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

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.