| Title: |
A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors |
| Authors: |
Schultheiß, Christoph; Paschold, Lisa; Mohebiany, Alma Nazlie; Escher, Moritz; Kattimani, Yogita Mallu; Müller, Melanie; Schmidt-Barbo, Paul; Mensa-Vilaró, Anna; Aróstegui, Juan Ignacio; Boursier, Guilaine; de Moreuil, Claire; Hautala, Timo; Willscher, Edith; Jonas, Hanna; Chinchuluun, Namuun; Grosser, Bianca; Märkl, Bruno; Klapper, Wolfram; Oommen, Prasad Thomas; Gössling, Katharina; Hoffmann, Katrin; Tiegs, Gisa; Czernilofsky, Felix; Dietrich, Sascha; Freeman, Alexandra; Schwartz, Daniella; Waisman, Ari; Aksentijevich, Ivona; Binder, Mascha |
| Contributors: |
University Hospital Basel Basel; Martin-Luther-Universität Halle Wittenberg - Martin-Luther-University Halle Wittenberg (MLU); Universitätsmedizin der Johannes Gutenberg-Universität Mainz - University Medical Center of the Johannes Gutenberg-University Mainz Germany; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Universitat de Barcelona (UB); Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB); Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM); Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST); Université de Brest (UBO EPE); University of Oulu Finland = Oulun yliopisto Suomi = Université d'Oulu Finlande; Universität Augsburg Deutschland = University of Augsburg Germany = Université d'Augsbourg Allemagne (UNIA); University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH); Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel (CAU); Heinrich Heine Universität Düsseldorf = Heinrich Heine University Düsseldorf; Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf Hamburg (UKE); University of Heidelberg, Medical Faculty; National Institute of Allergy and Infectious Diseases Bethesda (NIAID-NIH); National Institutes of Health Bethesda, MD, USA (NIH); University of Pittsburgh Medical Center Pittsburgh, PA, États-Unis (UPMC); National Human Genome Research Institute (NHGRI); Financial supportfrom the deutsche Forschungsgemeinschaft (SFB841 and Bi 1711/4-1 to M.B.) as well asintramural Funding of the Research Program of the national human Genome Research institute(to i.A.) is acknowledged. this work was also funded by the deutsche Forschungsgemeinschaft(dFG, German Research Foundation) – SFB 1648/1 2024 – 512741711 and the Swiss nationalScience Foundation (SnSF) 10.001.762 (both to M.B.) |
| Source: |
ISSN: 2375-2548 ; Science Advances ; https://hal.science/hal-04954712 ; Science Advances , 2024, 10 (34), pp.eadl3975. ⟨10.1126/sciadv.adl3975⟩. |
| Publisher Information: |
CCSD; American Association for the Advancement of Science (AAAS) |
| Publication Year: |
2024 |
| Collection: |
Inserm: HAL (Institut national de la santé et de la recherche médicale) |
| Subject Terms: |
MESH: Tumor Necrosis Factor alpha-Induced Protein 3; MESH: Animals; MESH: Signal Transduction; MESH: Middle Aged; MESH: Lymphocytes; MESH: B-Lymphocytes; MESH: Adult; MESH: Tumor Necrosis Factor-alpha; MESH: T-Lymphocytes; MESH: Lymphoma; MESH: Humans; MESH: Homeostasis; MESH: Haploinsufficiency; MESH: Mice; MESH: NF-kappa B; Knockout; MESH: Female; MESH: Male; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B ( CD81 , BACH2 , and NEAT1 ) or T ( GATA3 , TOX , and PDCD1 ) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional TNFAIP3 knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB–mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39167656; PUBMED: 39167656; PUBMEDCENTRAL: PMC11338232 |
| DOI: |
10.1126/sciadv.adl3975 |
| Availability: |
https://hal.science/hal-04954712; https://hal.science/hal-04954712v1/document; https://hal.science/hal-04954712v1/file/sciadv.adl3975.pdf; https://doi.org/10.1126/sciadv.adl3975 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.AF5418EB |
| Database: |
BASE |