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Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scor...

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Autores principales: Galbraith, Matthew D., Rachubinski, Angela L., Smith, Keith P., Araya, Paula, Waugh, Katherine A., Enriquez-Estrada, Belinda, Worek, Kayleigh, Granrath, Ross E., Kinning, Kohl T., Paul Eduthan, Neetha, Ludwig, Michael P., Hsieh, Elena W. Y., Sullivan, Kelly D., Espinosa, Joaquin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10306300/
https://www.ncbi.nlm.nih.gov/pubmed/37379383
http://dx.doi.org/10.1126/sciadv.adg6218
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author Galbraith, Matthew D.
Rachubinski, Angela L.
Smith, Keith P.
Araya, Paula
Waugh, Katherine A.
Enriquez-Estrada, Belinda
Worek, Kayleigh
Granrath, Ross E.
Kinning, Kohl T.
Paul Eduthan, Neetha
Ludwig, Michael P.
Hsieh, Elena W. Y.
Sullivan, Kelly D.
Espinosa, Joaquin M.
author_facet Galbraith, Matthew D.
Rachubinski, Angela L.
Smith, Keith P.
Araya, Paula
Waugh, Katherine A.
Enriquez-Estrada, Belinda
Worek, Kayleigh
Granrath, Ross E.
Kinning, Kohl T.
Paul Eduthan, Neetha
Ludwig, Michael P.
Hsieh, Elena W. Y.
Sullivan, Kelly D.
Espinosa, Joaquin M.
author_sort Galbraith, Matthew D.
collection PubMed
description Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.
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spelling pubmed-103063002023-06-29 Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition Galbraith, Matthew D. Rachubinski, Angela L. Smith, Keith P. Araya, Paula Waugh, Katherine A. Enriquez-Estrada, Belinda Worek, Kayleigh Granrath, Ross E. Kinning, Kohl T. Paul Eduthan, Neetha Ludwig, Michael P. Hsieh, Elena W. Y. Sullivan, Kelly D. Espinosa, Joaquin M. Sci Adv Biomedicine and Life Sciences Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS. American Association for the Advancement of Science 2023-06-28 /pmc/articles/PMC10306300/ /pubmed/37379383 http://dx.doi.org/10.1126/sciadv.adg6218 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Galbraith, Matthew D.
Rachubinski, Angela L.
Smith, Keith P.
Araya, Paula
Waugh, Katherine A.
Enriquez-Estrada, Belinda
Worek, Kayleigh
Granrath, Ross E.
Kinning, Kohl T.
Paul Eduthan, Neetha
Ludwig, Michael P.
Hsieh, Elena W. Y.
Sullivan, Kelly D.
Espinosa, Joaquin M.
Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title_full Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title_fullStr Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title_full_unstemmed Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title_short Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
title_sort multidimensional definition of the interferonopathy of down syndrome and its response to jak inhibition
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10306300/
https://www.ncbi.nlm.nih.gov/pubmed/37379383
http://dx.doi.org/10.1126/sciadv.adg6218
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