Sheffield Dermatology Research
|Gene-Environment Interactions In the Development of Atopic Dermatitis||
Atopic eczema/dermatitis (AD) is a multifactorial, heterogenous, disease that arises as a consequence of the interaction between genetic and environmental factors. Genetic variants found within several groups of genes have been associated with the development of a defective skin barrier including protease, protease inhibitor and structural genes. Loss-of-function mutations affecting the structural protein filaggrin in particular are a high risk factor for predisposing to AD. One common consequence expected of these ‘genetic factors’ is an increase in protease activity and decreased synthesis of lipid lamellae, leading to skin barrier breakdown.
The use of soap and other detergents enhances this by raising stratum corneum pH, resulting in the inhibition of lipid biosynthesis and the activation of degradatory proteases. Exogenous proteases from sources including Staphylococcus aureus and house dust mite also contribute to degradation of the barrier. The combination of these environmental factors with genetic factors appears to result in varying degrees of skin barrier breakdown, which is dependent on the ‘dosage’ of each. Ultimately the breakdown of the skin barrier can permit the penetration of allergens, with subsequent Th2 switching, the first step along the so-called atopic march. The interaction between genetic and environmental factors can therefore be considered the initial event in the development of AD. [Prof Michael Cork; Dr. Simon Danby]
|Development of Treatments for Atopic Dermatitis||
Atopic eczema/dermatitis (AD) is a chronic, inflammatory disease of the skin, which is characterized by xerosis, pruritus and erythematous lesions with increased trans-epidermal water loss (TEWL). The prevalence of AD is high, affecting 15-30% of children and 2 to 10% of adults. AD develops as a non-atopic condition associated with a skin barrier defect, and later, in about 60-80% of cases progresses to true atopic dermatitis. Furthermore AD is thought to be the first step along the atopic march leading to asthma and allergic rhinitis.
Combining experience from the treatment of AD in the clinic and basic laboratory research into the mechanisms of skin barrier disruption in AD we are actively involved in the development and formulation of new and existing treatments for AD. At the forefront of this research is our investigation of skin protease inhibitors as novel treatments for AD. Elevated protease activity in the SC is a key mechanism linking genetic and environmental factors in the breakdown of the epidermal barrier. [Prof Michael Cork; Dr. Simon Danby]
|The improvement of neonatal skincare||
When we are born our skin appears fully developed, however its function as a barrier to the potentially harmful external environment does not reach maturity for a number of months-years. The rate and level of maturation of the skin barrier is dependent on our genetics: genetic changes within the FLG gene for instance predispose to reduced skin barrier function. This means that the neonate is extremely vulnerable to irritants, allergens and potentially pathogenic bacteria. A combination of genetic changes and negative environmental challenges lead to the development of a defective skin barrier, and atopic dermatitis (AD), the first signs of which coincide with the period of skin barrier optimization. For some infants this is the first step along the Atopic March: the development of one or more of food allergy, allergic asthma, and allergic rhinitis. This has led to the idea that there is a window of opportunity in the first few months of an infants life to modify the environment the skin is exposed to in order to prevent the breakdown of the skin barrier, the development of AD and the atopic march. We are committed to improving neonatal skincare with a view to preventing the development of AD through evidence-based research. Together with our collaborators we have now been involved in several major clinical trials in neonates to assess early skincare practices. Currently we are a recruiting centre for the NIHR HTA-funded Barrier Enhancement Eczema Prevention (BEEP) trial led by Prof Hywel Williams (Nottingham Centre for Evidence Based Dermatology) and the Skin Testing for Atopic eczema Risk (STAR) study led by our team. [Prof Michael Cork; Dr. Simon Danby]
|Interaction of Topical Pharmaceutical and Cosmetic Agents with the Skin Barrier||
Atopic Dermatitis (AD) has historically been considered a disorder of immune dysfunction, however a growing body of evidence supports a primary role for the epidermal skin barrier. Genetic variants within genes encoding key epidermal barrier structural proteins are strongly associated with the development of AD. Furthermore environmental insults including the use of harsh surfactants and/or exogenous proteases from colonising bacteria and house dust mite for example interact with the existing skin barrier defect to exacerbate the condition. We believe that an understanding of gene-environment interactions in the development of AD can lead to the better use of some topical products, avoidance of others, and the future development of products that can repair the skin barrier.
