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

• Published in: PloS one Vol. 16; no. 1; p. e0244187
• Main Authors: Ptacek, Jason, Hawtin, Rachael E, Sun, Dongmei, Louie, Brent, Evensen, Erik, Mittleman, Barbara B, Cesano, Alessandra, Cavet, Guy, Bingham, 3rd, 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, Jr, S Louis
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.01.2021; Public Library of Science (PLoS)
• Subjects: Abatacept - therapeutic use; Adult; Aged; Aged, 80 and over; Analysis; Arthritis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biology and Life Sciences; Biomarkers - metabolism; Cartilage; Case-Control Studies; Cellular signal transduction; College campuses; Cytokines; Data analysis; Development and progression; Diamonds; Dihydrofolate reductase; Drugs; Editing; Female; Fibroblasts; Health aspects; Health care facilities; Hospitals; Humans; Immune system; Inflammation; Interferon-alpha - pharmacology; Interleukin-10 - pharmacology; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Lymphocytes; Macrophages; Male; Medical research; Medicine; Medicine and Health Sciences; Methodology; Methotrexate - therapeutic use; Middle Aged; Natural killer cells; Peripheral blood; Phosphorylation; Physiological aspects; Rheumatoid arthritis; Risk factors; Severity of Illness Index; Signal transduction; Signal Transduction - drug effects; Signaling; STAT proteins; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - metabolism; Surgery; Synovium; TNF inhibitors; Tumor necrosis factor; United States; New York; United States > US; Colorado; Massachusetts; South San Francisco California; California; Alabama; Nebraska
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0244187

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.