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Dr Clive Robinson
Department of Basic Medical Sciences, Pharmacology & Clinical Pharmacology
St George's Hospital Medical School
Cranmer Terrace, London SW17 0RE, UK
Email: c.robinson@sghms.ac.uk
Tel: +44 (0) 20 8725 5620
Fax: +44 (0) 20 8725 0685

Our research studies how endogenous and exogenous proteases perturb structural-functional cohesion at mucosal surfaces to cause disease. In particular, our work with exogenous proteases has highlighted novel therapeutic targets as described below.
Growing evidence suggest that proteolytic activity is an important factor contributing to the immunogenicity of inhaled allergens. To cause respiratory allergy, inhaled allergens must make contact with dendritic antigen presenting cells located beneath the protective barrier formed by the airway epithelium. Our research has established that peptidase allergens, such as the cysteine and serine peptidase allergens of house dust mites, are important drivers of this process because their proteolytic activity (1) promotes transepithelial allergen delivery, (2) skews cytokine and receptor expression towards a pro-allergic, tissue remodelling phenotype, and (3) generally upregulates inflammation. The first of these is of interest because it underlies both the initiation and maintenance of allergic sensitization. Our studies have established that peptidase allergens promote transepithelial delivery by cleaving the extracellular domains of occludin and claudins, the membrane-spanning adhesion proteins of intercellular tight junctions (TJs). Disruption of TJs, the principal components of the epithelial paracellular permeability barrier, results in a localised increase in permeability that facilitates delivery of any inhaled allergen to dendritic cells. Our current work is directed towards characterization of a cleavage hot spot in TJs responsible for this process, and exploration of enzyme-specific inhibitors as therapeutic modulators of allergen delivery.
Professor David Garrod, University of Manchester, UK.
Professor Geoff Stewart, University of Western Australia.
Professor Phil Thompson, University of Western Australia.
Wan,H., Winton,H.L., Soeller,C., Tovey,E.R., Gruenert,D.C., Thompson,P.J., Stewart,G.A., Taylor,G.W., Garrod,D.R., Cannell,M.B., Robinson C. 1999. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J.Clin.Invest 104:123-133.

Wan,H., Winton,H.L., Soeller,C., Gruenert,D.C., Thompson,P.J., Cannell,M.B., Stewart,G.A., Garrod,D.R., and Robinson,C. 2000. Quantitative structural and biochemical analyses of tight junction dynamics following exposure of epithelial cells to house dust mite allergen der p 1. Clin.Exp.Allergy 30:685-698.

Wan,H., Winton,H.L., Soeller,C., Taylor,G.W., Gruenert,D.C., Thompson,P.J., Cannell,M.B., Stewart,G.A., Garrod,D.R., and Robinson,C. 2001. The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin.Exp.Allergy 31:279-294.

Baker,S.F., Yin,Y., Runswick,S.K., Stewart,G.A., Thompson,P.J., Garrod,D.R., and Robinson,C. 2003. Peptidase allergen Der p 1 initiates apoptosis of epithelial cells independently of tight junction proteolysis. Mol.Membr.Biol. 20:71-81.

Stewart,G.A. and Robinson,C. 2003. Allergen structure and function. In Middleton's Allergy. Principles and Practice. N.F.Adkinson, Yunginger,J.W., Busse,W.W., Bochner,B.S., Holgate,S.T., and Simons,F.E.R., editors. Mosby, Philadelphia. 585-609.

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