Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma.
Atopy
Gain-of-function
Lymphoma
STAT6
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
05
10
2022
accepted:
29
05
2023
medline:
14
9
2023
pubmed:
15
6
2023
entrez:
14
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37316763
doi: 10.1007/s10875-023-01530-7
pii: 10.1007/s10875-023-01530-7
pmc: PMC10499697
doi:
Substances chimiques
Interleukin-4
207137-56-2
STAT6 Transcription Factor
0
Janus Kinases
EC 2.7.10.2
STAT6 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1611-1622Subventions
Organisme : Department of Health
Pays : United Kingdom
Investigateurs
Zoe Adhya
(Z)
Hana Alachkar
(H)
Ariharan Anantharachagan
(A)
Richard Antrobus
(R)
Gururaj Arumugakani
(G)
Chiara Bacchelli
(C)
Helen Baxendale
(H)
Claire Bethune
(C)
Shahnaz Bibi
(S)
Barbara Boardman
(B)
Claire Booth
(C)
Michael Browning
(M)
Mary Brownlie
(M)
Siobhan Burns
(S)
Anita Chandra
(A)
Hayley Clifford
(H)
Nichola Cooper
(N)
Sophie Davies
(S)
John Dempster
(J)
Lisa Devlin
(L)
Rainer Doffinger
(R)
Elizabeth Drewe
(E)
David Edgar
(D)
William Egner
(W)
Tariq El-Shanawany
(T)
Bobby Gaspar
(B)
Rohit Ghurye
(R)
Kimberley Gilmour
(K)
Sarah Goddard
(S)
Pavel Gordins
(P)
Sofia Grigoriadou
(S)
Scott Hackett
(S)
Rosie Hague
(R)
Lorraine Harper
(L)
Grant Hayman
(G)
Archana Herwadkar
(A)
Stephen Hughes
(S)
Aarnoud Huissoon
(A)
Stephen Jolles
(S)
Julie Jones
(J)
Peter Kelleher
(P)
Nigel Klein
(N)
Taco Kuijpers
(T)
Dinakantha Kumararatne
(D)
James Laffan
(J)
Hana Lango Allen
(HL)
Sara Lear
(S)
Hilary Longhurst
(H)
Lorena Lorenzo
(L)
Jesmeen Maimaris
(J)
Ania Manson
(A)
Elizabeth McDermott
(E)
Hazel Millar
(H)
Anoop Mistry
(A)
Valerie Morrisson
(V)
Sai Murng
(S)
Iman Nasir
(I)
Sergey Nejentsev
(S)
Sadia Noorani
(S)
Eric Oksenhendler
(E)
Mark Ponsford
(M)
Waseem Qasim
(W)
Ellen Quinn
(E)
Isabella Quinti
(I)
Alex Richter
(A)
Crina Samarghitean
(C)
Ravishankar Sargur
(R)
Sinisa Savic
(S)
Suranjith Seneviratne
(S)
Carrock Sewall
(C)
Fiona Shackley
(F)
Ilenia Simeoni
(I)
Kenneth G C Smith
(KGC)
Emily Staples
(E)
Hans Stauss
(H)
Cathal Steele
(C)
James Thaventhiran
(J)
Moira Thomas
(M)
Adrian Thrasher
(A)
Steve Welch
(S)
Lisa Willcocks
(L)
Sarita Workman
(S)
Austen Worth
(A)
Nigel Yeatman
(N)
Patrick Yong
(P)
Sofie Ashford
(S)
John Bradley
(J)
Debra Fletcher
(D)
Tracey Hammerton
(T)
Roger James
(R)
Nathalie Kingston
(N)
Willem Ouwehand
(W)
Christopher Penkett
(C)
F Lucy Raymond
(FL)
Kathleen Stirrups
(K)
Marijke Veltman
(M)
Tim Young
(T)
Matthew Brown
(M)
Naomi Clements-Brod
(N)
John Davis
(J)
Eleanor Dewhurst
(E)
Marie Erwood
(M)
Amy Frary
(A)
Rachel Linger
(R)
Jennifer Martin
(J)
Sofia Papadia
(S)
Karola Rehnstrom
(K)
William Astle
(W)
Antony Attwood
(A)
Marta Bleda
(M)
Keren Carss
(K)
Louise Daugherty
(L)
Sri Deevi
(S)
Stefan Graf
(S)
Daniel Greene
(D)
Csaba Halmagyi
(C)
Matthias Haimel
(M)
Fengyuan Hu
(F)
Vera Matser
(V)
Stuart Meacham
(S)
Karyn Megy
(K)
Olga Shamardina
(O)
Catherine Titterton
(C)
Salih Tuna
(S)
Ernest Turro
(E)
Ping Yu
(P)
Julie von Ziegenweldt
(J)
Abigail Furnell
(A)
Rutendo Mapeta
(R)
Simon Staines
(S)
Jonathan Stephens
(J)
Deborah Whitehorn
(D)
Paula Rayner-Matthews
(P)
Christopher Watt
(C)
Informations de copyright
© 2023. Crown.