Our aim is to investigate the interaction of topical pharmaceutical and cosmetic agents with the skin barrier. We study the effect of these agents, including emollients, anti-inflammatory treatments and massage oils for example, by designing and conducting comprehensive functional mechanistic studies. These studies, conducted at our Skin Barrier Research Facility, involve the use of a range of biophysical diagnostic tests and biochemical assays to determine the structure and function of the skin barrier in human volunteers. [Prof Michael Cork; Dr. Simon Danby]
|Genetics of Skin Diseases||
Our group has been involved in dissecting the genetics of some complex skin diseases such as psoriasis, atopic dermatitis, alopecia areata and vitiligo. For each disease, candidate genes within susceptibility loci are screened for single nucleotide polymorphisms (SNPs) and the distribution of each SNP is then compared between cases and controls.
We also use genome-wide association studies using SNPs to identify the major genetic variants contributing to the pathogenesis of the disease, which might lead to the identification of potentially novel targets for therapeutic intervention in the treatment of these diseases. [Prof Michael Cork; Dr. Rachid Tazi-Ahnini]
|The Vitamin A Metabolic Pathway and Hyper-Proliferative Disorders of the Skin||
Several diseases are characterised by cellular hyper-proliferation and an altered state of differentiation. These include cancer, psoriasis and cutaneous viral infections. Psoriasis is a common, genetically determined, inflammatory disease of the skin characterised by red scaly, raised areas of skin (plaques). The condition can arise at any age but appears most often between the ages of 15 and 40. Psoriasis affects about 2% of the world’s population, (ranging from 0.5% in Japan up to 2.5 % in Scandinavia) and causes enormous distress to those affected by it.
Treatment with retinoids has been found to be effective in controlling psoriasis (Mendonça and Burden, 2003), some cancers (Freemantle et al., 2003) and acne vulgaris (Webster 2002). Despite the beneficial effects of retinoid treatment; its use is limited by potentially serious adverse effects including hepatotoxicity, alopecia and teratogenicity (Kemmet & Hunter, 1988). These effects are related to the pharmacological dosages needed to achieve a therapeutic response.
The research into alopecia areata and androgenetic alopecia is at the forefront internationally; the RHH Hair Clinic involves both clinical and academic research and is a resource for pathobiology and clinical trials. Academic work concentrates on autoantibodies and investigation into the role of environmental factors in bald pattern hair loss and scarring alopecia. [Prof. Andrew Messenger; Dr. Rachid Tazi-Ahnini; Dr. Andrew McDonagh]
The autoimmune regulator gene in the pathogenesis of alopecia areata
In addition to sporadic cases, alopecia areata (AA) occurs with very high frequency (>50%) in APS-1 patients. This is a rare disease characterised by hyperparathyroidism, Addison’s disease and chronic candidiasis, with a variety of autoimmune disorders present as secondary manifestations. The disease is caused by loss of function mutations in the autoimmune regulator (AIRE) gene that encodes a 57.7-kDa protein. AIRE is expressed in the thymus, particularly in thymic medullary epithelial cells (mTEC’s), and is required for the ectopic expression of a diverse range of peripheral tissue antigens (PTAs) by mTECs, conferring on them the ability to perform the negative selection of T cells. The role of the autoimmune regulator (AIRE) gene is fundamental to alopecia areata (AA) arising in the autoimmune polyendocrine syndrome type 1 (APS-1). We are using a cellular model of thymic cell gene expression to demonstration that autoantigens identified in AA cases unassociated with APS-1 are also regulated by the AIRE gene would strongly support the role of AIRE in the pathogenesis of AA. [Dr Rachid Tazi-Ahnini, Dr Andrew McDonagh, Dr Helen Kemp and Prof Anthony Weetman]
|Contact Dermatitis and Pigment Cell Research||The contact dermatitis and pigment cell research also has an international reputation. The work is currently targeted at getting narrow band UVB operational and to develop research into T-cell mediated autoimmunity in pigment cell disease. [Prof. David Gawkroger]|