@article{ef87273937f04795bc572d4535f1e6de,
title = "Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity",
abstract = "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!pSTAT5 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.",
author = "Jason Ptacek and Hawtin, {Rachael E.} and Dongmei Sun and Brent Louie and Erik Evensen and Mittleman, {Barbara B.} and Alessandra Cesano and Guy Cavet and Bingham, {Clifton O.} and Cofield, {Stacey S.} and Curtis, {Jeffrey R.} and Danila, {Maria I.} and Chander Raman and Furie, {Richard A.} and Genovese, {Mark C.} and Robinson, {William H.} and Levesque, {Marc C.} and Moreland, {Larry W.} and Nigrovic, {Peter A.} and Shadick, {Nancy A.} and O{\textquoteright}Dell, {James R.} and Thiele, {Geoffrey M.} and {St Clair}, {E. William} and Striebich, {Christopher C.} and Hale, {Matthew B.} and Houman Khalili and Franak Batliwalla and Cynthia Aranow and Meggan Mackay and Betty Diamond and Nolan, {Garry P.} and Gregersen, {Peter K.} and Bridges, {S. Louis}",
note = "Funding Information: This work was supported by grants NIH RC2 AR058964 (SLB), Department of Defense - Congressionally Directed Medical Research Program Grant PR151462 (SLB and CR) and the Fundaci{\'o}n Bechara (PAN). Nodality, Inc., a now inactive company, provided in-kind support for this work, but no financial contributions, and Investigators at Nodality played important roles in the study design, hands-on analysis of samples, and preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the {\textquoteleft}author contributions{\textquoteright} section. The authors thank all of the patients with RA and HC who provided samples for this study. This manuscript is dedicated to the memory of Betty Hawtin. We appreciate the careful review and comments of Frances Lund, PhD, of the UAB Department of Microbiology. Publisher Copyright: {\textcopyright} 2021 Ptacek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2021",
month = jan,
doi = "10.1371/journal.pone.0244187",
language = "English (US)",
volume = "16",
journal = "PloS one",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",
}