Date: Sunday, October 21, 2018
Session Title: 3S106 ACR Abstract: Pediatric Rheumatology–Basic Science (922–927)
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever and rash at disease onset, which are mediated in part by IL-1β and IL-6. In 40-50% of patients, the disease resolves while in others a chronic inflammatory arthritis develops. The mechanisms that drive the establishment of chronic arthritis are unknown. IL-1β and IL-6 promote Th17 differentiation and impair regulatory T (Treg) cell function. We aimed to characterize Treg cells in sJIA to determine if these inflammatory cytokines polarize Treg cells to a Th17 fate, potentially contributing to the development of arthritis in this disease.
Methods: Peripheral blood (PB) and/or synovial fluid (SF) samples were collected from acute sJIA (disease duration < 4 months), chronic sJIA (disease duration > 4 months with persistent arthritis), and control subjects. For flow cytometry, PBMCs were stimulated, stained for cell surface markers, fixed, and permeabilized for intracellular staining. For mass cytometry, PBMC/SFMCs were stained for cell surface markers, barcoded, fixed, permeabilized, and then samples were randomized to 1 of 2 mass cytometry runs. RNA was extracted from sorted PB and SF Treg (CD4+CD25+CD127lo) and effector T (CD4+CD25–) cells. The Smart-Seq2 platform was used for RNA sequencing. Data analysis was done with GraphPad Prism, FlowJo, Cytobank, and Gene Set Enrichment Analysis.
Results: 10 acute sJIA, 15 chronic sJIA, 5 pediatric control, and 5 adult control subjects were studied. viSNE plots of mass cytometry of SF samples from sJIA patients showed a distinct population of activated Treg cells in the arthritic joints that expressed high levels of CD45RO, HLADR, PD1, Ki67, ICOS, and CD39. A similar population of Treg was also identified in PB of acute and chronic sJIA patients but not adult or pediatric controls. By flow cytometry, acute sJIA patients had a significantly higher frequency of Helioshi Treg cells (78.8 ± SD 8.4%) than chronic sJIA patients (62.3 ± 12.3%) and pediatric controls (57.5 ± 10.6%) (p=0.004). In addition, the percentage of Treg cells from acute sJIA patients expressing IL-17 (5.8 ± SD 3.2%) was significantly higher than chronic sJIA patients (1.2 ± 1.1%), pediatric controls (0.45 ± 0.3%), and adult controls (1.4 ± 1.0%) (p<0.0001). There was a trend towards increased IL-17+ and CCR6+ CD4+ memory T cells in chronic sJIA patients vs adult controls. Compared to pediatric controls, acute sJIA PB Treg cells upregulated Th17 pathway and downregulated Treg signature genes. Similarly, sJIA SF Treg cells overexpressed IL6/JAK/STAT3 and Th17 pathway genes.
Conclusion: Our data demonstrate an evolving Th17 immune response in sJIA. Treg cells in acute and chronic sJIA express high levels of activation markers, which are not seen in controls. In acute sJIA, Treg cells are subverted to a Th17 phenotype and the generation of peripherally induced Treg cells (Helioslo Tregs) is impaired. In patients with chronic arthritis, there is a trend towards increased Th17 cells in the PB and sJIA SF Treg cells up regulate Th17 related genes. These data suggest that IL-1β and IL-6 may be reprogramming Treg cells into Th17 cells in sJIA.
To cite this abstract in AMA style:Henderson LA, Hoyt K, Nguyen JP, Lee P, Rao D, Jonsson AH, Janssen E, Dedeoglu F, Hazen MM, Lo MS, Meidan E, Son MB, Sundel R, Stoll ML, Nusbaum C, Lederer JA, Chatila TA, Nigrovic PA. The Reprogramming of Regulatory T Cells to a Th17 Phenotype in Systemic Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/the-reprogramming-of-regulatory-t-cells-to-a-th17-phenotype-in-systemic-juvenile-idiopathic-arthritis/. Accessed March 21, 2023.
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