Abstract
Original language | English |
---|---|
Pages (from-to) | 1611-1622 |
Number of pages | 12 |
Journal | Journal of clinical immunology |
Volume | 43 |
Issue number | 7 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Oct 2023 |
Keywords
- Atopy
- Gain-of-function
- Lymphoma
- STAT6
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In: Journal of clinical immunology, Vol. 43, No. 7, 10.2023, p. 1611-1622.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma
AU - Minskaia, Ekaterina
AU - Maimaris, Jesmeen
AU - Jenkins, Persephone
AU - Albuquerque, Adriana S.
AU - Hong, Ying
AU - Eleftheriou, Despina
AU - Gilmour, Kimberly C.
AU - Grace, Richard
AU - Moreira, Fernando
AU - Grimbacher, Bodo
AU - NIHR Bioresource-Rare Diseases Consortium
AU - Adhya, Zoe
AU - Alachkar, Hana
AU - Anantharachagan, Ariharan
AU - Antrobus, Richard
AU - Arumugakani, Gururaj
AU - Bacchelli, Chiara
AU - Baxendale, Helen
AU - Bethune, Claire
AU - Bibi, Shahnaz
AU - Boardman, Barbara
AU - Booth, Claire
AU - Browning, Michael
AU - Brownlie, Mary
AU - Burns, Siobhan
AU - Chandra, Anita
AU - Clifford, Hayley
AU - Cooper, Nichola
AU - Davies, Sophie
AU - Dempster, John
AU - Devlin, Lisa
AU - Doffinger, Rainer
AU - Drewe, Elizabeth
AU - Edgar, David
AU - Egner, William
AU - el-Shanawany, Tariq
AU - Gaspar, Bobby
AU - Ghurye, Rohit
AU - Gilmour, Kimberley
AU - Goddard, Sarah
AU - Gordins, Pavel
AU - Grigoriadou, Sofia
AU - Hackett, Scott
AU - Hague, Rosie
AU - Harper, Lorraine
AU - Hayman, Grant
AU - Herwadkar, Archana
AU - Hughes, Stephen
AU - Huissoon, Aarnoud
AU - Kuijpers, Taco
AU - Nejentsev, Sergey
AU - Jolles, Stephen
N1 - Funding Information: SOB has received grant support from CSL Behring and personal fees or travel expenses from Immunodeficiency Canada/IAACI, CSL Behring, Baxalta US Inc and Biotest. ECM has received honoraria from GlaxoSmithKline, AstraZeneca and Orchard Therapeutics. BG was an advisor to the following companies: UCB Pharma S.A., Epimune GmbH, Octapharma, Atheneum Partners GmbH, and GigaGen Inc. and a speaker for Janssen-Cilag GmbH. The rest of the authors declare that they have no conflicts of interest. Funding Information: This work was supported by the National Institute for Health Research UCLH Biomedical Research Centre (ASA, ECM) and the National Institute for Health Research Integrated Academic Training scheme (JM). Funding Information: We thank the patients for their valuable contribution in this study. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. NIHR BioResource – Rare Diseases Consortium: The members of the NIHR BioResource – Rare Diseases PID Consortium are Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Barbara Boardman, Claire Booth, Michael Browning, Mary Brownlie, Siobhan Burns, Anita Chandra, Hayley Clifford, Nichola Cooper, Sophie Davies, John Dempster, Lisa Devlin, Rainer Doffinger, Elizabeth Drewe, David Edgar, William Egner, Tariq El-Shanawany, Bobby Gaspar, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Stephen Hughes, Aarnoud Huissoon, Stephen Jolles, Julie Jones, Peter Kelleher, Nigel Klein, Taco Kuijpers (principal investigator), Dinakantha Kumararatne, James Laffan, Hana Lango Allen, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewall, Fiona Shackley, Ilenia Simeoni, Kenneth G. C. Smith (principal investigator), Emily Staples, Hans Stauss, Cathal Steele, James Thaventhiran, Moira Thomas, Adrian Thrasher (principal investigator), Steve Welch, Lisa Willcocks, Sarita Workman, Austen Worth, Nigel Yeatman, and Patrick Yong. The members of the NIHRBR-RD Management Team are Sofie Ashford, John Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Willem Ouwehand, Christopher Penkett, F. Lucy Raymond, Kathleen Stirrups, Marijke Veltman, Tim Young. The members of the NIHRBR-RD Enrolment and Ethics Team are Sofie Ashford, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Marie Erwood, Amy Frary, Rachel Linger, Jennifer Martin, Sofia Papadia, and Karola Rehnstrom. The members of the NIHRBR-RD Bioinformatics Team are William Astle, Antony Attwood, Marta Bleda, Keren Carss, Louise Daugherty, Sri Deevi, Stefan Graf, Daniel Greene, Csaba Halmagyi, Matthias Haimel, Fengyuan Hu, Roger James, Hana Lango Allen, Vera Matser, Stuart Meacham, Karyn Megy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Catherine Titterton, Salih Tuna, Ernest Turro, Ping Yu, and Julie von Ziegenweldt. The members of the Cambridge Translational Genomics Laboratory are Abigail Furnell, Rutendo Mapeta, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Kathleen Stirrups, Deborah Whitehorn, Paula Rayner-Matthews, and Christopher Watt. Publisher Copyright: © 2023, Crown.
PY - 2023/10
Y1 - 2023/10
N2 - The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis. 245 words.
AB - The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis. 245 words.
KW - Atopy
KW - Gain-of-function
KW - Lymphoma
KW - STAT6
UR - http://www.scopus.com/inward/record.url?scp=85161841672&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s10875-023-01530-7
DO - https://doi.org/10.1007/s10875-023-01530-7
M3 - Article
C2 - 37316763
SN - 0271-9142
VL - 43
SP - 1611
EP - 1622
JO - Journal of clinical immunology
JF - Journal of clinical immunology
IS - 7
ER -