Saw, V.P.J.; (2009) The role of inflammation and fibroblasts in conjunctival scarring in ocular mucous membrane pemphigoid. Doctoral thesis , UCL (University College London).

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Abstract

Ocular mucous membrane pemphigoid (ocular MMP) is a visually devastating disease where up to 30% of patients become blind due to the consequences of conjunctival inflammation and aggressive fibrosis. Standard systemic immunosuppression controls inflammation, but is limited by toxicity. How well immunosuppressive therapy prevents fibrosis is unknown. The cellular and molecular mechanisms that lead to excessive conjunctival fibrosis in ocular MMP are incompletely understood. Chronic inflammation and repair play an important role, but the conjunctival fibroblasts may also be autonomously activated. This thesis aimed to investigate potential mechanisms involved in conjunctival fibrosis in ocular MMP, for the purpose of proposing future anti-fibrotic therapies, to be used in conjunction with systemic immunosuppression. A retrospective review established that whilst conjunctival inflammation appeared to be controlled in 70% of patients, fibrosis progressed in 53%. A pilot randomised trial of adjunctive pulse intravenous methylprednisolone in patients with severe ocular MMP commencing both oral cyclophosphamide and oral corticosteroids did not reduce the time to control of inflammation, which had been hypothesised to prevent the progression of scarring. Both tumour necrosis factor-alpha (TNFα) and the T cell-derived fibrogenic cytokine interleukin-13 (IL-13) were expressed in active ocular MMP. Although this expression was reduced after treatment in clinically uninflamed ocular MMP, it was still significantly elevated compared to normal conjunctiva. Both TNFα and IL-13 stimulated migration and altered matrix metalloproteinase expression by normal conjunctival fibroblasts. IL-13 also stimulated collagen contraction. Both TNFα and IL-13 upregulated surface expression of costimulatory molecules by conjunctival fibroblasts, which suggests facilitation of a potential mechanism for fibroblast-T cell cross talk. Finally, pemphigoid conjunctival fibroblasts showed an altered phenotype compared to normal conjunctival fibroblasts, with increased cell division, migration, collagen contraction, type I collagen secretion, and secretion of eotaxin and matrix metalloproteinase-3. This thesis increases our understanding of the mechanisms involved in conjunctival fibrosis in ocular MMP, and provides new avenues for investigation of potential adjuvant therapies which could improve the prognosis in this poorly understood disease.

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