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Title: Immune regulation in health and Juvenile Idiopathic Arthritis (JIA) : molecular mechanisms and regulatory T cells
Author: Pesenacker, A. M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Immune regulation is essential to fighting pathogens and tolerance to self and non-harmful (food and commensal) antigens. The immune system has several mechanisms in place to keep the immune system in balance. In this study some of these mechanisms are more closely investigated in health and disease. In autoimmune Juvenile Idiopathic Arthritis (JIA) immune regulation fails at the site of disease, with large pro-inflammatory cell infiltrates and inflammation. In the first part of this thesis potential mechanisms in regulating the severity of JIA are examined through analysis of previously acquired gene expression array data from oligoarticular JIA synovial fluid cells at the time of diagnosis, stratified by disease severity outcome after one year. Expression of three genes (SMAD3, ERRFI1 and VIPR1) was tested using RT-PCR. Particular focus was put on vasoactive intestinal peptide receptor type one (VIPR1), as it was expressed at lower levels and with an apparent variant at the inflamed site of JIA. Regulatory T cells (Treg) are one essential part of immune regulation. Recent studies have suggested some pro-inflammatory potential by Treg producing cytokines including IL-17 and IFN-γ. In this thesis Treg cytokine production was linked to CD161 expression. CD161+ Treg were characterized in health, throughout development and in JIA. CD161+ Treg showed a memory effector T cell like phenotype, including expression of transcription factors (Tbet, RORCv2). However CD161+ Treg were also potent suppressors in vitro and showed a predominantly demethylated Treg specific demethylated region (TSDR). CD161+ Treg appeared pathogen specific and behaved differently to TCR stimulation as CD161- Treg. Furthermore CD161+ Treg were highly enriched in the synovial fluid of JIA and correlated with disease. This thesis suggests that immune regulation is influenced by the inflammatory environment and has more facets to it, with cytokine-producing Treg playing an important part in health and disease.
Supervisor: Wedderburn, L. R. ; Crompton, T. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available