Human inborn errors of immunity: a quarter-century of paradigm shifts in classification, clinical phenotyping, and molecular diagnosis
DOI:
https://doi.org/10.5281/zenodo.22271455Keywords:
inborn errors of immunity; primary immunodeficiency diseases; immune system diseases; immunologic deficiency syndromes; inborn genetic diseases; autoimmune diseasesAbstract
Introduction: inborn errors of immunity (IEI) are predominantly monogenic disorders presenting with infections, autoimmunity, autoinflammation, allergy, and malignancy. Over the last 25 years, the International Union of Immunological Societies (IUIS) Expert Committee has published 14 classification reports, tracking the field's evolution.
Objective: to synthesize the conceptual and quantitative evolution of IEI as documented in IUIS classification reports from 1999 to 2024.
Method: scoping review following Arksey & O'Malley's framework. We systematically searched PubMed for IUIS reports (1999–2024). Data extracted included number of recognized disorders, genetic defects, classification structure, and clinical manifestations. Clinical phenotypes were categorized as infectious, autoimmune, autoinflammatory, allergic, malignant, or non-immunological.
Results: recognized IEI increased eightfold from 59 disorders in 1999 to 559 in 2024, arising from 508 genes plus 17 phenocopies. Three growth phases were identified: linear (1999–2005), accelerated (2005–2015), and exponential with structural consolidation (2015–2024). Major paradigm shifts included: creation of immune dysregulation and autoinflammatory tables (2005), nomenclature change to "inborn errors of immunity" (2017), and introduction of somatic mutation phenocopies (2014). In 2024, 43% of newly described IEI fall into autoinflammatory or immune dysregulation categories. Non-immunological manifestations are present in 100% of syndromic IEI and bone marrow failure syndromes.
Conclusions: the evolution of IEI classification reflects a fundamental reconceptualization of immune dysfunction, from infection-focused deficiencies to multi-system dysregulation disorders. This framework supports pathway-based diagnosis and precision therapy, with implications for rheumatology, hematology, allergy, and neurology.
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Copyright (c) 2026 Carlos Alfredo Miló Valdés, Adrián Alejandro Vitón-Castillo, Lidia Cecilia Pérez Acevedo, Marla González Martínez
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