation, immune and nonimmune cells showed defective upregulation of IFN-stimulated genes and increased susceptibility to viral infection in vitro. Increased viral infection rates were paralleled by hyperinflammatory ex vivo cytokine responses with increased production of TNF, IL-6, and IL-18.
CONCLUSIONS
Complete STAT1 deficiency is a devastating disorder characterized by severe viral infections and ensuing hyperinflammatory responses. Early diagnosis can be made by exome sequencing and variant validation by functional testing of STAT1-dependent programmed cell death 1 ligand 1 surface expression on monocytes. Furthermore, high awareness for hyperinflammatory complications and potential targeted treatment strategies such as IL-18 binding protein could be considered. Hematopoietic stem cell transplantation is the only definitive treatment strategy but remains challenging.
Identifiants
pubmed: 32603902
pii: S2213-2198(20)30669-3
doi: 10.1016/j.jaip.2020.06.034
pmc: PMC9188869
pii:
doi:
Substances chimiques
STAT1 Transcription Factor
0
STAT1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3102-3111Informations de copyright
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Références
J Allergy Clin Immunol Pract. 2016 Jul-Aug;4(4):777-9
pubmed: 27117246
Blood. 2018 Jul 5;132(1):89-100
pubmed: 29632024
N Engl J Med. 2013 Jan 10;368(2):161-70
pubmed: 23301733
N Engl J Med. 2014 Jul 31;371(5):434-46
pubmed: 25075835
PLoS Pathog. 2013;9(11):e1003773
pubmed: 24278020
J Clin Invest. 2009 Jun;119(6):1502-14
pubmed: 19436109
Nat Genet. 2003 Mar;33(3):388-91
pubmed: 12590259
Blood. 2017 Dec 21;130(25):2728-2738
pubmed: 28935695
Nat Rev Immunol. 2016 Jul;16(7):407-20
pubmed: 27291964
JAKSTAT. 2013 Oct 1;2(4):e27521
pubmed: 24498542
J Exp Med. 2011 Aug 1;208(8):1635-48
pubmed: 21727188
J Clin Immunol. 2017 Oct;37(7):701-706
pubmed: 28815344
Blood. 2010 Dec 23;116(26):5895-906
pubmed: 20841510
Annu Rev Immunol. 2014;32:461-88
pubmed: 24655297
Blood. 2011 Aug 18;118(7):1806-17
pubmed: 21772053
Pediatr Blood Cancer. 2007 Feb;48(2):124-31
pubmed: 16937360
Nat Rev Mol Cell Biol. 2002 Sep;3(9):651-62
pubmed: 12209125
Cancer Cell. 2003 Oct;4(4):263-75
pubmed: 14585354
Expert Rev Clin Immunol. 2018 Dec;14(12):1029-1041
pubmed: 30280610
Front Immunol. 2017 Jan 26;8:29
pubmed: 28184222
Nat Commun. 2017 Jan 23;8:14209
pubmed: 28112205
Br J Haematol. 2001 Sep;114(4):761-9
pubmed: 11564062
Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S82-9
pubmed: 19932759
Cytokine. 2014 Jan;65(1):74-8
pubmed: 24084330
N Engl J Med. 2011 Jul 7;365(1):54-61
pubmed: 21714643
Nat Rev Immunol. 2014 Jan;14(1):36-49
pubmed: 24362405
J Immunol. 2006 Apr 15;176(8):5078-83
pubmed: 16585605
J Clin Immunol. 2011 Apr;31(2):265-71
pubmed: 21057861
Annu Rev Immunol. 2014;32:513-45
pubmed: 24555472
J Exp Med. 2019 Aug 5;216(8):1777-1790
pubmed: 31213488