Functional and molecular diversity of skin fibroblasts in systemic sclerosis.

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Systemic sclerosis (SSc), also called scleroderma, is an uncommon autoimmune rheumatic condition leading to thickened skin (sclerosis) with fibrosis, or scarring, in the skin and vital organs such as the lungs and heart, kidneys and bowel. These complications are responsible for major impact of the disease on almost all aspects of everyday life and in the most severe cases can lead to death. The pattern and severity of skin thickening can be used to identify cases most at risk of severe internal organ involvement and reduced long-term survival. However, the relationship between skin disease and overall outcome is imprecise because the basic mechanisms of disease in scleroderma remain poorly understood. The extent of skin involvement helps to classify patients, and distinct trajectories of skin involvement are associated with differing prognosis and survival. As a result, scleroderma remains a challenging disease to treat and is responsible for more deaths than any other rheumatic disease.Although scleroderma is rare, the processes that have malfunctioned and that determine severity of the disease are likely to be relevant to many commoner conditions such as lung and liver fibrosis, or excessive scarring after surgery, burns or skin wounding. In this way scleroderma offers a possible route to understand and ultimately prevent or treat these other important disorders.Previous work in scleroderma has suggested that a key type of cell in the skin and internal organs called the fibroblast acts as a driver of fibrosis in skin disease. Fibroblasts can be grown from small pieces of skin (biopsies) taken under local anaesthetic from scleroderma patients. However only some of the fibroblasts grow out of the biopsy and recent research suggests that these may not be the most important cells determining skin fibrosis. This has limited previous studies because there are likely to be many different types of fibroblasts that have different roles in normal healthy skin and in diseases such as scleroderma.New laboratory techniques provide exciting tools to distinguish between the different populations of fibroblasts in skin and we have developed a new method to isolate different populations of fibroblasts from skin biopsies in scleroderma. This is a major step forward because unlike other cell types, such as immune cells or blood cells, fibroblasts examined using traditional methods and laboratory tools are often indistinguishable from each other. The present application will use modern scientific approaches to examine gene and protein expression and to define the distinct types of fibroblasts in the skin, and further understand their potential importance in the scleroderma disease process. We will ask patients with scleroderma attending our routine clinic to donate small samples of skin and will analyse each cell in the biopsy individually to identify the types of cells present. We expect to find small groups of cells within the biopsy expressing similar proteins. The technique we propose to use has already been applied in rheumatoid arthritis, another autoimmune disease affecting the joints, as well as in healthy skin.We fully expect that there will be different fibroblast populations, and that these will have distinct properties at different stages of scleroderma. Definition of the detailed properties and function of these cells will have implications on future treatment targets and determine which of the emerging therapies for scleroderma will work best for an individual patient. This is vital considering the very high clinical burden of scleroderma and current variation in response to available drugs.As well as providing important information about scarring and fibrosis, this work will also have wider implications on other common autoimmune diseases affecting the skin, such as psoriasis, where there may be overlap in the types of cells driving the disease, and similar treatments may be applicable.