Melanocyte behaviour is altered in chronic plaque Psoriasis during disease progression and upon resolution

Psoriasis is a chronic, relapsing, inflammatory potentially autoimmune skin disease characterised mainly by sustained inflammation and keratinocyte hyperplasia. Given the altered biology of keratinocytes, a dysregulated melanocyte behaviour is inferred. In fact, melanocytes in the human epidermis reside in the basal layer in a ratio of 1 melanocyte to ~10 keratinocytes. In Psoriasis, this ratio is maintained despite significant keratinocyte expansion, suggesting an increase in melanocyte numbers even though they have a quiescent post-mitotic nature. Effective Psoriasis therapies have been developed, however detailed investigation into the early stages of pathogenesis and into the role of melanocytes in the disease, has yet to be pursued. Evidence suggests melanocyte involvement as antigen presenting cells (APC), harbouring the autoantigen ADAMTSL5, and the influence of inflammatory cytokines on pigmentation. Identifying details on melanocyte proliferation and the effect of long-term therapies on their biology would benefit the field. This project investigated whether melanocyte numbers change in active Psoriasis plaques and after plaque resolution upon treatment, and the impact of Psoriasis-related cytokines on melanogenesis. For the first time, this study detected early melanocyte dysregulated proliferation in non-lesional and lesional Psoriasis tissue at baseline and upon treatment. Melanocyte proliferation was also detected in clinically clear Psoriasis skin supporting a role for melanocytes in Psoriasis pathogenesis and recurrence. In fact, the higher melanocyte numbers are preserved even after treatment, and melanocytes do not perish despite a reduction in keratinocyte number, but they retain their proliferative state. The data presented in this thesis show the direct negative impact of Psoriasis cytokines on melanogenesis and the altered melanin-distribution pattern in lesional Psoriasis skin. Moreover, it showed the stimulation of melanocyte proliferation by key inflammatory cytokines that concurrently inhibit melanogenesis, leading to depigmentation, which is often responsible for post-inflammatory pigmentary changes in Psoriasis patients. VII This thesis outlines the potential for melanocyte proliferation to be a primary event in the pathogenesis of Psoriasis, supporting a role for melanocytes as APC via an ADAMSTL5-initiated inflammation. Importantly, it is the first study to report melanocyte proliferation outside of the setting of melanoma or lentigo maligna. This raises intriguing questions about the nature of melanocytic proliferation in benign inflammatory skin disease and suggests that melanocytic proliferation in the epidermis may not be a harbinger of malignancy.