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

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

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.

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