A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors

Genetic <i>TNFAIP3</i> (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 <i>TNFAIP3</i> 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 (<i>CD81</i>, <i>BACH2</i>, and <i>NEAT1</i>) or T (<i>GATA3</i>, <i>TOX</i>, and <i>PDCD1</i>) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional <i>TNFAIP3</i> 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.

Authors

Institutions

Publication Details

Journal
Science Advances
Published
2024-08-21
DOI
https://doi.org/10.1126/sciadv.adl3975
Citations
14
Primary Topic
NF-κB Signaling Pathways
Type
article
Field-Weighted Citation Impact
3.99
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors

Claire de Moreuil, Katrin Hoffmann, Gisa Tiegs, Paul Schmidt-Barbo et al.
14 citations
Science Advances
NF-κB Signaling Pathways
3.99
article

A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors

Claire de Moreuil, Katrin Hoffmann, Gisa Tiegs, Paul Schmidt-Barbo, Lisa Paschold, Alma N. Mohebiany, Prasad T. Oommen, Anna Mensa‐Vilaró, Bruno Märkl, Ivona Aksentijevich, Ari Waisman, Guilaine Boursier, Daniella M. Schwartz, Christoph Schultheiß, Sascha Dietrich, Yogita Kattimani, Hanna Jonas, Alexandra F. Freeman, Bianca Grosser, Katharina L. Gössling, Juan I. Aróstegui, Timo Hautala, Edith Willscher, Moritz Escher, Mascha Binder, Felix Czernilofsky, Melanie Müller, Wolfram Klapper, Namuun Chinchuluun
article en
14 citations

Abstract

Genetic <i>TNFAIP3</i> (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 <i>TNFAIP3</i> 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 (<i>CD81</i>, <i>BACH2</i>, and <i>NEAT1</i>) or T (<i>GATA3</i>, <i>TOX</i>, and <i>PDCD1</i>) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional <i>TNFAIP3</i> 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.

Science AdvancesVol. 10(34)
National Institutes of Health (US), European Molecular Biology Organization (DE), University of Antwerp (BE), Inserm (FR), Universität Hamburg (DE), Université de Bretagne Occidentale (FR), University of Pittsburgh (US), University of Augsburg (DE), German Cancer Research Center (DE), Johannes Gutenberg University Mainz (DE), Université de Montpellier (FR), Heidelberg University (DE), Oulu University Hospital (FI), University Hospital of Basel (CH), Düsseldorf University Hospital (DE), National Human Genome Research Institute (US), University Medical Center of the Johannes Gutenberg University Mainz (DE), Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR), University Medical Center Hamburg-Eppendorf (DE), National Center for Tumor Diseases (DE), University Hospital Schleswig-Holstein (DE), Hospital Clínic de Barcelona (ES), VIB-UAntwerp Center for Molecular Neurology (BE), National Institute of Allergy and Infectious Diseases (US), European Molecular Biology Laboratory (DE), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Heinrich Heine University Düsseldorf (DE), Martin Luther University Halle-Wittenberg (DE), Universitat de Barcelona (ES), University of Lübeck (DE), University of Oulu (FI)
Good health and well-being
Openalex Percentile: Top 5%
NF-κB Signaling Pathways
3.99
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.