Références
Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol. 2010;10(4):225–35.
doi: 10.1038/nri2735
pubmed: 20336151
pmcid: 3496776
Walker JA, McKenzie ANJ. T(H)2 cell development and function. Nat Rev Immunol. 2018;18(2):121–33.
doi: 10.1038/nri.2017.118
pubmed: 29082915
Mikita T, et al. Requirements for interleukin-4-induced gene expression and functional characterization of Stat6. Mol Cell Biol. 1996;16(10):5811–20.
doi: 10.1128/MCB.16.10.5811
pubmed: 8816495
pmcid: 231582
Li J, et al. Structural basis for DNA recognition by STAT6. Proc Natl Acad Sci U S A. 2016;113(46):13015–20.
doi: 10.1073/pnas.1611228113
pubmed: 27803324
pmcid: 5135355
Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011;50(1):87–96.
doi: 10.1007/s12026-011-8205-2
pubmed: 21442426
pmcid: 3107597
Elo LL, et al. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity. 2010;32(6):852–62.
doi: 10.1016/j.immuni.2010.06.011
pubmed: 20620947
Ritz O, et al. Constitutively active STAT6 represses BCL6 in primary mediastinal B cell lymphoma. Blood. 2012;120(21):2417–2417.
doi: 10.1182/blood.V120.21.2417.2417
Stokes K, et al. Cutting edge: STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation. J Immunol. 2015;194(6):2477–81.
doi: 10.4049/jimmunol.1402096
pubmed: 25681342
Anderson CA, et al. A degradatory fate for CCR4 suggests a primary role in Th2 inflammation. J Leukoc Biol. 2020;107(3):455–66.
doi: 10.1002/JLB.2A0120-089RR
pubmed: 32052476
Kakinuma T, et al. Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol. 2002;127(2):270–3.
doi: 10.1046/j.1365-2249.2002.01727.x
pubmed: 11876749
pmcid: 1906347
Howell MD, et al. The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J Allergy Clin Immunol. 2011;128(5):1006–14.
doi: 10.1016/j.jaci.2011.06.003
pubmed: 21762972
pmcid: 3205328
Kaplan MH, et al. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4(3):313–9.
doi: 10.1016/S1074-7613(00)80439-2
pubmed: 8624821
Kaplan MH, et al. Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity. 1996;4(3):313–9.
doi: 10.1016/S1074-7613(00)80439-2
pubmed: 8624821
Morimoto Y, et al. Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development. J Leukoc Biol. 2005;78(3):753–61.
doi: 10.1189/jlb.0305139
pubmed: 16126843
Suratannon N, et al. A germline STAT6 gain-of-function variant is associated with early-onset allergies. J Allergy Clin Immunol. 2023;151(2):565-571.e9.
doi: 10.1016/j.jaci.2022.09.028
pubmed: 36216080
Takeuchi I, et al. STAT6 gain-of-function variant exacerbates multiple allergic symptoms. J Allergy Clin Immunol. 2022.
Baris S, et al. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. J Allergy Clin Immunol. 2023.
Sharma M, et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J Exp Med. 2023;220(5).
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.
doi: 10.1006/meth.2001.1262
pubmed: 11846609
Tangye SG, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;2022:1–35.
Rentzsch P, et al. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886-d894.
doi: 10.1093/nar/gky1016
pubmed: 30371827
Sim NL, et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(Web Server issue):W452-7.
doi: 10.1093/nar/gks539
pubmed: 22689647
pmcid: 3394338
Adzhubei IA, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.
doi: 10.1038/nmeth0410-248
pubmed: 20354512
pmcid: 2855889
Karczewski KJ, et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res. 2017;45(D1):D840-d845.
doi: 10.1093/nar/gkw971
pubmed: 27899611
Karczewski KJ, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43.
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Chen H, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147(2):436–46.
doi: 10.1016/j.cell.2011.09.022
pubmed: 22000020
Chen HC, Reich NC. Live cell imaging reveals continuous STAT6 nuclear trafficking. J Immunol. 2010;185(1):64–70.
doi: 10.4049/jimmunol.0903323
pubmed: 20498360
Schroder AJ, et al. Cutting edge: STAT6 serves as a positive and negative regulator of gene expression in IL-4-stimulated B lymphocytes. J Immunol. 2002;168(3):996–1000.
doi: 10.4049/jimmunol.168.3.996
pubmed: 11801631
Maier E, Duschl A, Horejs-Hoeck J. STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol. 2012;42(11):2827–33.
doi: 10.1002/eji.201242433
pubmed: 23041833
pmcid: 3557721
Mole DR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284(25):16767–75.
doi: 10.1074/jbc.M901790200
pubmed: 19386601
pmcid: 2719312
Ouyang W, et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity. 2000;12(1):27–37.
doi: 10.1016/S1074-7613(00)80156-9
pubmed: 10661403
Sharma M, et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. medRxiv. 2022; 2022.04.25.22274265.
Yildiz M, et al. Activating STAT6 mutations in follicular lymphoma. Blood. 2015;125(4):668–79.
doi: 10.1182/blood-2014-06-582650
pubmed: 25428220
pmcid: 4729538
Morin RD, et al. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas. Clin Cancer Res. 2016;22(9):2290–300.
doi: 10.1158/1078-0432.CCR-15-2123
pubmed: 26647218
Yuasa K, Hijikata T. Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression. Genes Cells. 2016;21(1):25–40.
doi: 10.1111/gtc.12316
pubmed: 26592235
Hebenstreit D, et al. Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev. 2006;17(3):173–88.
doi: 10.1016/j.cytogfr.2006.01.004
pubmed: 16540365
Cho W, et al. STAT6 and JAK1 are essential for IL-4-mediated suppression of prostaglandin production in human follicular dendritic cells: opposing roles of phosphorylated and unphosphorylated STAT6. Int Immunopharmacol. 2012;12(4):635–42.
doi: 10.1016/j.intimp.2012.02.012
pubmed: 22406175
Cui X, et al. Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer. Oncogene. 2007;26(29):4253–60.
doi: 10.1038/sj.onc.1210222
pubmed: 17237818