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. 2025 Jun;155(6):2022-2037.
doi: 10.1016/j.jaci.2024.11.041. Epub 2025 Mar 11.

A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics

Hyoungjun Ham  1 , Crescent R Isham  2 , Elizabeth H Ristagno  3 , Cristina Correia  4 , Scott M Ennis  2 , Richard K Kandasamy  5 , Kishore Garapati  6 , Cheng Zhang  4 , Mindy C Kohlhagen  2 , Elham Sadighi Akha  7 , Maria F Rodriguez-Quevedo  1 , Destiny F Schultz  1 , Baoyu Chen  8 , Thomas G Boyce  3 , Seth W Gregory  3 , Mira A Kohorst  3 , Surendra Dasari  2 , David L Murray  2 , Kevin C Halling  2 , Benjamin R Kipp  2 , Attila Kumánovics  2 , Hu Li  4 , Akhilesh Pandey  2 , Daniel D Billadeau  9 , Amir A Sadighi Akha  10
Affiliations

A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics

Hyoungjun Ham et al. J Allergy Clin Immunol. 2025 Jun.

Abstract

Background: The few reported patients with pathogenic IRF8 variants have manifested 2 distinct phenotypes: (1) an autosomal recessive severe immunodeficiency with significant neutrophilia and absence of or significant decrease in monocytes and dendritic cells and (2) a dominant-negative form with only a decrease in conventional type 2 dendritic cells (cDC2s) and susceptibility to mycobacterial disease.

Objectives: 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 a human papillomavirus-positive tumor. We sought to examine the pathogenicity of the identified IRF8 variant and its phenotypic and functional characteristics.

Methods: Immunophenotypic and functional flow cytometry, natural killer cell cytotoxicity, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, T-cell receptor Vβ spectratyping, Sanger sequencing, RNA-sequencing, Olink proteomics, immunoblotting, molecular cloning, dual-luciferase reporter assay, immunofluorescence microscopy, and image analysis.

Results: The 42 amino acid C-terminal extension of the mutant IRF8 (∼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 (pDCs) and in cDC1s, a mild neutrophilia and a mild monocytosis. Their existing pDCs had impaired IFN-α production. On TLR engagement, the production of IL-1β, IL-6, IL-10, and IL-12 by their monocytes and of IL-12 by their myeloid DCs were within normal limits. Natural killer cell development and cytolytic activity were essentially normal. RNA-sequencing and proteomic approaches bolstered the phenotypic and functional findings.

Conclusions: 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.

Keywords: EBV; HPV; IRF8; dendritic cell; interferon; loss-of-stop variant; monocyte.

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Conflict of interest statement

Disclosure Statement This work was supported in part by a National Institutes of Health grant AI120949 (to D.D.B.); a National Cancer Institute Grant P30CA15083 (to A.P.); a DBT/Wellcome Trust India Alliance Grant IA/CRC/20/1/600002 (to A.P.); David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy Program Funds, Mayo Clinic (to H.L.); and Collaborative Research Funds, Department of Laboratory Medicine and Pathology, Mayo Clinic (to A.A.S.A.). Disclosure of potential conflict of interest: D. L. Murray and S. Dasari have patent rights on the analysis of immunoglobulins by mass spectrometry for detecting monoclonal gammopathy, currently licensed to Binding Site (Thermo Fisher Scientific), with potential royalties. The rest of the authors declare that they have no relevant conflicts of interest.

References

    1. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 2008; 26:535–84. - PubMed
    1. Tanaka N, Kawakami T, Taniguchi T. Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system. Mol Cell Biol 1993; 13:4531–8. - PMC - PubMed
    1. Takahasi K, Suzuki NN, Horiuchi M, Mori M, Suhara W, Okabe Y, et al. X-ray crystal structure of IRF-3 and its functional implications. Nat Struct Biol 2003; 10:922–7. - PubMed
    1. Driggers PH, Ennist DL, Gleason SL, Mak WH, Marks MS, Levi BZ, et al. An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc Natl Acad Sci U S A 1990; 87:3743–7. - PMC - PubMed
    1. Politis AD, Sivo J, Driggers PH, Ozato K, Vogel SN. Modulation of interferon consensus sequence binding protein mRNA in murine peritoneal macrophages. Induction by IFN-gamma and down-regulation by IFN-alpha, dexamethasone, and protein kinase inhibitors. J Immunol 1992; 148:801–7. - PubMed

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