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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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Main Authors: Schultheiß, Christoph (Author) , Paschold, Lisa (Author) , Mohebiany, Alma Nazlie (Author) , Escher, Moritz (Author) , Kattimani, Yogita Mallu (Author) , Müller, Melanie (Author) , Schmidt-Barbo, Paul (Author) , Willschel, Edith (Author) , Jonas, Hanna (Author) , Chinchuluun, Namuun (Author) , Hoffmann, Katrin (Author) , Czernilofsky, Felix (Author) , Dietrich, Sascha (Author)
Format: Article (Journal)
Language:English
Published: August 2024
In: Science advances
Year: 2024, Volume: 10, Issue: 34, Pages: 1-16
ISSN:2375-2548
DOI:10.25673/116884
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 12.11.2024
Physical Description:Online Resource
ISSN:2375-2548
DOI:10.25673/116884

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