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

Author:

Schultheiß Christoph12ORCID,Paschold Lisa3ORCID,Mohebiany Alma Nazlie456ORCID,Escher Moritz3ORCID,Kattimani Yogita Mallu4,Müller Melanie4ORCID,Schmidt-Barbo Paul127,Mensa-Vilaró Anna89,Aróstegui Juan Ignacio8910ORCID,Boursier Guilaine11ORCID,de Moreuil Claire12,Hautala Timo13ORCID,Willscher Edith3ORCID,Jonas Hanna3,Chinchuluun Namuun3,Grosser Bianca14,Märkl Bruno14ORCID,Klapper Wolfram15,Oommen Prasad Thomas16ORCID,Gössling Katharina1617,Hoffmann Katrin18,Tiegs Gisa19,Czernilofsky Felix202122ORCID,Dietrich Sascha2021222324,Freeman Alexandra25ORCID,Schwartz Daniella M.26ORCID,Waisman Ari4ORCID,Aksentijevich Ivona27ORCID,Binder Mascha127ORCID

Affiliation:

1. Division of Medical Oncology, University Hospital Basel, Basel, Switzerland.

2. Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.

3. Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

4. Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.

5. Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.

6. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

7. Collaborative Research Institute Intelligent Oncology (CRIION), Freiburg, Germany.

8. Department of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain.

9. Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.

10. School of Medicine, University of Barcelona, Barcelona, Spain.

11. Department of molecular and cytogenomics, Rare and Autoinflammatory Diseases Laboratory, CHU Montpellier, IRMB, University of Montpellier, INSERM, CEREMAIA, Montpellier, France.

12. Department of Internal Medicine, CHU Brest, Université de Bretagne Occidentale, Brest, France.

13. Research Unit of Biomedicine, University of Oulu and Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

14. Institute for Pathology, University Medical Center Augsburg, Augsburg, Germany.

15. Institute of Pathology, Hematopathology Section, and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

16. Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Center for Child and Adolescent Health, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

17. Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.

18. Institute for Human Genetics and Molecular Biology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

19. Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

20. Department of Medicine V, Hematology, Oncology, and Rheumatology, University of Heidelberg, Heidelberg, Germany.

21. European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

22. Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.

23. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

24. Department of Hematolgy, Oncology, and Immunolgy, University Hospital of Düsseldorf, Düsseldorf, Germany.

25. Laboratory of Clinical Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.

26. Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

27. Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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