Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE
Volume 8, Issue 9, Pages 3102-3111Publisher
ELSEVIER
DOI: 10.1016/j.jaip.2020.06.034
Keywords
Primary immune deficiency; Hyperinflammation; STAT1; Hematopoietic stem cell transplantation; Hemophagocytic lymphohistiocytosis; LOF; PD-L1; CXCL10; IL-18
Categories
Funding
- Care-for-Rare Foundation [160073]
- German Center for Infection Research [TTU 07.909]
- Else Kroner-Fresenius-Stiftung [2017_A110, 2017_A50]
- German Federal Ministry of Education and Research [01GM1910C]
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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. (C) 2020 American Academy of Allergy, Asthma & Immunology
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