Evidence map›Paper›PMID 40545182›Full record

ArticleThe Journal of allergy and clinical immunology2025

Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes.

Lisa Ehlers, Marjon Wouters, Bethany Pillay, Selket Delafontaine, Mariia Dzhus, Marco Baggio, Tim Niehues, Gregor Dückers, Lieve Sevenants, Kristina Casteels and 12 more

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In one paragraph

Article in The Journal of allergy and clinical immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Lisa EhlersDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, 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, partner site Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association, Berlin, Germany.
Marjon WoutersDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Bethany PillayDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Selket DelafontaineDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium; Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Mariia DzhusDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Marco BaggioDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium; Laboratory of Computational and Developmental Biology, Berlin Institute for Medical Systems Biology, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Tim NiehuesHelios Children's Hospital, Krefeld, Germany.
Gregor DückersHelios Children's Hospital, Krefeld, Germany.
Lieve SevenantsDepartment of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Kristina CasteelsDepartment of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Lien De SomerDepartment of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Laboratory of Immunobiology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
Rik SchrijversDepartment of Microbiology, Immunology and Transplantation, Allergy and Clinical immunology Research Group, KU Leuven, Leuven, Belgium.
Steven VanderschuerenDepartment of General Internal Medicine, Research Department Microbiology, Immunology, and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disorders, University Hospitals Leuven, Leuven, Belgium.
Maarten JacquemynKU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega Institute for Medical Research, Leuven, Belgium.
Dirk DaelemansKU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega Institute for Medical Research, Leuven, Belgium.
Anneleen HombrouckDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Eugene P ChambersVanderbilt University Medical Center, Nashville, Tenn; DADA2 Foundation, Nashville, Tenn.
Thomas TousseynDepartment of Pathology, University Hospitals Leuven, Leuven, Belgium.
Giorgia BucciolDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium; Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Patrizia AgostinisCell Death Research and Therapy Lab, Department of Cellular and Molecular Medicine, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium.
Leen MoensDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Isabelle MeytsDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium; Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Electronic address: isabelle.meyts@uzleuven.be.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundDeficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity causing vasculitis and bone marrow failure. Bone marrow failure is mostly unresponsive to TNF-α inhibitors. The limited understanding of the pathomechanisms driving the disease impedes the development of new treatment options. Unlike cellular model systems expressing pathogenic ADA2 variants, primary monocytes from patients with DADA2 lack ADA2 protein expression.

objectivesThis study aimed to analyze the role of protein degradation in the pathogenesis of DADA2 and the therapeutic potential of the lysosomotropic drug hydroxychloroquine in the treatment of patients with DADA2.

methodsADA2 protein expression in CD14

resultsWe demonstrated that inhibition of lysosomal degradation restores ADA2 protein expression in DADA2 monocytes in vitro. DADA2 monocytes exhibited increased autophagic activity. We observed clinical improvement in 2 cytopenic patients with DADA2 who were treated with hydroxychloroquine, and we showed a concomitant increase in ADA2 protein levels in monocytes from one of these patients in vivo.

conclusionWe identified lysosomal protein degradation of ADA2 as a pathomechanism of DADA2 and introduced hydroxychloroquine as a potential treatment option in patients with DADA2 with refractory cytopenia.

Indexed as

Adenosine DeaminaseAgammaglobulinemiaIntercellular Signaling Peptides and ProteinsLysosomesMonocytesSevere Combined ImmunodeficiencyAdultCells, CulturedChildChild, PreschoolFemaleHumansHydroxychloroquineInfantMaleMutationADA2 protein, humanAdenosine DeaminaseHydroxychloroquineIntercellular Signaling Peptides and ProteinscytopeniaDeficiency of ADA2hydroxychloroquinelysosomal degradationTLR9 signaling

Identifiers

PMID40545182
PMCPMC12499373

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.