IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency

Background: The nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB) pathway is a key regulator of immune responses, cell survival, and proliferation. Dysregulation of this signaling pathway is implicated in various human diseases, including inborn errors of immunity. Objective: We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB. Methods: Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing. An NF-κB reporter assay was performed to investigate NF-κB activity. Extensive immunophenotyping, a lymphocyte proliferation assay, and signaling pathway analysis were performed to gain biological insight into the impact on B- and T-cell phenotype and function. Results: Whole-exome sequencing revealed 2 gain-of-function variants in the IKBKB gene, of which one was a novel variant. While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers. Although still normal in their proliferative capacity, B and T cells show defective activation at day 3 (CD70, CD25, and CD40L expression) and impaired B-cell differentiation into plasmablasts. Altered NF-κB signaling was evidenced by phosphoflow experiments. These findings coincide with autoinflammatory skin manifestations, systemic infections with progressive lymphopenia, and potentially fatal diseases occurring later in life. Conclusion: This study broadens the clinical spectrum of IKBKB gain-of-function variants as a progressive immunodeficiency in adulthood.