A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors
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...
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| Hauptverfasser: | , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
August 2024
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| In: |
Science advances
Year: 2024, Jahrgang: 10, Heft: 34, Pages: 1-16 |
| ISSN: | 2375-2548 |
| DOI: | 10.25673/116884 |
| Online-Zugang: | Resolving-System, kostenfrei: https://doi.org/10.25673/116884 Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/sciadv.adl3975 
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| Verfasserangaben: | Christoph Schultheiß, Lisa Paschold, Alma Nazlie Mohebiany, Moritz Escher, Yogita Mallu Kattimani, Melanie Müller, Paul Schmidt-Barbo, Edith Willschel, Hanna Jonas, Namuun Chinchuluun, Katrin Hoffmann, Felix Czernilofsky, Sascha Dietrich ... [und weitere] |
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| 520 | |a 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. | ||
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