Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function

[Purpose] Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates infl...

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Autores: Blanco Lobo, Pilar, Gilabert-Prieto, Paula, Felipe, Beatriz de, Moreno-Fuentes, David, Guisado Hernández, Paloma, Ortiz-Ramírez, Ana, Mensa-Vilaró, Anna, Arostegui, Juan Ignacio, Palmou, Natalia, Velasco González, Valle, Deyá-Martinez, Ángela, Ramakers, Jan, Ivorra-Cortés, José, Roca, Cristina, Cordero, Elisa, Guillen, Inmaculada, Valerdiz Menéndez, Nicolás, Lucena, Jose M., Gaboli, Mirella, Olbrich, Peter, Neth, Olaf
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412034
Acceso en línea:http://hdl.handle.net/10261/412034
https://api.elsevier.com/content/abstract/scopus_id/105022899621
Access Level:acceso abierto
Palabra clave:Down syndrome
Inborn errors of immunity
Interferon
JAK inhibitors
Ruxolitinib
STAT1 gain-of-function
STAT1 transcription factor
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spelling Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of FunctionBlanco Lobo, PilarGilabert-Prieto, PaulaFelipe, Beatriz deMoreno-Fuentes, DavidGuisado Hernández, PalomaOrtiz-Ramírez, AnaMensa-Vilaró, AnnaArostegui, Juan IgnacioPalmou, NataliaVelasco González, ValleDeyá-Martinez, ÁngelaRamakers, JanIvorra-Cortés, JoséRoca, CristinaCordero, ElisaGuillen, InmaculadaValerdiz Menéndez, NicolásLucena, Jose M.Gaboli, MirellaOlbrich, PeterNeth, OlafDown syndromeInborn errors of immunityInterferonJAK inhibitorsRuxolitinibSTAT1 gain-of-functionSTAT1 transcription factor[Purpose] Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1’s key biomarkers (STAT1 levels, IFN signature, TNFα, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique “experiment of nature”, offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.This work was supported by Instituto de Salud Carlos III, Madrid (Spain) [Sara Borrell, CD20/00124 to P.B.L, Juan Rodés JR18/00042 to P.O, FIS PI19/01471 to O.N, FIS PI22/01254 to ON and PO], contract for the Intensification of Research Activity AISNS (INT23/00089) to ON, contract from University of Seville (Programa Propio de I + D + I de la Universidad de Sevilla), and Jerome Lejeune Foundation (2023) to ON. PI19/01567 grant from Instituto de Salud Carlos III (ISCIII) co-funded by the European Union (AM-V).Peer reviewedSpringer NatureInstituto de Salud Carlos IIIUniversidad de SevillaJérôme Lejeune FoundationEuropean CommissionBlanco Lobo, Pilar [0000-0003-1893-8198]Felipe, Beatriz de [0000-0001-9226-0552]Gaboli, Mirella [0000-0002-1600-0916]Olbrich, Peter [0000-0001-9853-7903]Neth, Olaf [0000-0001-5018-0466]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412034https://api.elsevier.com/content/abstract/scopus_id/105022899621reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1007/s10875-025-01957-0https://doi.org/10.1007/s10875-025-01957-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4120342026-05-22T06:33:51Z
dc.title.none.fl_str_mv Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
title Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
spellingShingle Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
Blanco Lobo, Pilar
Down syndrome
Inborn errors of immunity
Interferon
JAK inhibitors
Ruxolitinib
STAT1 gain-of-function
STAT1 transcription factor
title_short Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
title_full Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
title_fullStr Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
title_full_unstemmed Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
title_sort Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
dc.creator.none.fl_str_mv Blanco Lobo, Pilar
Gilabert-Prieto, Paula
Felipe, Beatriz de
Moreno-Fuentes, David
Guisado Hernández, Paloma
Ortiz-Ramírez, Ana
Mensa-Vilaró, Anna
Arostegui, Juan Ignacio
Palmou, Natalia
Velasco González, Valle
Deyá-Martinez, Ángela
Ramakers, Jan
Ivorra-Cortés, José
Roca, Cristina
Cordero, Elisa
Guillen, Inmaculada
Valerdiz Menéndez, Nicolás
Lucena, Jose M.
Gaboli, Mirella
Olbrich, Peter
Neth, Olaf
author Blanco Lobo, Pilar
author_facet Blanco Lobo, Pilar
Gilabert-Prieto, Paula
Felipe, Beatriz de
Moreno-Fuentes, David
Guisado Hernández, Paloma
Ortiz-Ramírez, Ana
Mensa-Vilaró, Anna
Arostegui, Juan Ignacio
Palmou, Natalia
Velasco González, Valle
Deyá-Martinez, Ángela
Ramakers, Jan
Ivorra-Cortés, José
Roca, Cristina
Cordero, Elisa
Guillen, Inmaculada
Valerdiz Menéndez, Nicolás
Lucena, Jose M.
Gaboli, Mirella
Olbrich, Peter
Neth, Olaf
author_role author
author2 Gilabert-Prieto, Paula
Felipe, Beatriz de
Moreno-Fuentes, David
Guisado Hernández, Paloma
Ortiz-Ramírez, Ana
Mensa-Vilaró, Anna
Arostegui, Juan Ignacio
Palmou, Natalia
Velasco González, Valle
Deyá-Martinez, Ángela
Ramakers, Jan
Ivorra-Cortés, José
Roca, Cristina
Cordero, Elisa
Guillen, Inmaculada
Valerdiz Menéndez, Nicolás
Lucena, Jose M.
Gaboli, Mirella
Olbrich, Peter
Neth, Olaf
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Universidad de Sevilla
Jérôme Lejeune Foundation
European Commission
Blanco Lobo, Pilar [0000-0003-1893-8198]
Felipe, Beatriz de [0000-0001-9226-0552]
Gaboli, Mirella [0000-0002-1600-0916]
Olbrich, Peter [0000-0001-9853-7903]
Neth, Olaf [0000-0001-5018-0466]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Down syndrome
Inborn errors of immunity
Interferon
JAK inhibitors
Ruxolitinib
STAT1 gain-of-function
STAT1 transcription factor
topic Down syndrome
Inborn errors of immunity
Interferon
JAK inhibitors
Ruxolitinib
STAT1 gain-of-function
STAT1 transcription factor
description [Purpose] Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1’s key biomarkers (STAT1 levels, IFN signature, TNFα, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique “experiment of nature”, offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/412034
https://api.elsevier.com/content/abstract/scopus_id/105022899621
url http://hdl.handle.net/10261/412034
https://api.elsevier.com/content/abstract/scopus_id/105022899621
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1007/s10875-025-01957-0
https://doi.org/10.1007/s10875-025-01957-0
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,808905

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