The immunopathogenesis of ankylosing spondylitis

Wright, Pamela Burnby (2013) The immunopathogenesis of ankylosing spondylitis. PhD thesis, University of Glasgow.

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Abstract

The Spondyloarthritides (SpA) are a group of genetically and pathophysiologically related diseases. Ankylosing spondylitis (AS), the prototypic SpA family member, is a systemic inflammatory disease primarily affecting the axial skeleton, characterised by sacroiliitis and bone formation, promoting joint inhibition. AS is highly heritable; approximately 90% of AS susceptibility is defined by an individuals’ genetic background, to which the MHC class I molecule HLA-B27 contributes approximately 30%. This association was discovered 40 years ago, yet the pathogenic role of HLA-B27 remains elusive.

Dendritic cells (DCs) belong to the myeloid lineage and, the principal antigen presenting cells (APCs) of the immune system, activate naïve T cells and contribute to the balance between activation and suppression of the immune response. If affected by HLA-B27, DCs are therefore likely to contribute to the T cell-mediated aspects of AS pathogenesis. Studies in our laboratory, using HLA-B27 transgenic (HLA-B27 TG) rats, have revealed HLA-B27-mediated effects on DC populations. The affected DCs induce abnormally high levels of IL-17 production from T cells; CCR6+ IL-17-secreting cells appear to be important in driving pathology both in the HLA-B27 TG rats and in AS patients. We therefore aimed to perform the first characterisations of the phenotype and functions of DCs and other myeloid populations purified directly from AS patients, to understand their role in AS pathogenesis.

Analyses of circulating myeloid populations revealed that AS patients have a reduced proportion of the CD1c-expressing blood DCs, offset by an increase in CD14- CD16+ mononuclear cells. Interactions between CD14- CD16+ mononuclear cells and CD4+ T cells generated high levels of IL-6 secretion, required for the generation of Th17 cells. CD14- CD16+ mononuclear cells also induced T cells to express CCR6, and may therefore contribute to pathology by promoting Th17 responses. Interestingly, our data also indicate that APCs of mucosal origin may make a significant contribution to the systemic inflammation observed in AS patients. These observations give new insights into the pathogenic mechanisms in AS.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Dendritic cells, Ankylosing spondylitis, disease mechanisms, human
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Supervisor's Name: Milling, Dr. Simon
Date of Award: 2013
Depositing User: Miss Pamela Wright
Unique ID: glathesis:2013-4882
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 29 Jan 2014 15:21
Last Modified: 25 Jan 2017 09:59
URI: http://theses.gla.ac.uk/id/eprint/4882

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