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

Rae, William; Sowerby, John M; Verhoeven, Dorit; Youssef, Mariam; Kotagiri, Prasanti; Savinykh, Natalia; Coomber, Eve L; ... Smith, Kenneth GC; + view all (2022) Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations. Science Immunology , 7 (74) 10.1126/sciimmunol.abn3800. Green open access

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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.

Type: Article
Title: Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/sciimmunol.abn3800
Publisher version: https://doi.org/10.1126/sciimmunol.abn3800
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Autoimmunity, B-Lymphocytes, Humans, Mutation, Neoplasms, TNF Receptor-Associated Factor 3
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10157186
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