Understanding the formation, function and inhibition of multinucleated giant cells in giant cell arteritis

Peacock, Annie (2026) Understanding the formation, function and inhibition of multinucleated giant cells in giant cell arteritis. PhD thesis, University of Glasgow.

Abstract

Giant cell arteritis (GCA) is the most common form of vasculitis in patients over 50 which can lead to irreversible blindness and strokes if not properly treated. GCA is characterised by immune mediated destruction of the medial layer of small blood vessels followed by aberrant repair leading to intimal hyperplasia and narrowing of the vessel. Multinucleated giant cells (MGCs) are a hallmark of disease pathology. Despite these cells being observed close to sites of both media destruction and intimal hyperplasia, their role and formation in GCA pathogenesis have not yet been fully explored. Furthermore, reliable models to investigate the early stages of GCA pathogenesis, particularly the migration of circulating monocyte precursors and the generation of MGCs, remain scarce. Accordingly, this thesis seeks to elucidate the mechanisms underlying the development and functional roles of MGCs and their precursors.

To address this gap in knowledge, this thesis employed spatial transcriptomics to characterise macrophages and MGCs within distinct vascular layers and to elucidate the mechanisms underlying their development and functional roles. The results showed that macrophages in the intima of GCA vessels were transcriptionally similar to MGCs. Furthermore, cell deconvolution analysis of MGCs showed that these cells were transcriptionally akin to an undifferentiated macrophage suggesting they could be both pro- and anti-inflammatory in nature.

Furthermore, it was important to understand the mechanisms involved in MGC formation. This thesis showed that GCA like MGCs could be generated by stimulating monocytes with GM-CSF+IFNg. This culture produced both Langhans, and foreign body giant cells as observed in GCA tissue. These cultured cells produced markers observed in the tissue such as MMP9 and CTSD.

Differences in MGC formation by cultured monocytes from healthy controls and GCA patients suggested that there are differences in circulating monocyte precursors of MGCs. Flow cytometric analysis, RNA sequencing and epigenetic profile analysis of these monocytes revealed that GCA monocytes express high CCR5 and GM-CSF receptor on their surface. Analysis also showed differences in H3K427me3 and H3K4me3 profiles in GCA monocytes compared to healthy controls.

Lastly, as CCR5 was shown to be highly expressed on GCA monocytes, it was assessed in the context of MGC formation. CCR5 and its ligands CCL3, and 5 could be observed in GCA tissue localized to and surrounding MGCs. CCR5 modulation by small molecules and monoclonal antibodies (such as maraviroc and Leronlimab respectively) were added to the previously described culture. This inhibition led to a large reduction in the number of MGCs observed in culture suggesting a role for this chemokine receptor in the formation of MGCs.

In summary, this thesis established a role of MGCs in GCA pathogenesis. It presented the first in vitro model of GCA MGC formation from enriched monocytes, enabling investigation of their initiation and modulation. It also identified differences in protein expression and epigenetic modifications between healthy and GCA monocytes and implicates the chemokine receptor CCR5 in MGC formation, highlighting CCR5 modulators such as Maraviroc and Leronlimab as potential therapies. Future work should explore GCA monocyte co-culture systems and develop 3D models to extend these findings.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from The Lauren Currie Twilight Foundation.
• Subjects: Q Science > QR Microbiology > QR180 Immunology; Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Funder's Name: The Lauren Currie Twilight Foundation
• Supervisor's Name: Ansalone, Dr. Cecilia, Goodyear, Professor Carl and Basu, Professor Neil
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-85741
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 18 Feb 2026 13:58
• Last Modified: 18 Feb 2026 13:59
• Thesis DOI: 10.5525/gla.thesis.85741
• URI: https://theses.gla.ac.uk/id/eprint/85741