Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

  • Sci Immunol. 2022 Aug 12;7(74):eabn3800. doi: 10.1126/sciimmunol.abn3800.
William Rae  1  2 ,  John M Sowerby  1  2 ,  Dorit Verhoeven  3  4 ,  Mariam Youssef  5 ,  Prasanti Kotagiri  1  2 ,  Natalia Savinykh  6 ,  Eve L Coomber  7 ,  Alexis Boneparth  5 ,  Angela Chan  5 ,  Chun Gong  8 ,  Machiel H Jansen  3  4 ,  Romy du Long  9 ,  Giorgia Santilli  10 ,  Ilenia Simeoni  11  12 ,  Jonathan Stephens  11  12 ,  Kejia Wu  13 ,  Marta Zinicola  10 ,  Hana Lango Allen  12  14 ,  Helen Baxendale  15 ,  Dinakantha Kumararatne  16 ,  Effrossyni Gkrania-Klotsas  14  17 ,  Selma C Scheffler Mendoza  18 ,  Marco Antonio Yamazaki-Nakashimada  18 ,  Laura Berrón Ruiz  19 ,  Cesar Mauricio Rojas-Maruri  20 ,  Saul O Lugo Reyes  19 ,  Paul A Lyons  1  2 ,  Anthony P Williams  21 ,  Daniel J Hodson  8 ,  Gail A Bishop  22  23  24 ,  Adrian J Thrasher  10  25 ,  David C Thomas  26 ,  Michael P Murphy  2  27 ,  Timothy J Vyse  13 ,  Joshua D Milner  5 ,  Taco W Kuijpers  3  4 ,  Kenneth G C Smith  1  2
Affiliations
  • 1. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
  • 2. Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • 3. Emma Children's Hospital, Amsterdam University Medical Center (AUMC), University of Amsterdam, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam, Netherlands.
  • 4. Amsterdam University Medical Center (AUMC), University of Amsterdam, Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.
  • 5. Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
  • 6. NIHR Cambridge BRC Cell Phenotyping Hub, Department of Medicine, University of Cambridge, Cambridge, UK.
  • 7. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  • 8. Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 9. Amsterdam University Center (AUMC), University of Amsterdam, Department of Pathology, Amsterdam, Netherlands.
  • 10. UCL Great Ormond Street Institute of Child Health, London, UK.
  • 11. Department of Hematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 12. NIHR Bioresource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
  • 13. Department of Medical and Molecular Genetics, King's College London, London, UK.
  • 14. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
  • 15. Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK.
  • 16. Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.
  • 17. Department of Infectious Diseases, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
  • 18. Clinical Immunology Service, National Institute of Pediatrics, Secretariat of Health, Mexico City, Mexico.
  • 19. Immune Deficiencies Laboratory, National Institute of Pediatrics, Secretariat of Health, Mexico City, Mexico.
  • 20. Pathology Department, National Institute of Pediatrics, Secretariat of Health, Mexico City, Mexico.
  • 21. Wessex Investigational Sciences Hub, Faculty of Medicine, University of Southampton, Southampton, UK.
  • 22. Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
  • 23. Department of Internal Medicine, University of Iowa, IA, USA.
  • 24. Veterans Affairs Medical Center, Iowa City, IA, USA.
  • 25. Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
  • 26. Department of Immunology and Inflammation, Center for Inflammatory Diseases, Imperial College London, London, UK.
  • 27. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
PMID: 35960817 DOI: 10.1126/sciimmunol.abn3800
Abstract

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent Bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and Bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

Products