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. 2025 Jun;155(6):2052-2062.e5.
doi: 10.1016/j.jaci.2025.02.038. Epub 2025 Mar 14.

IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation

Chioma Udemgba  1 , Bethany Pillay  2 , Samantha Shafer  1 , Angelika Alberstadt  1 , Michael Abers  1 , Olivier Gilliaux  2 , Karin Chen  3 , William Rae  4 , Leif Hanitsch  5 , Horst Von Bernuth  6 , Joao Farela Neves  7 , Nikita Raje  8 , Leen Moens  2 , P Martin van Hagen  9 , Jenna Bergerson  1 , Nicholas Hartog  10 , Tim Niehues  11 , Gregor Dückers  11 , Emilia Falcone  1 , Michael Keller  12 , Amy Hsu  1 , Isabelle Meyts  2 , Steven M Holland  13
Affiliations

IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation

Chioma Udemgba et al. J Allergy Clin Immunol. 2025 Jun.

Abstract

Background: IRF2BP2 is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency.

Objectives: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test 34 individuals with IRF2BP2 variants.

Methods: We collected 34 subjects across 18 families with mutations in IRF2BP2. Records were abstracted for clinical phenotypes. Functional testing was performed on PBMCs. NFAT luciferase gene reporter constructs and quantitative cDNA determinations were used to evaluate repressor activity associated with ectopic expression of various IRF2BP2 mutant constructs in Jurkat cells.

Results: Most subjects had immunodeficiency (91%, n = 30 of 33) with variable gastrointestinal (65%, n = 20 of 31) and inflammatory or autoimmune features (57%, n = 17 of 30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes. There was a reduced frequency of memory B cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli. PBMCs had increased apoptosis in vitro compared to healthy controls. Impaired IRF2BP2 repression of NFAT activation was observed using patient-derived mutant IRF2BP2 constructs compared to wild-type constructs. Similarly, TNF-α transcript levels were higher using patient-derived mutations compared to wild-type IRF2BP2 constructs.

Conclusions: IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation. Impaired repression of the NFAT pathway appears to enhance proinflammatory signaling through proinflammatory cytokine expression.

Keywords: B-cell failure; Common variable immunodeficiency; IRF2BP2; autoimmunity; autoinflammatory; immunodysregulation; inborn errors of immunity; primary immunodeficiency diseases.

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Conflict of interest statement

Disclosure statement Funded in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Funding was also provided from The Wellcome Trust PhD for Clinicians Fellowship (216382/Z/19/Z). Additional funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 948959 and from FwO Vlaanderen G0B5120N and a Katholieke Universiteit Leuven C1 Grant C16/18/007 was used. Disclosure of potential conflict of interest: N. Raje serves on the Medical Advisory Board for Amgen and as a speaker for Pharming Inc and X4. N.L. Hartog serves on the scientific advisory board and as a speaker for Pharming, Takeda, and Horizon Pharma; and also serves as a consultant for Chiesi and Pharming. T. Niehues receives author fees from UptoDate. M.D. Keller is an author for UptoDate. I. Meyts has received funding and consultancy honorary, paid to Katholieke Universiteit Leuven Research and Development, from CSL Behring and Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest.

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