Understanding the underlying immune mechanisms of Dupuytren’s Disease

Carter, Kristyn Alexaundria (2022) Understanding the underlying immune mechanisms of Dupuytren’s Disease. PhD thesis, University of Glasgow.

Abstract

Background: Dupuytren’s disease, also called Dupuytren’s contracture, is a fibroproliferative condition in which the palmar tissue becomes inflamed and, as the disease progresses, reduced mobility of the hand and affected fingers occurs. Dupuytren’s disease consists of two microenvironments: cellular nodules and a fibrous cord. Clinical presentation of the disease is a claw like configuration of the hand with the fingers curling inward. Treatment options vary from enzymatic digestion of nodules, appearing as hardened tissue, to fasciectomy of the affected tissue. Unfortunately, treatment is not always successful as some cases of Dupuytren’s recur during the individual’s lifetime. As a model of tissue fibrosis, Dupuytren’s is characterised by chronic inflammation and excess matrix protein production. This, coupled with the recurring nature of the disease, suggests the immune system could play a role in mediating persistent, chronic inflammation of the affected tissue. The work encompassed in this thesis aims to understand the immune mechanisms at play and highlight specific cell to cell interactions which could unveil potential therapeutic targets.

Key results: Preliminary bulk RNA sequencing results describe a heightened presence of myofibroblast and fibrosis related genes in Dupuytren’s microenvironments compared to control, carpal tunnel tissue. Cellular characterisation of Dupuytren’s tissue led to the identification of activated fibroblasts and myofibroblasts as well as increased matrix protein production. An activated stromal cell phenotype was seen in Dupuytren’s tissue and this phenotype, coupled with fibroblast behaviour, was enhanced in response to in vitro mechanical damage and/or stimulation with inflammatory or immune cell related cytokines. Outlining the immune cell landscape of Dupuytren’s tissue, via RNA sequencing and flow cytometry, pointed to macrophage and T lymphocytes as the leading cells within the tissue. Visualization of the immune cell populations via immunohistochemistry described not only the presence of dendritic cells and macrophages but also various T cell subsets. Bulk sequencing further supported the presence of T cells by describing T cell related genes within Dupuytren’s tissue. T cell activation marker, CD27, and its sole ligand, CD70, were expressed in the tissue and confirmed by immunohistochemistry to be expressed by fibroblasts. Their presence highlights the possibility of stromal-immune interaction between T cells and fibroblasts. Stimulation of Dupuytren’s fibroblasts with CD27 enhanced gene and protein expression of stromal, inflammatory, matrix, and angiogenic related markers; suggesting a role of CD27-CD70 axis in perpetuating Dupuytren’s disease.

Conclusion: This body of work describes an exaggerated stromal activation profile in Dupuytren’s disease tissue as well as described enhancement of this stromal activation profile in response to in vitro cytokine stimulation. Characterization of immune cell landscape of Dupuytren’s tissue featured stromal-immune crosstalk between T cells and fibroblasts and pointed to a signalling axis that could aid in understanding the etiology of Dupuytren’s disease.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Millar, Professor Neal
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-82954
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2022 15:06
• Last Modified: 14 Jun 2022 15:10
• Thesis DOI: 10.5525/gla.thesis.82954
• URI: https://theses.gla.ac.uk/id/eprint/82954