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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Public Library of Science (PLoS)
2021-01-01
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| author | Jason Ptacek Rachael E Hawtin Dongmei Sun Brent Louie Erik Evensen Barbara B Mittleman Alessandra Cesano Guy Cavet Clifton O Bingham Stacey S Cofield Jeffrey R Curtis Maria I Danila Chander Raman Richard A Furie Mark C Genovese William H Robinson Marc C Levesque Larry W Moreland Peter A Nigrovic Nancy A Shadick James R O'Dell Geoffrey M Thiele E William St Clair Christopher C Striebich Matthew B Hale Houman Khalili Franak Batliwalla Cynthia Aranow Meggan Mackay Betty Diamond Garry P Nolan Peter K Gregersen S Louis Bridges |
| author_facet | Jason Ptacek Rachael E Hawtin Dongmei Sun Brent Louie Erik Evensen Barbara B Mittleman Alessandra Cesano Guy Cavet Clifton O Bingham Stacey S Cofield Jeffrey R Curtis Maria I Danila Chander Raman Richard A Furie Mark C Genovese William H Robinson Marc C Levesque Larry W Moreland Peter A Nigrovic Nancy A Shadick James R O'Dell Geoffrey M Thiele E William St Clair Christopher C Striebich Matthew B Hale Houman Khalili Franak Batliwalla Cynthia Aranow Meggan Mackay Betty Diamond Garry P Nolan Peter K Gregersen S Louis Bridges |
| author_sort | Jason Ptacek |
| collection | DOAJ |
| 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 | Article |
| id | doaj-art-9b1ea73e854343108c3cc3ca29f2e25a |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-9b1ea73e854343108c3cc3ca29f2e25a2025-08-20T02:55:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01161e024418710.1371/journal.pone.0244187Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity.Jason PtacekRachael E HawtinDongmei SunBrent LouieErik EvensenBarbara B MittlemanAlessandra CesanoGuy CavetClifton O BinghamStacey S CofieldJeffrey R CurtisMaria I DanilaChander RamanRichard A FurieMark C GenoveseWilliam H RobinsonMarc C LevesqueLarry W MorelandPeter A NigrovicNancy A ShadickJames R O'DellGeoffrey M ThieleE William St ClairChristopher C StriebichMatthew B HaleHouman KhaliliFranak BatliwallaCynthia AranowMeggan MackayBetty DiamondGarry P NolanPeter K GregersenS Louis BridgesRheumatoid 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0244187&type=printable |
| spellingShingle | Jason Ptacek Rachael E Hawtin Dongmei Sun Brent Louie Erik Evensen Barbara B Mittleman Alessandra Cesano Guy Cavet Clifton O Bingham Stacey S Cofield Jeffrey R Curtis Maria I Danila Chander Raman Richard A Furie Mark C Genovese William H Robinson Marc C Levesque Larry W Moreland Peter A Nigrovic Nancy A Shadick James R O'Dell Geoffrey M Thiele E William St Clair Christopher C Striebich Matthew B Hale Houman Khalili Franak Batliwalla Cynthia Aranow Meggan Mackay Betty Diamond Garry P Nolan Peter K Gregersen S Louis Bridges Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity. PLoS ONE |
| 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0244187&type=printable |
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