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

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

doi:10.1126/sciimmunol.abn3800

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

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

Medical & Molecular Genetics

Cambridge University Hospitals NHS Foundation Trust
Department of Medicine
Amsterdam Medical Center
AMC Academic Medical Center
Columbia University
University of Amsterdam
UCL Great Ormond Street Institute of Child Health
Royal Papworth Hospital NHS Foundation Trust
Cambridge University Hospital NHS Foundation Trust
National Institute of Pediatrics
University of Southampton
University of Iowa
Iowa City VA Health Care System
Great Ormond Street Hospital for Children NHS Foundation Trust
Imperial College London
MRC Mitochondrial Biology Unit

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

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.

Original language	English
Article number	eabn3800
Pages (from-to)	eabn3800
Journal	Science Immunology
Volume	7
Issue number	74
DOIs	https://doi.org/10.1126/sciimmunol.abn3800
Publication status	Published - 12 Aug 2022

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10.1126/sciimmunol.abn3800

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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., ... Smith, K. G. C. (2022). Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations. Science Immunology, 7(74), eabn3800. Article eabn3800. https://doi.org/10.1126/sciimmunol.abn3800

@article{7dac1be58baa4a6daa42bd1fa90467d6,

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

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{\textquoteright} 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 na{\"i}ve 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.",

author = "William Rae and Sowerby, \{John M.\} and Dorit Verhoeven and Mariam Youssef and Prasanti Kotagiri and Natalia Savinykh and Coomber, \{Eve L.\} and Alexis Boneparth and Angela Chan and Chun Gong and Jansen, \{Machiel H.\} and \{du Long\}, Romy and Giorgia Santilli and Ilenia Simeoni and Jonathan Stephens and Kejia Wu and Marta Zinicola and Allen, \{Hana Lango\} and Helen Baxendale and Dinakantha Kumararatne and Effrossyni Gkrania-Klotsas and \{Scheffler Mendoza\}, \{Selma C.\} and Yamazaki-Nakashimada, \{Marco Antonio\} and Ruiz, \{Laura Berr{\'o}n\} and Rojas-Maruri, \{Cesar Mauricio\} and \{Lugo Reyes\}, \{Saul O.\} and Lyons, \{Paul A.\} and Williams, \{Anthony P.\} and Hodson, \{Daniel J.\} and Bishop, \{Gail A.\} and Thrasher, \{Adrian J.\} and Thomas, \{David C.\} and Murphy, \{Michael P.\} and Vyse, \{Timothy J.\} and Milner, \{Joshua D.\} and Kuijpers, \{Taco W.\} and Smith, \{Kenneth G.C.\}",

note = "Funding Information: W.R. was supported by a Wellcome Trust PhD for Clinicians Fellowship (216382/Z/19/Z). M.Z. was supported by the NIHR Blood and Transplant Research Unit, University College London (2104-10074). E.G.-K. is funded by an NIHR Greenshoots Award. C.G. was supported by a fellowship from the Kay Kendall Leukaemia Fund (KKLF1398). A.J.T. is supported by the Wellcome Trust (217112/Z/19/Z) and the NIHR BRC at Great Ormond Street Hospital for Children NHS Foundation Trust. M.P.M. is supported by the Medical Research Council U.K. (MR\_U105663142) and by a Wellcome Trust Investigator award (110159/A15/Z). D.J.H. was supported by a Senior Research Fellowship from CRUK (RCCFEL/100072) and receives core support from the Wellcome Trust to the Wellcome–MRC Cambridge Stem Cell Institute (203151/Z/16/Z). K.G.C.S. was supported by the MRC (Programme grant MR/L019027) and is a Wellcome Investigator. The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the MRC (MR/N003284/1, MC-PC\_13048, MC-UU\_12015/1). The NIHR Bioresource is funded by the NIHR (RG65966). The “Primary Immunodeficiency: mechanism and diagnosis via integrative clinical immunogenomics” (INTREPID) collaboration is funded by a Wellcome Trust Collaborative Award (219506/Z/19/Z). Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = aug,

