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THURSDAYOctober 14OPEN SESSION4:05 – 4:35Click here to return to Dermatology Update 2004 Schedule and Abstracts |
Thomas LugerAtopic dermatitis (AD) is a chronic inflammatory, severely itchy skin disease, with an increasing global prevalence affecting 10 - 20 % children. It may persist in the adulthood and is believed to be the first step in the “atopic marathon” that results in asthma and allergic rhinitis. The clinical phenotype of the disease is regarded as a result of the interaction between susceptibility genes, immunological abnormalities, defective skin barrier functions and environmental factors. So far, more than 12 candidate genes have been proposed. There is clear evidence for an important role of the innate and the adoptive immune system in the pathophysiology of AD. The majority of AD patients have elevated total serum IgE levels, IgE specific for ubiquitous allergens and a predominant T2- cell response. However, in AD lesions two distinct patterns of inflammation have been identified. In early skin lesions T2 lymphocytes are predominant, whereas the chronic inflammatory phase is characterized by a switch towards a T1 immuneresponse. There is also evidence that autoimmunity may serve as an amplifier of the chronic allergic inflammation since IgE-autoantibodies against proteins derived from damaged chronically inflamed skin have been identified in the sera of patients with AD. Accumulating evidence suggests that the interaction of several newly described chemokines with skin-homing T cells, dendritic cells (DC), eosinophils and mast cells plays an important role in the pathogenesis of AD. Moreover, keratinocyte derived mediators such as TSLP via activating DC's and inducing the T2 attracting cytokine TARC may play a role in the acute phase of AD. Different subsets of DC's which express the high-affinity receptor for IgE (Fc e RI) recently have been identified to play a crucial role in the outcome of T-cell responses in AD. Accordingly, in acute AD Fc e RI low Langerhans cells (LC) primarily give rise to a T2 immuneresponse, whereas in chronic AD IL-12 producing Fc e RI high inflammatory dendritic epidermal cells (IDEC) appear to be responsible for the switch to T1. In acute AD mast cells are markedly degranulated whereas the number of MC's is increased in chronic AD. Mediators released by mast cells such as histamine, tryptase, VEGF and TNF a significantly contribute to allergic and inflammatory responses. Moreover, mast cell tryptase may contribute to the pathophysiology of AD by activating specific receptors, defined as proteinase-activated receptors (PAR's). Importantly, a ctivation of PAR's results in the induction of several factors which are involved in the pathophysiology of AD such as neurogenic inflammation, recruitment of eosinophils and monocytes, activation of NF- ? B, as well as the induction of pruritogenic mediators. Novel findings suggest an important functional interaction between the nervous system and the immune system. Accordingly, an imbalance of certain “pro- versus anti-inflammatory” neuropeptides (e.g. substance P, VIP, PACAP) and of neurotrophins (e.g. nerve growth factor) in the microenvironment of the inflamed skin significantly appears to contribute to the pathophysioloogy of AD. This may also explain the frequently observed stress dependency of AD. There is increasing evidence for a role of the innate defense such as antimicrobial peptides and Toll-like receptors (TLR) in atopic dermatitis. Accordingly, keratinocyte derived defensins and cathelicidins recently were found to be downregulated in lesional skin. This may explain the patient's increased susceptibility to skin infections and the frequently observed staphylococcal superantigen-mediated worsening of the disease. Moreover, a TLR-2 polymorphism was found to be associated with with S. aureus infections and very high IgE levels. The enormous progress in our understanding of the complex pathophysiology of AD has allowed to distinguish allergic and non-allergic subtypes of the disease and ultimately will allow for the development of novel therapeutic strategies. Click here to return to Dermatology Update 2004 Schedule and Abstracts |