Defining the role of Filaggrin in skin barrier function and eczema.
Lead Research Organisation:
University of Edinburgh
Department Name: Dermatology
Abstract
Eczema is a very common disease, causing a red, itchy rash and affecting more than 1 in 5 people. Its cause is poorly understood, but a recent finding is that about half of eczema patients have a deficiency in the gene which makes filaggrin. All patients with a related condition, ichthyosis vulgaris have these gene changes, but they do not have inflamed skin. Filaggrin is a protein that plays an important part in forming the protective barrier at the outer layer of the skin. These data suggests that an underlying cause of eczema is a defective skin barrier, which allows substances to enter the skin and spark of an immune reaction and the classic itchy red rash. Over half of eczema patients apparently have normal filaggrin however. I will test this theory by measuring the skin barrier function in eczema patients with normal and abnormal filaggrin and see if they differ. I will see how icthyosis and eczema patients differ and whether there is a difference between patients with ‘allergic‘ (atopic) and non-allergic eczema. If patients with an apparently normal filaggrin gene have a defective skin barrier, I will find out if there are unidentified abnormalities in filaggrin or other skin barrier proteins.
Technical Summary
Atopic eczema (AD) is one of the commonest chronic conditions affecting the UK population.
Its aetiology includes genetic and environmental components. Most recent research on eczema has postulated immunological dysfunction as the key underlying aetiological factor. In 2006, McLean described two independent loss-of-function genetic variants in the filaggrin gene (FLG) predisposing to atopic eczema, and to asthma and allergic rhinitis in association with eczema. These mutations also cause ichthyosis vulgaris (IV) in a semidominant Mendelian fashion. In independent European eczema cohorts the filaggrin null allele frequency varies between 0.27 and 0.336 compared to a normal population frequency of 0.045. FLG codes for the profilaggrin which plays a pivotal role in the formation of the stratum corneum. Mclean hypothesizes that the absence of filaggrin leads to a defect in barrier function of the skin which secondarily allows enhanced antigen presentation to the immune system. There is no proof yet that FLG mutations cause a functional failure of the skin barrier. Only half of European AD patients and few non-European ADs carry such mutations. AD usually spontaneously improves after childhood. The same FLG mutations cause different phenotypes- IV and AD. The clinical phenotype of AD may result from different mechanisms- one initiated by a FLG defective barrier failure in which secondary immunological changes occur, and the other an immunologically mediated disease.
The focus of my proposal is to determine whether a physiological and structural barrier defect is associated with FLG variants and whether the barrier defect in AD patients correlates with these variants. I will measure trans epidermal water loss (TEWL), a sensitive indicator of skin barrier function in AD and IV patients, and normal controls. I will correlate this with FLG status and serum IgE levels (a marker for atopy). In a subset of patients I will study barrier function more intensively by polyethylene glycol penetration. In collaboration with the Edinburgh Protein Interaction Centre I will determine filaggrin structure in healthy controls, subjects with known FLG mutations (if filaggrin is present), and those with abnormal TEWL but lacking the known FLG mutations. I will fully sequence FLG from patients with abnormal filaggrin structure, but without known mutations.
This project is a necessary translational study built on a genuine genetic break-through in understanding of one of our commonest diseases. Additional protein studies will show whether other barrier structural defects are also involved in the aetiology of AD.
Its aetiology includes genetic and environmental components. Most recent research on eczema has postulated immunological dysfunction as the key underlying aetiological factor. In 2006, McLean described two independent loss-of-function genetic variants in the filaggrin gene (FLG) predisposing to atopic eczema, and to asthma and allergic rhinitis in association with eczema. These mutations also cause ichthyosis vulgaris (IV) in a semidominant Mendelian fashion. In independent European eczema cohorts the filaggrin null allele frequency varies between 0.27 and 0.336 compared to a normal population frequency of 0.045. FLG codes for the profilaggrin which plays a pivotal role in the formation of the stratum corneum. Mclean hypothesizes that the absence of filaggrin leads to a defect in barrier function of the skin which secondarily allows enhanced antigen presentation to the immune system. There is no proof yet that FLG mutations cause a functional failure of the skin barrier. Only half of European AD patients and few non-European ADs carry such mutations. AD usually spontaneously improves after childhood. The same FLG mutations cause different phenotypes- IV and AD. The clinical phenotype of AD may result from different mechanisms- one initiated by a FLG defective barrier failure in which secondary immunological changes occur, and the other an immunologically mediated disease.
The focus of my proposal is to determine whether a physiological and structural barrier defect is associated with FLG variants and whether the barrier defect in AD patients correlates with these variants. I will measure trans epidermal water loss (TEWL), a sensitive indicator of skin barrier function in AD and IV patients, and normal controls. I will correlate this with FLG status and serum IgE levels (a marker for atopy). In a subset of patients I will study barrier function more intensively by polyethylene glycol penetration. In collaboration with the Edinburgh Protein Interaction Centre I will determine filaggrin structure in healthy controls, subjects with known FLG mutations (if filaggrin is present), and those with abnormal TEWL but lacking the known FLG mutations. I will fully sequence FLG from patients with abnormal filaggrin structure, but without known mutations.
This project is a necessary translational study built on a genuine genetic break-through in understanding of one of our commonest diseases. Additional protein studies will show whether other barrier structural defects are also involved in the aetiology of AD.