Key and emerging concepts in inborn errors of immunity and immune dysregulation.

Abstract

Advances in clinical immunology have led to substantial developments in the diagnosis and treatment of patients with inborn errors of immunity. Still, publications between 2023 and 2025 reveal several persistent needs. First, ongoing reports from the International Union of Immunological Societies demonstrate the need for continued gene discoveries. Second, growing data illustrate the important need for phenotype improvement in not only new diseases but also established ones. Third, recognition of the potentially pleiomorphic nature of heterozygous variants exposes the critical need to challenge prior hypotheses about accepted disease models of inborn errors of immunity. Next, continued pursuit of genetic etiologies for inborn errors of immunity in unsolved cases portends the need to embrace new disease mechanisms, such as somatic mosaicism and monoallelic expression. Furthermore, the rising number of variants of uncertain significance underscores the vital need to investigate multiple variant pathogenicity at scale. Also, recent studies reflect avid realization of the constant need for biomarkers and enhanced detection, such as through bioassays, specific clinically available tests, or even artificial intelligence. Last, key reports support the further need to study innovative treatment approaches and disease outcomes. Overall, the field of clinical immunology must continue to push forward to address these needs.