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Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation

Lookup NU author(s): Dr Venetia BigleyORCiD, Dr Urszula Cytlak-ChaudhuriORCiD, Dr Laura JardineORCiD, Dr Kile GreenORCiD, Dr Merry Gunawan, Dr Paul Milne, Dr Rachel Dickinson, Dr Sarah Wiscombe, Dr Arian Laurence, Professor Andrew GenneryORCiD, Professor Andrew Cant, Professor John SimpsonORCiD, Professor Sophie HambletonORCiD, Professor Matthew CollinORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The Authors. Background: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. Objective: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. Methods: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. Results: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. Conclusions: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.

Publication metadata

Author(s): Bigley V, Maisuria S, Cytlak U, Jardine L, Care MA, Green K, Gunawan M, Milne P, Dickinson R, Wiscombe S, Parry D, Doffinger R, Laurence A, Fonseca C, Stoevesandt O, Gennery A, Cant A, Tooze R, Simpson AJ, Hambleton S, Savic S, Doody G, Collin M

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2018

Volume: 141

Issue: 6

Pages: 2234-2248

Print publication date: 01/06/2018

Online publication date: 08/11/2017

Acceptance date: 31/08/2017

Date deposited: 17/01/2018

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Mosby Inc.


DOI: 10.1016/j.jaci.2017.08.044


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Funder referenceFunder name
Wellcome Trust