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

Abstract

BackgroundThe 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.ObjectiveWe 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.MethodsVariant 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.ResultsBoth 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.ConclusionsThis 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.

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

“…The heterozygous T80A variant in the key DNA-binding helix is associated with milder immunodeficiency and a selective depletion of CD1c + compartment of CD11c + circulating DCs (25) . The compound heterozygous mutations R83C/R291Q lead to complex immunodeficiency syndrome caused by DC and monocyte deficiency (31) . The biallelic A201V/P224L mutation within the IAD domain leads to NK cell deficiency with decreased NK cell number and CD56 dim subset, which is also observed in Irf8 −/− mice but not in Irf8 +/− mice (32) .…”

Human dendritic cell subsets: an update

“…Generally speaking, more severe losses of IRF8 activity incur earlier defects in haematopoiesis. Hence homozygous deletion causes excess production of neutrophils and loss of monocytes and all DC . At the other extreme, subtle losses of IRF8 activity may only affect the production of cDC1, as documented in BXH2 mice carrying the IRF8 hypomorphic allele R294C and IRF8 hemizygous mice .…”

“…). Heterozygous GATA2 mutation and bi‐allelic IRF8 mutation abrogate pDC development in humans . Humans with an IKZF1 mutation have a selective pDC deficiency EcDC1 production …”

“…Gene dosage is a critical determinant in understanding the effect of IRF8 variants upon DC development. This has been thoroughly explored in the mouse through targeted hemizygous and homozygous deletion but becomes even more complex when amino acid substitutions are considered, as in human examples of IRF8 variation . Generally speaking, more severe losses of IRF8 activity incur earlier defects in haematopoiesis.…”

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

“…Whole exome sequencing and analysis identified biallelic variants in the IRF association domain (IAD) of IRF8 that segregated appropriately within the family and were novel and damaging . Additional families were identified, including a child with homozygous variants in IRF8 and disseminated BCG disease, and a second child with compound heterozygous mutations and recurrent respiratory infections …”