Journal article
Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
Science immunology, Vol.7(74), pp.eabn3800-eabn3800
08/12/2022
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.
Details
- Title: Subtitle
- Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
- Creators
- William Rae - University of CambridgeJohn M Sowerby - University of CambridgeDorit Verhoeven - University of AmsterdamMariam Youssef - Columbia University Irving Medical CenterPrasanti Kotagiri - University of CambridgeNatalia Savinykh - University of CambridgeEve L Coomber - Wellcome Sanger InstituteAlexis Boneparth - Columbia University Irving Medical CenterAngela Chan - Columbia University Irving Medical CenterChun Gong - Wellcome/MRC Cambridge Stem Cell InstituteMachiel H Jansen - University of AmsterdamRomy du Long - University of AmsterdamGiorgia Santilli - UCL Institute of Child HealthIlenia Simeoni - University of CambridgeJonathan Stephens - University of CambridgeKejia Wu - King's College LondonMarta Zinicola - UCL Institute of Child HealthHana Lango Allen - MRC Epidemiology UnitHelen Baxendale - Papworth HospitalDinakantha Kumararatne - Addenbrooke's HospitalEffrossyni Gkrania-Klotsas - MRC Epidemiology UnitSelma C Scheffler MendozaMarco Antonio Yamazaki-Nakashimada - Clinical Immunology Service, National Institute of Pediatrics, Secretariat of Health, Mexico City, Mexico.Laura Berrón RuizCesar Mauricio Rojas-Maruri - Pathology Department, National Institute of Pediatrics, Secretariat of Health, Mexico City, Mexico.Saul O Lugo ReyesPaul A Lyons - University of CambridgeAnthony P Williams - University of SouthamptonDaniel J Hodson - Wellcome/MRC Cambridge Stem Cell InstituteGail A Bishop - University of IowaAdrian J Thrasher - Great Ormond Street Hospital for Children NHS Foundation TrustDavid C ThomasMichael P Murphy - University of CambridgeTimothy J Vyse - King's College LondonJoshua D Milner - Columbia University Irving Medical CenterTaco W Kuijpers - University of AmsterdamKenneth G C Smith - University of Cambridge
- Resource Type
- Journal article
- Publication Details
- Science immunology, Vol.7(74), pp.eabn3800-eabn3800
- DOI
- 10.1126/sciimmunol.abn3800
- eISSN
- 2470-9468
- Language
- English
- Date published
- 08/12/2022
- Academic Unit
- Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297328602771
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