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

Abstract

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. We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB. 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. 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. This study broadens the clinical spectrum of IKBKB gain-of-function variants as a progressive immunodeficiency in adulthood.