IRF2BP2 was originally identified as a co-repressor of IRF2 in the JAK–STAT signaling pathway. Upon stimulation with type I or type II interferons (IFNs), STAT1 levels increase. STAT1 then forms either the ISGF3 complex (STAT1/STAT2/IRF9) or GAF (STAT1 homodimers), which translocate to the nucleus and bind ISRE or GAS sequences, respectively, to induce transcription of interferon-stimulated genes (ISGs). STAT1 also regulates IRF1 expression. IRF1 and IRF2 compete for the same ISRE regulatory elements but have opposing effects: IRF1 activates ISGs, while IRF2 represses them. Germline variants in IRF2BP2 have been linked to common variable immunodeficiency (CVID) and immune dysregulation.
We functionally analyzed four novel heterozygous IRF2BP2 variants of uncertain significance, identified by whole exome sequencing in five patients presenting with isolated immune dysregulation, and one CVID patient with autoimmunity (P6, p.Glu253fs). P1 (p.Val7_Aladup) and P2 (p.Met192Ile) developed hemophagocytic lymphohistiocytosis. Inflammatory symptoms included skin and gastrointestinal involvement. P3, P4, and P5 (p.Ser501Ile) belong to the same family, all with arthritis and lymphoproliferation. To assess the functional impact of these variants, we examined IFN–JAK–STAT pathway activation in patient samples using droplet digital PCR. Our results revealed upregulation of STAT1 mRNA in all patients except P6. IRF1, a GAS-responsive ISG mainly induced by IFN-γ, was also elevated in most cases. Given IRF1’s role in amplifying ISG expression via ISRE binding, we measured expression of ISGs linked to type I (MX1, ISG15, IFIT1, RSAD2) and type II IFN signatures (IRF1, IRF8, GBP1, ICAM1). P6, the only patient without inflammation, showed normal signatures. In contrast, 4/5 patients with inflammatory symptoms had elevated IFN-α signatures, and all patients had increased IFN-γ signatures.
Our data reveal consistent hyperactivation of the IFN–JAK–STAT1 axis in IRF2BP2-deficient patients associated with inflammation. This aligns with IRF2BP2 loss-of-function variants lacking suppression of STAT1–IRF1 activity, suggesting dysregulated type I/II IFN signaling. JAK inhibitors may offer an effective therapeutic strategy.
