Ezeonyeji, Amara N; (2018) Expression and regulation of Th-17, Th-1 and Th-22 cells in psoriatic arthritis. Doctoral thesis (M.D(Res)), UCL (University College London).

Abstract

Dysregulation of Th-1 and Th-17 cytokines, is associated with the development of autoimmune diseases. In this study, CD4+ T cells from psoriatic arthritis (PsA) patients were characterized with view to understanding the role IL-22, IFN-γ and IL-17 producing cells in disease pathogenesis. CD4+T cell differentiation patterns were defined in PsA patients and healthy controls and the specific CD4+T cell subset contribution to cytokine dysregulation examined. Finally, the role of aryl hydrocarbon receptor (AhR) ligands in regulating aberrant cytokine production was evaluated. CCR6 expressing CD4+ T cells were globally depleted from PsA patients with loss of CCR6 expressing IL-22+ and IL-17+ CD4+ cells from the peripheral blood. IL-22 production was reduced in PsA CD4+ T cells and the CD4+ T cell IFN-γ:IL-22 ratio altered. IL-22 expressing cells were depleted primarily from the central memory CD4+ T cell subset in PsA patients. CD4+ T cell differentiation was dysregulated in PsA and increased frequency of circulating ‘naïve’ CD4+ T cells in untreated and Adalimumab treated patients was observed which correlated with disease activity. IL-22 and IFN-γ production was increased in activated naïve CD4+ T cells from PsA patients. These unconventional naïve CD4+ T expressed more CXCR3, reduced CD62L and proliferated rapidly upon stimulation compared to healthy controls. The unconventional naïve CD4+ T cells also promoted greater expression of the chemoattractant CXCL-9 from HaCaT keratinocytes. This effect was partially reversed in patients treated with Adalimumab. Blockade of IL-22 resulted in increased IFN-γ mediated CXCL-9 production indicating a potential regulatory role for IL-22 in PsA. Culture of whole PBMCs with the AhR ligands TCDD and FICZ boosted IL-22 and IL-10 production but suppressed IL-17 and IFN-γ production in PsA CD4+ T cells. CD4+ T cells from PsA patients with high disease activity were however resistant to AhR ligand mediated IL-17 suppression indicating this pathway may be dysregulated in PsA.

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