day = "12",

doi = "10.1126/sciimmunol.abn3800",

language = "English",

volume = "7",

pages = "eabn3800",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "74",

}

Rae, W, Sowerby, JM, Verhoeven, D, Youssef, M, Kotagiri, P, Savinykh, N, Coomber, EL, Boneparth, A, Chan, A, Gong, C, Jansen, MH, du Long, R, Santilli, G, Simeoni, I, Stephens, J, Wu, K, Zinicola, M, Allen, HL, Baxendale, H, Kumararatne, D, Gkrania-Klotsas, E, Scheffler Mendoza, SC, Yamazaki-Nakashimada, MA, Ruiz, LB, Rojas-Maruri, CM, Lugo Reyes, SO, Lyons, PA, Williams, AP, Hodson, DJ, Bishop, GA, Thrasher, AJ, Thomas, DC, Murphy, MP, Vyse, TJ, Milner, JD, Kuijpers, TW & Smith, KGC 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

TY - JOUR

T1 - Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

AU - Rae, William

AU - Sowerby, John M.

AU - Verhoeven, Dorit

AU - Youssef, Mariam

AU - Kotagiri, Prasanti

AU - Savinykh, Natalia

AU - Coomber, Eve L.

AU - Boneparth, Alexis

AU - Chan, Angela

AU - Gong, Chun

AU - Jansen, Machiel H.

AU - du Long, Romy

AU - Santilli, Giorgia

AU - Simeoni, Ilenia

AU - Stephens, Jonathan

AU - Wu, Kejia

AU - Zinicola, Marta

AU - Allen, Hana Lango

AU - Baxendale, Helen

AU - Kumararatne, Dinakantha

AU - Gkrania-Klotsas, Effrossyni

AU - Scheffler Mendoza, Selma C.

AU - Yamazaki-Nakashimada, Marco Antonio

AU - Ruiz, Laura Berrón

AU - Rojas-Maruri, Cesar Mauricio

AU - Lugo Reyes, Saul O.

AU - Lyons, Paul A.

AU - Williams, Anthony P.

AU - Hodson, Daniel J.

AU - Bishop, Gail A.

AU - Thrasher, Adrian J.

AU - Thomas, David C.

AU - Murphy, Michael P.

AU - Vyse, Timothy J.

AU - Milner, Joshua D.

AU - Kuijpers, Taco W.

AU - Smith, Kenneth G.C.

N1 - Funding Information: W.R. was supported by a Wellcome Trust PhD for Clinicians Fellowship (216382/Z/19/Z). M.Z. was supported by the NIHR Blood and Transplant Research Unit, University College London (2104-10074). E.G.-K. is funded by an NIHR Greenshoots Award. C.G. was supported by a fellowship from the Kay Kendall Leukaemia Fund (KKLF1398). A.J.T. is supported by the Wellcome Trust (217112/Z/19/Z) and the NIHR BRC at Great Ormond Street Hospital for Children NHS Foundation Trust. M.P.M. is supported by the Medical Research Council U.K. (MR_U105663142) and by a Wellcome Trust Investigator award (110159/A15/Z). D.J.H. was supported by a Senior Research Fellowship from CRUK (RCCFEL/100072) and receives core support from the Wellcome Trust to the Wellcome–MRC Cambridge Stem Cell Institute (203151/Z/16/Z). K.G.C.S. was supported by the MRC (Programme grant MR/L019027) and is a Wellcome Investigator. The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the MRC (MR/N003284/1, MC-PC_13048, MC-UU_12015/1). The NIHR Bioresource is funded by the NIHR (RG65966). The “Primary Immunodeficiency: mechanism and diagnosis via integrative clinical immunogenomics” (INTREPID) collaboration is funded by a Wellcome Trust Collaborative Award (219506/Z/19/Z). Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

PY - 2022/8/12

Y1 - 2022/8/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85136342099

U2 - 10.1126/sciimmunol.abn3800

DO - 10.1126/sciimmunol.abn3800

M3 - Article

C2 - 35960817

AN - SCOPUS:85136342099

SN - 2470-9468

VL - 7

SP - eabn3800

JO - Science Immunology

JF - Science Immunology

IS - 74

M1 - eabn3800

ER -

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

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