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Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously qua...

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Autores principales: Ptacek, Jason, Hawtin, Rachael E., Sun, Dongmei, Louie, Brent, Evensen, Erik, Mittleman, Barbara B., Cesano, Alessandra, Cavet, Guy, Bingham, Clifton O., Cofield, Stacey S., Curtis, Jeffrey R., Danila, Maria I., Raman, Chander, Furie, Richard A., Genovese, Mark C., Robinson, William H., Levesque, Marc C., Moreland, Larry W., Nigrovic, Peter A., Shadick, Nancy A., O’Dell, James R., Thiele, Geoffrey M., Clair, E. William St, Striebich, Christopher C., Hale, Matthew B., Khalili, Houman, Batliwalla, Franak, Aranow, Cynthia, Mackay, Meggan, Diamond, Betty, Nolan, Garry P., Gregersen, Peter K., Bridges, S. Louis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808603/
https://www.ncbi.nlm.nih.gov/pubmed/33444321
http://dx.doi.org/10.1371/journal.pone.0244187
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author Ptacek, Jason
Hawtin, Rachael E.
Sun, Dongmei
Louie, Brent
Evensen, Erik
Mittleman, Barbara B.
Cesano, Alessandra
Cavet, Guy
Bingham, Clifton O.
Cofield, Stacey S.
Curtis, Jeffrey R.
Danila, Maria I.
Raman, Chander
Furie, Richard A.
Genovese, Mark C.
Robinson, William H.
Levesque, Marc C.
Moreland, Larry W.
Nigrovic, Peter A.
Shadick, Nancy A.
O’Dell, James R.
Thiele, Geoffrey M.
Clair, E. William St
Striebich, Christopher C.
Hale, Matthew B.
Khalili, Houman
Batliwalla, Franak
Aranow, Cynthia
Mackay, Meggan
Diamond, Betty
Nolan, Garry P.
Gregersen, Peter K.
Bridges, S. Louis
author_facet Ptacek, Jason
Hawtin, Rachael E.
Sun, Dongmei
Louie, Brent
Evensen, Erik
Mittleman, Barbara B.
Cesano, Alessandra
Cavet, Guy
Bingham, Clifton O.
Cofield, Stacey S.
Curtis, Jeffrey R.
Danila, Maria I.
Raman, Chander
Furie, Richard A.
Genovese, Mark C.
Robinson, William H.
Levesque, Marc C.
Moreland, Larry W.
Nigrovic, Peter A.
Shadick, Nancy A.
O’Dell, James R.
Thiele, Geoffrey M.
Clair, E. William St
Striebich, Christopher C.
Hale, Matthew B.
Khalili, Houman
Batliwalla, Franak
Aranow, Cynthia
Mackay, Meggan
Diamond, Betty
Nolan, Garry P.
Gregersen, Peter K.
Bridges, S. Louis
author_sort Ptacek, Jason
collection PubMed
description Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.
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spelling pubmed-78086032021-02-02 Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity Ptacek, Jason Hawtin, Rachael E. Sun, Dongmei Louie, Brent Evensen, Erik Mittleman, Barbara B. Cesano, Alessandra Cavet, Guy Bingham, Clifton O. Cofield, Stacey S. Curtis, Jeffrey R. Danila, Maria I. Raman, Chander Furie, Richard A. Genovese, Mark C. Robinson, William H. Levesque, Marc C. Moreland, Larry W. Nigrovic, Peter A. Shadick, Nancy A. O’Dell, James R. Thiele, Geoffrey M. Clair, E. William St Striebich, Christopher C. Hale, Matthew B. Khalili, Houman Batliwalla, Franak Aranow, Cynthia Mackay, Meggan Diamond, Betty Nolan, Garry P. Gregersen, Peter K. Bridges, S. Louis PLoS One Research Article Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response. Public Library of Science 2021-01-14 /pmc/articles/PMC7808603/ /pubmed/33444321 http://dx.doi.org/10.1371/journal.pone.0244187 Text en © 2021 Ptacek et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ptacek, Jason
Hawtin, Rachael E.
Sun, Dongmei
Louie, Brent
Evensen, Erik
Mittleman, Barbara B.
Cesano, Alessandra
Cavet, Guy
Bingham, Clifton O.
Cofield, Stacey S.
Curtis, Jeffrey R.
Danila, Maria I.
Raman, Chander
Furie, Richard A.
Genovese, Mark C.
Robinson, William H.
Levesque, Marc C.
Moreland, Larry W.
Nigrovic, Peter A.
Shadick, Nancy A.
O’Dell, James R.
Thiele, Geoffrey M.
Clair, E. William St
Striebich, Christopher C.
Hale, Matthew B.
Khalili, Houman
Batliwalla, Franak
Aranow, Cynthia
Mackay, Meggan
Diamond, Betty
Nolan, Garry P.
Gregersen, Peter K.
Bridges, S. Louis
Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title_full Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title_fullStr Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title_full_unstemmed Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title_short Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
title_sort diminished cytokine-induced jak/stat signaling is associated with rheumatoid arthritis and disease activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808603/
https://www.ncbi.nlm.nih.gov/pubmed/33444321
http://dx.doi.org/10.1371/journal.pone.0244187
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