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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional corepressor involved in cellular signaling.
• Mutations in IRF2BP2 are linked to common variable immunodeficiency (CVID) and immune dysregulation.
• Understanding IRF2BP2's role is crucial for diagnosing and treating primary antibody deficiencies and autoimmune disorders.

Purpose of the Study:

• To investigate the functional impact of three novel IRF2BP2 variants identified in patients with primary antibody deficiency and autoimmunity.
• To analyze the effects of these variants on IRF2BP2 expression, localization, and interaction with IRF2 and NFκB1(p50).
• To elucidate the pathogenic mechanisms underlying IRF2BP2-associated immune dysregulation.

Main Methods:

• Whole exome sequencing (WES) to identify IRF2BP2 variants.
• Transient overexpression of EGFP-fused IRF2BP2 mutants in HEK293 and Jurkat cell lines.
• Fluorescence microscopy, real-time PCR, and Western blotting to assess protein expression, localization, and nuclear translocation of IRF2 and NFκB1(p50).

Main Results:

• Mutated IRF2BP2 showed altered mRNA and protein expression levels compared to wild type.
• C-terminal RING finger domain variants exhibited irregular aggregate formation and impaired nuclear localization.
• Mutants displayed impaired nuclear translocation of IRF2 and NFκB1(p50), with reduced IRF2BP2 mRNA expression upon LPS stimulation.

Conclusions:

• Novel IRF2BP2 variants disrupt its function as a transcriptional regulator, impacting immune cell signaling.
• Impaired nuclear translocation of IRF2 and NFκB1(p50) due to IRF2BP2 mutations contributes to immunodeficiency and autoimmunity.
• These findings highlight the clinical significance of IRF2BP2 in immune system pathogenesis and regulation.