Tu169 - Characterizing a Novel IRF8 Variant Through a Multidisciplinary Approach

Abstract Text: The few reported patients with pathogenic interferon regulatory factor 8 (IRF8) variants have manifested two distinct phenotypes: an autosomal recessive severe immunodeficiency with significant neutrophilia and absence/significant decrease in monocytes and dendritic cells; and a dominant-negative form with only a decrease in cDC2 dendritic cells and susceptibility to mycobacterial disease.

Genetic testing of a child with persistent EBV viremia identified a novel IRF8 variant: c.1279dupT (p.*427Leuext*42). The variant was also found in his mother, who was subsequently diagnosed with an HPV+ tumor. We sought to examine the pathogenicity of the identified IRF8 variant and its phenotypic and functional characteristics.

The 42 amino acid C-terminal extension of the mutant IRF8 protein (~4 kDa heavier than wild-type) impaired IRF8 nuclear localization in a dominant-negative manner, and inhibited IRF1/IRF8-mediated transcriptional activities. Both patients had a decrease in plasmacytoid dendritic cells (pDC) and in cDC1 cells, a mild neutrophilia and a mild monocytosis. Their existing pDCs had impaired IFN- production. Upon TLR engagement, the production of IL-1, IL-6, IL-10 and IL-12 by their monocytes, and of IL-12 by their myeloid DCs were within normal limits. NK cell development and cytolytic activity were essentially normal. RNA-seq and proteomic approaches bolstered the phenotypic and functional findings.

This study defines the pathogenic nature of the c.1279dupT (p.*427Leuext*42) IRF8 variant, determines its dominant-negative mechanism of action and broadens the existing phenotype of human IRF8 immunodeficiency.