Novel hypermorphic variants in IRF2BP2 identified in patients with common variable immunodeficiency and autoimmunity.

Autor: Anim M; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; Hannover Biomedical Research School (HBRS), Hannover Medical School, Hanover, Germany., Sogkas G; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany., Camacho-Ordonez N; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany., Schmidt G; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Elsayed A; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany., Proietti M; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany.; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Witte T; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany., Grimbacher B; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany.; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany., Atschekzei F; Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany.. Electronic address: Atschekzei.Faranaz@mh-hannover.de.
Jazyk: angličtina
Zdroj: Clinical immunology (Orlando, Fla.) [Clin Immunol] 2024 Sep; Vol. 266, pp. 110326. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1016/j.clim.2024.110326
Abstrakt: The interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional regulator, functioning a transcriptional corepressor by interacting with the interferon regulatory factor-2. The ubiquitous expression of IRF2BP2 by diverse cell types and tissues suggests its potential involvement in different cell signalling pathways. Variants inIRF2BP2have been recently identified to cause familial common variable immunodeficiency (CVID) characterized by immune dysregulation. This study investigated three rare novel variants inIRF2BP2, identified in patients with primary antibody deficiency and autoimmunity by whole exome-sequencing (WES). Following transient overexpression of EGFP-fused mutants in HEK293 cells and transfection in Jurkat cell lines, we used fluorescence microscopy, real-time PCR and Western blotting to analyze their effects on IRF2BP2 expression, subcellular localization, nuclear translocation of IRF2, and the transcriptional activation of NFκB1(p50). We found altered IRF2BP2 mRNA and protein expression levels in the mutants compared to the wild type after IRF2BP2 overexpression. In confocal fluorescence microscopy, variants in the C-terminal RING finger domain showed an irregular aggregate formation and distribution instead of the expected nuclear localization compared to the variants in the N-terminal zinc finger domain and their wildtype counterpart. Immunoblotting revealed an impaired IRF2 and NFκB1 (p50) nuclear localization in the mutants compared to the IRF2BP2 wildtype counterpart. LPS stimulation reduced IRF2BP2 mRNA expression in the variants compared to the wild type. Our findings significantly contribute to understanding the clinical significance of IRF2BP2 mutations in the pathogenesis of immunodeficiency and immune dysregulation. We observed impairment of the nuclear translocation of IRF2 and NFκB1 (p50) due to the upregulation of IRF2BP2, potentially affecting specific gene expressions involved in immune regulation.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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