The characterisation and regulation of T cell immune responses in psoriatic arthritis

Wilson, Hilary E. (2003) The characterisation and regulation of T cell immune responses in psoriatic arthritis. MD thesis, University of Glasgow.

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis. It affects approximately 0.05% of the general population presenting as peripheral arthritis, axial disease or a combination of both. About 10% of patients with psoriasis suffer from PsA. Currently available therapies have limited efficacy with associated toxicity. PsA is therefore a common arthropathy for which novel therapies are urgently required. Our understanding of the role of the immune system in the pathogenesis of rheumatic disease has led to the development of specific targeted therapies. The identification of tumour necrosis factor alpha (TNFα) as a key player in the inflammatory response has been a major advance in the field of rheumatology. The effects of blocking this pro inflammatory molecule have resulted in dramatic clinical effects across the spectrum of rheumatic diseases. Unfortunately however there remain a proportion of non-responders and concerns have been raised surrounding the adverse effects of these therapies (Furst, Keystone et al. 2001). It is therefore important to continue to elucidate other key players in the inflammatory cascade that can be modified to achieve clinical response. A critical advance in understanding the immune system's role in driving inflammation has been the recognition of different functional subsets of T helper (Th) cells according to their cytokine profile. Techniques have evolved that enable us to achieve clarification of a true in vivo Th1 response by identifying cells in SF that spontaneously secrete IFNγ. In this thesis, spontaneously secreting cells were identified in SF of patients with active PsA. That such IFNγ expressing cells may have a pathogenic role in PsA is supported by the following observations: IFNγ is the prototype macrophage activator of TNFα that drives inflammation in psoriasis and PsA. IFNγ when tested as a potential treatment for psoriasis induced synovitis in a subset of patients. (O'Connell, Gerber et al. 1992). The injection of IFNγ into the skin induces hyperkeratosis (Fierlbeck, Rassner et al. 1990). Autologous Natural Killer T (NKT) cells, potent producers of IL-4 and IFNγ, are able to induce psoriasis in 'normal skin' grafted onto a SCID mouse (Nickoloff, Wrone- Smithetal. 1999). Those factors regulating the expression of IFNγ may therefore be of considerable interest as they may offer potential targets to modify Th1 responses in PsA. Cytokines such as interleukin 18 (IL-18) and interleukin 12 (IL-12) have been shown to regulate Th1 responses in animal models of arthritis (Leung, McInnes et al. 2000). Whether such cytokines are present and indeed induce inflammation in PsA is unknown. The first part of this thesis focuses on the characterisation of the predominant Th response in PsA and the identification of key regulatory cytokines such as IL-12 and IL-18 that may drive TNFα production and as such lead to inflammation. The presence of other regulatory cells capable of driving the inflammatory response was explored briefly. NKT cells are a subset of T cell, which secrete IFNγ and IL-4 depending on the predominant cytokine milieu (Hafner, Falk et al. 1999). A pathogenic role for NKT cells in psoriasis has been suggested. (Bonish, Jullien et al. 2000). The ability of synovial fluid mononuclear cells (SF MC) to proliferate and secrete TNFα in response to glycolipid presented to NK T cells was investigated. Although TNFα contributes directly to synovial inflammation, the blockade of TNFα does not protect completely against cartilage damage (Joosten, Helsen et al. 1999). IFNγ and IL- 17 have opposing effects on bone resorption. IFNγ inhibits bone resorption whereas IL-17 enhances resorption through the degradation or enhancement of TNF receptor associated factor 6 (TRAF6) respectively (Chabaud, Lubberts et al. 2001). The expression of IL-17 and the functional effects of this cytokine on MMP3 expression by fibroblasts were therefore studied as a final section in this thesis.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: McInnes, Prof. I.B.
• Date of Award: 2003
• Depositing User: Mrs Marie Cairney
• Unique ID: glathesis:2003-41077
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Mar 2019 17:04
• Last Modified: 07 Mar 2019 17:04
• URI: https://theses.gla.ac.uk/id/eprint/41077