Open AccessDiminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
Author(s) -
Jason Ptacek,
Rachael E. Hawtin,
Dongmei Sun,
Brent Louie,
Erik Evensen,
Barbara Mittleman,
Alessandra Cesano,
G. Cavet,
Clifton O. Bingham,
Stacey S. Cofield,
Jeffrey R. Curtis,
Maria I. Danila,
Chander Raman,
Richard Furie,
Mark C. Genovese,
William H. Robinson,
Marc C. Levesque,
Larry W. Moreland,
Peter Nigrovic,
Nancy A. Shadick,
James Robert 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
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0244187
Subject(s) - immunology , stat5 , cytokine , medicine , immune system , rheumatoid arthritis , signal transduction , jak stat signaling pathway , peripheral blood mononuclear cell , janus kinase , t cell , inflammation , cancer research , biology , receptor , microbiology and biotechnology , tyrosine kinase , biochemistry , in vitro
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.