Year: 2026
Type: article
Abstract: Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2 -/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2 . Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13 C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.
Source: Cell Death Discovery
Authors: Lisa Ehlers, Marjon Wouters, Bethany Pillay, Selket Delafontaine, Giorgia Bucciol, Marco Baggio, Mariia Dzhus, Anneleen Hombrouck, Alexandra Damerau, Lien De Somer, Rik Schrijvers, Steven Vanderschueren, Maarten Jacquemyn, Tilmann Kallinich, Dirk Daelemans, Bart Ghesquière, Patrizia Agostinis, Leen Moens, Isabelle Meyts
Institutions: Leibniz Association, Humboldt-Universität zu Berlin, German Rheumatism Research Centre, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Charité - Universitätsmedizin Berlin, KU Leuven, Universitair Ziekenhuis Leuven, Max Delbrück Center, Rega Institute for Medical Research, VIB-KU Leuven Center for Cancer Biology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: Therapeutic harnessing of iron-dependent cell death in melanoma; the ApolipoproteinE and ferroptosis link, G263933635, G3491932767, Understanding ADA2 deficiency on a cellular level, G5773576668, G6108111472, CLINICAL, GENETIC AND IMMUNOLOGICAL STUDY OF HUMAN ADENOSINE DEAMINASE 2 DEFICIENCY, G703244163, Mechanometabolismus bei Osteoarthritis (OA): Beeinflusst mechanischer Stress den Stoffwechsel humaner synovialer Fibroblasten und trägt dies zum stromalen Gedächtnis bei OA bei?, Clinical, immunological and genetic unravelling of severe isolated central nervous system disorders in children., G770897334, G8761802835
OpenAlex ID: W7140036515