A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors
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 M; Waisman, Ari; Aksentijevich, Ivona; Binder, Mascha (2024-08-21)
American association for the advancement of science
21.08.2024
Schultheiß, C., Paschold, L., Mohebiany, A. N., Escher, M., Kattimani, Y. M., Müller, M., Schmidt-Barbo, P., Mensa-Vilaró, A., Aróstegui, J. I., Boursier, G., De Moreuil, C., Hautala, T., Willscher, E., Jonas, H., Chinchuluun, N., Grosser, B., Märkl, B., Klapper, W., Oommen, P. T., … Binder, M. (2024). A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors. Science Advances, 10(34), eadl3975. https://doi.org/10.1126/sciadv.adl3975
https://creativecommons.org/licenses/by-nc/4.0/
© 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a Creative Commons Attribution NonCommercial license 4.0 (CC BY- NC).
https://creativecommons.org/licenses/by-nc/4.0/
© 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a Creative Commons Attribution NonCommercial license 4.0 (CC BY- NC).
https://creativecommons.org/licenses/by-nc/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202408225547
https://urn.fi/URN:NBN:fi:oulu-202408225547
Tiivistelmä
Abstract
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.
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.
Kokoelmat
- Avoin saatavuus [38865]
Ellei muuten mainita, aineiston lisenssi on https://creativecommons.org/licenses/by-nc/4.0/