Bi-allelic IRF8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia and immune dysregulation

Publication date: Available online 8 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Venetia Bigley, Sheetal Maisuria, Urszula Cytlak, Laura Jardine, Matthew A. Care, Kile Green, Merry Gunawan, Paul Milne, Rachel Dickinson, Sarah Wiscombe, David Parry, Rainer Doffinger, Arian Laurence, Claudia Fonseca Lic, Oda Stoevesandt, Andrew Gennery, Andrew Cant, Reuben Tooze, A John Simpson, Sophie Hambleton, Sinisa Savic, Gina Doody, Matthew Collin
BackgroundHomozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function.ObjectiveWe sought to describe the effect on hematopoiesis and immunity of compound heterozygous R83C/ R291Q mutation of IRF8, present in a patient with recurrent viral infection, granulo-proliferation and intracerebral calcification.MethodsVariant IRF8 alleles were identified by exome sequencing and their function tested by reporter assays. The cellular phenotype was studied in detail using flow cytometry, functional immunologic assays transcriptional profiling and antigen receptor profiling.ResultsBoth mutations affected conserved residues and R291Q is orthologous to R294, 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, while R291Q retained BATF/JUN interactions. Dendritic cell deficiency and monocytopenia were observed in blood, dermis and lung lavage fluid. Granulocytes were consistently elevated, dysplastic and hypofunctional. NK development maturation was arrested. Th1, Th17 and CD8⁺ memory T cell differentiation was significantly reduced, and T cells failed to 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.ConclusionsThis analysis defines the clinical features of human bi-allelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by dendritic cell and monocyte deficiency combined with widespread immune dysregulation.



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