An investigation of Langerhans cell function in psoriasis

Psoriasis is a disfiguring, psychosocially disabling skin disease that affects 1 in 50 of people in the UK. The disease is chronic, currently incurable and carries an increased risk of coronary heart disease. Current suppressive treatments for psoriasis, although effective, carry with them significant side-effects. In early onset psoriasis genetic susceptibility plays an important role and is mediated by components of the immune system. One such component are Langerhans cells (LC) that represent the outpost of the immune system. Their normal role is to move from the outermost layer of the skin taking signals to the immune system in nearby lymph glands. This movement of LC is triggered in the skin by chemical signals such as interleukin-1-beta and tumour necrosis factor-alpha. We have shown previously that in the skin of psoriasis patients with early onset disease, i.e. beginning before the age of 40 years, LC are unable to migrate in response to these chemical signals. This is an important observation probably fundamental to our understanding of psoriasis. The proposed research will explore the underlying mechanisms that differentiate LC in the skin of patients with psoriasis from those of healthy subjects. This will be prosecuted at a number of levels: molecular, cellular and clinical. The results of the research are anticipated to define impaired LC function as a significant component of skin inflammation in psoriasis. Thereby allowing development of more targeted and more effective treatment of psoriasis. It is likely that these results could be relevant to an understanding of chronic inflammation of other organs such as bowel and joints.

Psoriasis is one of the commonest chronic immune-mediated diseases in the UK. It produces profound psychosocial disability and impairment of quality of life in patients and their immediate families. Furthermore, psoriasis carries a significant risk of cardiovascular morbidity and is a disease that affects people of all ages. To date, psoriasis is incurable and current therapies, particularly for severe disease, are limited by organ toxicity. Susceptibility to psoriasis is determined by gene-environment interactions and disease expression driven by elements of adaptive and innate immune responses. A fertile area for research is dendritic cells which are a bridge between innate and adaptive immune responses in that they have the ability to interact with and activate T-cells. Langerhans cells (LC) are members of this family of dendritic cells, they reside in the epidermis where they serve as the outermost sentinels of the immune system. The ability of LC to migrate from epidermis to deliver information (antigen) to regional lymph nodes is of pivotal importance to the regulation of cutaneous immune responses. Recent work from our group has shown that in psoriasis of early onset there is a profound impairment of epidermal LC migration in response to key migratory stimuli including TNF-alpha and interleukin 1beta. This indicates the existence in psoriasis of a fundamental abnormality of LC function. The current project will explore potential pathomechanisms that may underlie impairment of LC function in psoriasis. Patients with psoriasis and normal volunteers will be studied.We will use a variety of molecular and immunological research techniques to explore LC function from the standpoint of their clinical response to psoriasis treatments; gene expression; coordinated expression of receptors and their ligands; the cytokine milieu of epidermis and the phenotype of circulating progenitors of LC. If the mechanism(s) are elucidated this will produce a two-fold benefit: (i) to facilitate development of selective therapies targeted at the ?cause? of psoriasis; and (ii) to use this knowledge to interrogate other chronic immune-mediated diseases, such as inflammatory bowel disease and rheumatoid arthritis, which are less accessible to analysis than is psoriasis.