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

Autor: Ptacek J; Nodality, Inc., South San Francisco, California, United States of America., Hawtin RE; Nodality, Inc., South San Francisco, California, United States of America., Sun D; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America., Louie B; Nodality, Inc., South San Francisco, California, United States of America., Evensen E; Nodality, Inc., South San Francisco, California, United States of America., Mittleman BB; Nodality, Inc., South San Francisco, California, United States of America., Cesano A; Nodality, Inc., South San Francisco, California, United States of America., Cavet G; Nodality, Inc., South San Francisco, California, United States of America., Bingham CO 3rd; Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Cofield SS; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America., Curtis JR; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America., Danila MI; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America., Raman C; University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America., Furie RA; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Genovese MC; Stanford University School of Medicine, Stanford, California, United States of America., Robinson WH; Stanford University School of Medicine, Stanford, California, United States of America., Levesque MC; Abbvie, Inc., North Chicago, Illinois, United States of America., Moreland LW; University of Colorado Anschutz Medical Campus, Boulder, Colorado, United States of America., Nigrovic PA; Brigham and Women's Hospital, Harvard University, Boston, Massachusetts, United States of America., Shadick NA; Brigham and Women's Hospital, Harvard University, Boston, Massachusetts, United States of America., O'Dell JR; University of Nebraska Medical Center, Lincoln, Nebraska, United States of America., Thiele GM; University of Nebraska Medical Center, Lincoln, Nebraska, United States of America., Clair EWS; Duke University Medical Center, Durham, North Carolina, United States of America., Striebich CC; University of Colorado Anschutz Medical Campus, Boulder, Colorado, United States of America., Hale MB; Stanford University School of Medicine, Stanford, California, United States of America., Khalili H; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Batliwalla F; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Aranow C; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Mackay M; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Diamond B; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Nolan GP; Nodality, Inc., South San Francisco, California, United States of America., Gregersen PK; The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America., Bridges SL Jr; Hospital for Special Surgery and Weill Cornell Medical College, New York, New York, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Jan 14; Vol. 16 (1), pp. e0244187. Date of Electronic Publication: 2021 Jan 14 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0244187
Abstrakt: 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.
Competing Interests: The authors have read the journal’s policies and declare the following competing interest: Nodality, Inc., a now inactive company, provided in-kind support for this work and investigators at Nodality played important roles in the study design, hands-on analysis of samples, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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