T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.

Autor:	Ferguson ID; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Griffin P; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States., Michel JJ; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Yano H; Graduate Program in Microbiology and Immunology School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Gaffen SL; Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States., Mueller RG; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Dvergsten JA; Department of Pediatrics, Duke University Medical Center, Durham, NC, United States., Piganelli JD; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States., Rosenkranz ME; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Kietz DA; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Vallejo AN; Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2018 Aug 06; Vol. 9, pp. 1802. Date of Electronic Publication: 2018 Aug 06 (Print Publication: 2018).
DOI:	10.3389/fimmu.2018.01802
Abstrakt:	T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28 null CD31 + DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans -activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31 + CD28 null αβT cells and IL-17RA + CD38 + FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.
Databáze:	MEDLINE
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