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Macrophage phenotypes in giant cell arteritis

Graham, Amy Eve (2018) Macrophage phenotypes in giant cell arteritis. PhD thesis, University of Leeds.

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Abstract

Giant cell arteritis (GCA) is the commonest form of vasculitis that affects individuals over 50 years of age, predominantly occurring within medium and large-sized arteries. Without immediate glucocorticoid treatment, GCA can culminate in blindness and stroke. T-cells and macrophages are found to infiltrate through the arterial wall and are intricately involved in disease pathogenesis, from arterial destruction to neointimal hyperplasia resulting in tissue ischemia. Macrophages perform an array of different functions in GCA arteries however disease heterogeneity, along with poor characterisation of macrophage phenotypes has hindered studies into the role of macrophages. I hypothesise that the heterogeneity of histological and clinical manifestations seen between individuals with GCA is in part due to the phenotypic heterogeneity of macrophages found within the artery wall of different patients. A THP-1 cell line model was developed to enable identification of phenotype-specific macrophage markers which were confirmed at the RNA and protein level. M(LPS, IFN-gamma) markers ANKRD22 and GBP5 were used to characterise M1 macrophages and M(IL-4) marker MRC1, and M(IL-10) marker CD163 were used to characterise M2 macrophages in temporal artery biopsies using immunohistochemistry. M1 and M2 macrophages were found within each layer of the artery wall layer (adventitia, media and intima) and inter-individual variation in macrophage infiltration patterns was observed. M1 macrophages correlated with media destruction and greater expression of ANKRD22 was significantly associated with increased arterial inflammatory infiltration. Greater MRC1 staining was significantly associated with patients who reached 5mg of glucocorticoids sooner. Identification of all markers within each artery layer suggested different macrophage phenotypes co-exist. Arterial expression of ANKRD22 and MRC1 may identify different groups of patients who require different treatment strategies. Macrophage phenotype heterogeneity and downstream immunological processes may therefore in part explain the variation seen between patients in terms of their clinical presentation, long-term sequelae and response to treatment.

Item Type: Thesis (PhD)
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Musculoskeletal Disease (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds)
Depositing User: Miss Amy Graham
Date Deposited: 28 Jan 2019 11:09
Last Modified: 28 Jan 2019 11:09
URI: http://etheses.whiterose.ac.uk/id/eprint/22602

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