By underscoring concomitant B- and T-cell dysregulation caused by a novel heterozygous de novo variant in the IRF2BP2 gene, this case expands the clinical and immunological spectrum of IRF2BP2-related immunodeficiency, suggesting that the novel C555S substitution influences severe phenotypes in immunodeficiency, including inflammatory features (PBC and unclassified arthritis), activated IFN–STAT1 pathway leading to Th1 polarization, and the Tfh expansion (Supplementary Table S2). Here, IRF2BP2 is linked to primary biliary cholangitis.