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Mayo Clinic

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J. Allergy Clin. Immunol., March 11, 2025 | https://doi.org/10.1016/j.jaci.2024.11.041 A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics

Hyoungjun Ham, PhD,^a* Crescent R. Isham, BS, MA,^b* Elizabeth H. Ristagno, MD, MSc,^c Cristina Correia, PhD,^d Scott M. Ennis, BS,^b Richard K. Kandasamy, PhD,^b,e Kishore Garapati, MBBS,^b,f Cheng Zhang, PhD,^d Mindy C. Kohlhagen, BS,^b Elham Sadighi Akha, DDS, MSc, DPhil,^g Maria F. Rodriguez-Quevedo, BS,^a Destiny F. Schultz, PhD,^a Baoyu Chen, PhD,^h Thomas G. Boyce, MD, MPH,^c+ Seth W. Gregory, MD,^c Mira A. Kohorst, MD,^c Surendra Dasari, PhD,^b David L. Murray, MD, PhD,^b Kevin C. Halling, MD, PhD,^b Benjamin R. Kipp, PhD,^b Attila Kumanovics, MD,^b Hu Li, PhD,^d Akhilesh Pandey, MD, PhD,^bDaniel D. Billadeau, PhD,^a§ and Amir A. Sadighi Akha, MD, DPhil^b§

From the Departments of
^aImmunology,
^bLaboratory Medicine and Pathology,
^cPediatrics,
^dPharmacology, and
^eQuantitative Health Sciences, Mayo Clinic, Rochester;
^fthe Manipal Academy of Higher Education;
^gOxford; and
^hthe Roy J. Carver Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames.

^*Co-first authors.
⁺Current address: Marshfield Clinic Research Institute, Marshfield, Wis.
^§Co-senior authors.
Corresponding author: Amir A. Sadighi Akha, MD, DPhil, or Daniel D. Billadeau, PhD

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.

논문정보

형식Research article
게재일2025년 03월 (BRIC 등록일 2025-03-13)
연구진국외 연구진
분야 생명과학 > 면역학

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