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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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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. |
format | Online Article Text |
id | pubmed-7808603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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