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JCI Insight. 2018 Aug 9;3(15). pii: 121544. doi: 10.1172/jci.insight.121544. [Epub ahead of print]

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry.

Author information

1
Division of Pediatric Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.
3
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
4
Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
5
Department of Pathology and Immunology and.
6
The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
8
Division of Hematology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with IL-6 or IFN-γ and analyzed by mass cytometry. Following IFN-γ stimulation, increased STAT1 and/or STAT3 phosphorylation was observed in subsets of CD4 T cells and classical monocytes from treatment-naive patients. The enhanced IFN-γ signaling was associated with increased expression of JAK1 and SOCS1 in CD4 T cells. Furthermore, substantial heterogeneity in surface marker expression was observed among the subsets of CD4 T cells and classical monocytes with increased IFN-γ responsiveness. The identification of enhanced IFN-γ signaling in CD4 T cells and classical monocytes from treatment-naive polyarticular JIA patients provides mechanistic support for investigations into therapies that attenuate IFN-γ signaling in this disease.

KEYWORDS:

Autoimmune diseases; Immunology; Inflammation; Macrophages; T cells

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