Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
| العنوان: | Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations |
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| المؤلفون: | William Rae, John M. Sowerby, Dorit Verhoeven, Mariam Youssef, Prasanti Kotagiri, Natalia Savinykh, Eve L. Coomber, Alexis Boneparth, Angela Chan, Chun Gong, Machiel H. Jansen, Romy du Long, Giorgia Santilli, Ilenia Simeoni, Jonathan Stephens, Kejia Wu, Marta Zinicola, Hana Lango Allen, Helen Baxendale, Dinakantha Kumararatne, Effrossyni Gkrania-Klotsas, Selma C. Scheffler Mendoza, Marco Antonio Yamazaki-Nakashimada, Laura Berrón Ruiz, Cesar Mauricio Rojas-Maruri, Saul O. Lugo Reyes, Paul A. Lyons, Anthony P. Williams, Daniel J. Hodson, Gail A. Bishop, Adrian J. Thrasher, David C. Thomas, Michael P. Murphy, Timothy J. Vyse, Joshua D. Milner, Taco W. Kuijpers, Kenneth G. C. Smith |
| المساهمون: | Pathology, Rae, William [0000-0003-0095-2514], Sowerby, John M [0000-0001-6119-6965], Youssef, Mariam [0000-0002-9616-2172], Savinykh, Natalia [0000-0003-3929-2760], Coomber, Eve L [0000-0002-7093-2263], du Long, Romy [0000-0001-9679-1182], Santilli, Giorgia [0000-0003-1776-1984], Simeoni, Ilenia [0000-0001-5039-2194], Stephens, Jonathan [0000-0003-2020-9330], Wu, Kejia [0000-0002-7700-2907], Zinicola, Marta [0000-0002-3546-3297], Allen, Hana Lango [0000-0002-7803-8688], Baxendale, Helen [0000-0003-3838-3900], Kumararatne, Dinakantha [0000-0001-8438-4686], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], Scheffler Mendoza, Selma C [0000-0001-6548-5721], Yamazaki-Nakashimada, Marco Antonio [0000-0002-7609-3923], Ruiz, Laura Berrón [0000-0002-3290-8705], Lugo Reyes, Saul O [0000-0002-3730-4150], Lyons, Paul A [0000-0001-7035-8997], Hodson, Daniel J [0000-0001-6225-2033], Bishop, Gail A [0000-0002-1291-5078], Thrasher, Adrian J [0000-0002-6097-6115], Thomas, David C [0000-0002-9738-2329], Murphy, Michael P [0000-0003-1115-9618], Kuijpers, Taco W [0000-0002-7421-3370], Smith, Kenneth GC [0000-0003-3829-4326], Apollo - University of Cambridge Repository, Graduate School, Paediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development |
| المصدر: | Science immunology, 7(74):eabn3800. American Association for the Advancement of Science Rae, W, Sowerby, J M, Verhoeven, D, Youssef, M, Kotagiri, P, Savinykh, N, Coomber, E L, Boneparth, A, Chan, A, Gong, C, Jansen, M H, du Long, R, Santilli, G, Simeoni, I, Stephens, J, Wu, K, Zinicola, M, Allen, H L, Baxendale, H, Kumararatne, D, Gkrania-Klotsas, E, Scheffler Mendoza, S C, Yamazaki-Nakashimada, M A, Ruiz, L B, Rojas-Maruri, C M, Lugo Reyes, S O, Lyons, P A, Williams, A P, Hodson, D J, Bishop, G A, Thrasher, A J, Thomas, D C, Murphy, M P, Vyse, T J, Milner, J D, Kuijpers, T W & Smith, K G C 2022, ' Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations ', Science immunology, vol. 7, no. 74, eabn3800, pp. eabn3800 . https://doi.org/10.1126/sciimmunol.abn3800 |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | B-Lymphocytes, TNF Receptor-Associated Factor 3, Neoplasms, Immunology, Mutation, Humans, Autoimmunity, General Medicine |
| الوصف: | 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. |
| وصف الملف: | application/octet-stream; image/png |
| اللغة: | English |
| تدمد: | 2470-9468 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0139c7d397315777f60fb0684e7c389e https://research.vumc.nl/en/publications/31edb0c4-1aef-4910-9666-6fe6f7ad7f2d |
| حقوق: | RESTRICTED |
| رقم الأكسشن: | edsair.doi.dedup.....0139c7d397315777f60fb0684e7c389e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24709468 |
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