1. Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity
- Author
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Chander Raman, Jason Ptacek, Christopher C. Striebich, James R. O'Dell, Alessandra Cesano, Garry P. Nolan, Nancy A. Shadick, E. William St. Clair, Franak Batliwalla, S. Louis Bridges, Guy Cavet, Marc C. Levesque, William H. Robinson, Mark C. Genovese, Geoffrey M. Thiele, Erik Evensen, Barbara B. Mittleman, Cynthia Aranow, Maria I. Danila, Betty Diamond, Houman Khalili, Stacey S. Cofield, Dongmei Sun, Clifton O. Bingham, Larry W. Moreland, Matthew Hale, Peter K. Gregersen, Jeffrey R. Curtis, Rachael E. Hawtin, Peter A. Nigrovic, Richard A. Furie, Meggan Mackay, and Brent Louie
- Subjects
Male ,Cell signaling ,B Cells ,Physiology ,medicine.medical_treatment ,Cancer Treatment ,Signal transduction ,Severity of Illness Index ,Monocytes ,Pathogenesis ,Arthritis, Rheumatoid ,White Blood Cells ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Medicine ,Phosphorylation ,Aged, 80 and over ,Innate Immune System ,Multidisciplinary ,T Cells ,Middle Aged ,Interleukin-10 ,STAT signaling ,Cytokine ,STAT1 Transcription Factor ,Oncology ,Rheumatoid arthritis ,Biomarker (medicine) ,Cytokines ,Tumor necrosis factor alpha ,Female ,medicine.symptom ,Cellular Types ,Research Article ,Adult ,STAT3 Transcription Factor ,Science ,Immune Cells ,Immunology ,Inflammation ,Rheumatoid Arthritis ,Cytokine Therapy ,Autoimmune Diseases ,Abatacept ,Immune system ,Rheumatology ,Humans ,Antibody-Producing Cells ,Aged ,Autoimmune disease ,Blood Cells ,business.industry ,Arthritis ,Biology and Life Sciences ,Interferon-alpha ,Cell Biology ,Molecular Development ,medicine.disease ,Methotrexate ,Immune System ,Case-Control Studies ,Leukocytes, Mononuclear ,Clinical Immunology ,Clinical Medicine ,business ,Biomarkers ,Developmental Biology - 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→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.
- Published
- 2021