| 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; Mueller, Melanie; Schmidt-Barbo, Paul; Mensa-Vilaro, Anna; Arostegui, Juan Ignacio; Boursier, Guilaine; de Moreuil, Claire; Hautala, Timo; Willscher, Edith; Jonas, Hanna; Chinchuluun, Namuun; Grosser, Bianca; Markl, Bruno; Klapper, Wolfram; Oommen, Prasad Thomas; Goessling, Katharina; Hoffmann, Katrin; Tiegs, Gisa; Czernilofsky, Felix; Dietrich, Sascha; Freeman, Alexandra; Schwartz, Daniella M.; Waisman, Ari; Aksentijevich, Ivona; Binder, Mascha |
| Source: |
2375-2548 ; Science Advances |
| Publication Year: |
2024 |
| Collection: |
IRUA - Institutional Repository van de Universiteit Antwerpen |
| Subject Terms: |
Human medicine |
| Description: |
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 kappa B (NF-kappa B) 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-kappa B 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-kappa B-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/isi/001295497800021 |
| Availability: |
https://hdl.handle.net/10067/2087820151162165141; https://repository.uantwerpen.be/docstore/d:irua:25706 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.F3CB955D |
| Database: |
BASE |