Getting to know adenosine deaminase 2 deficiency inside and out

Lisa Ehlers; Isabelle Meyts

doi:10.1016/j.jaci.2025.01.040

Getting to know adenosine deaminase 2 deficiency inside and out

J Allergy Clin Immunol. 2025 Feb 14:S0091-6749(25)00164-2. doi: 10.1016/j.jaci.2025.01.040. Online ahead of print.

Authors

Lisa Ehlers¹, Isabelle Meyts²

Affiliations

¹ Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, Katholieke Universiteit (KU) Leuven, Leuven, Belgium; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association, Berlin, Germany.
² Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, Katholieke Universiteit (KU) Leuven, Leuven, Belgium; Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Electronic address: isabelle.meyts@uzleuven.be.

PMID: 39956283
DOI: 10.1016/j.jaci.2025.01.040

Abstract

Ten years after the description of the first cohorts of patients with adenosine deaminase (ADA2) deficiency (DADA2), the pathomechanisms underlying the disease on a cellular level remain poorly understood. With the establishment of the lysosomal localization of the ADA2 protein and its involvement in nucleic acid sensing, the pathophysiologic focus has shifted to the inside of the cell. At the same time, extracellular (serum) ADA2 enzyme activity continues to be the diagnostic reference standard in patients with suspected DADA2. The diverse clinical phenotype and weak genotype-phenotype correlations further complicate the identification of shared cellular mechanisms that cause inflammation, immunodeficiency, and bone marrow failure in the absence of functional ADA2. This review inspects the characteristics of the ADA2 protein and its proposed function. The latter is discussed in the context of possible mechanisms driving the clinical phenotype in patients lacking functional ADA2. We discuss established processes and introduce unexplored pathways in the pathogenesis of DADA2.

Keywords: Adenosine deaminase 2; autoinflammation; deficiency of ADA2; immunodeficiency; inborn errors of immunity; type I interferons.

Publication types

Review