Tissue factors are disease determinants in allergy

Abstract

Over 40% of the western population is atopic however, only a limited percentage develops allergic disease. Many chromosomal loci containing immune related genes have been associated with allergic disease, but immune dysregulation alone cannot explain disease development. In recent years the contribution of tissue restricted factors to development of allergic disease has become a research focus. The skin and the airway epithelium are highly structured barriers as the first line of defense against allergen entry and sensitization. Keratinocytes and epithelial cells are also now recognized to play a driving role in allergic inflammation. Epidermal barrier breakdown due to genetic polymorphisms and/or environmental factors can lead to the development of atopic dermatitis (AD). Genetic polymorphisms in filaggrin, a key component of the stratum corenum and lipid lamellae barriers of the skin, are associated with a higher risk of AD. Dysregulation of desquamation due to Kallikrein-related peptidase-7, Lymphoepithelial Kazal-type-related inhibitor and cystatin A polymorphisms and breakdown of the tight junction barrier due to claudin-1 polymorphisms are also associated with AD. Airway epithelial barrier integrity is essential in protection against asthma development. This barrier depends on cell-cell adhesion, primarily through tight and adherens junctions. Many adhesive proteins including claudin-1, occludin, zonula occludens-1, e-cadherin, α-catenin and protocadherin-1 have been associated with asthma development. Airway remodelling, a common feature of asthma, was believed to be caused by chronic airway inflammation in the asthmatic lung; however there are recent indications that it also has a genetic component. ADAM33 and claudin-1 have been associated with airway remodelling. With the evidence that tissue dysregulation is at the base of allergic disease, therapeutic approaches have shifted to address the underlying tissue irregularities rather than simply suppressing inflammation. This shift opens the door for development of preventative therapies.