The role of apoptosis in UVB-induced clearance of psoriasis

Abstract

Ultraviolet (UV) B therapy can induce complete clearance of psoriasis and often leads to prolonged remission following a treatment period. UVB phototherapy is a commonly used, highly effective treatment modality, but despite this its mechanism of action remains poorly understood. This thesis investigates the importance of keratinocyte apoptosis in UVB-induced clearance of psoriasis using a novel approach, and employs a mathematical model to explore the effects of this on epidermal homeostasis. The in vivo effects of two wavelengths of UVB were compared, one of which is clinically effective in clearing psoriasis (311nm), and one which is ineffective (290nm) even at high doses. This allowed investigation of which effects of UVB are relevant to plaque clearance; eliminating „bystander‟ effects such as erythema. The study showed significant keratinocyte apoptosis in lesional psoriatic epidermis following 311nm UVB compared to 290nm UVB; peaking 16-24h post irradiation. To determine clinical significance, a computational model of psoriatic epidermis was created utilising histological and kinetic parameters. The model predicted that apoptosis should occur in both stem and TA cells to account for plaque remodelling. This was confirmed and quantified experimentally, with real-time assays determining the rate of keratinocyte apoptosis. These data were fed back into the model and demonstrated that the observed level of keratinocyte apoptosis was sufficient to account for complete remodelling of psoriatic plaques in response to therapeutic UVB. The data was supported by gene array studies, which showed differential regulation of apoptotic genes at early time-points following 311nm rather than 290nm UVB. Finally, the wavelength dependence of UVB-induced apoptosis was examined, and only wavelengths which can clear psoriasis (i.e. greater than 300nm & less than 320nm UVB) induced significant epidermal apoptosis. In summary, this thesis demonstrates that keratinocyte apoptosis is a key mechanism of psoriatic clearance in response to UVB.