T cell behaviour in the pathogenesis of atopic dermatitis : how they get in and how to get them out

Abstract

AD skin is characterized by the infiltration of CD4+ T cells in the dermis and epidermis. Chemokines (chemoattracting cytokines), including TARC and CTACK play a pivotal role in the recruitment of T cells to the skin of AD patients. In chapter two we describe that the serum levels of chemokines TARC and CTACK are increased in AD patients compared to patients with allergic asthma and healthy controls. In addition we show that the serum levels correlate to disease severity. We put serum TARC levels forward as an objective parameter for disease severity. When other treatments fail, patients with severe refractory AD are regularly being treated with cyclosporin A (CsA). In chapter three we show that CsA treatment is highly effective and relatively safe, with regard to the most common side effects, including increased blood pressure and renal toxicity. However, patients regularly experience a relapse after discontinuation of therapy. In addition, in chapter four we describe a small subset of AD patients that experience an exacerbation during CsA treatment with signs and symptoms more severe than at onset of treatment. Increasing total serum IgE levels were found to parallel these exacerbations of eczema. Increasing IgE production had previously been described using in vitro experiments. We hypothesize that in this subset of AD patients CsA induces a shift towards Th2, resulting in increased IgE synthesis. In order to study the in vivo effects of CsA treatment, in chapter five we performed a detailed study of the effects of CsA treatment on peripheral blood T cell subsets with a focus on regulatory T cells (Tregs). We show that CsA treatment significantly reduces the percentage of Tregs. In addition, it was found that CsA treatment decreases the expressions of genes FOXP3 and GADD45A, involved in T cell regulation. Using a microarray approach we have found several genes that are suggested to be involved in the pathogenesis of AD. Chapter six describes two groups of genes found differentially expressed in CD4+ T cells from AD patients compared to allergic asthma patients and healthy control subjects. The first group included genes involved in migration of T cells to the skin, a second group of genes was related to T cell survival. In chapter seven we examined the expression of these genes in the preferentially skin homing, CLA-positive T cell population. These skin homing T cells were found to show decreased expression of apoptosis related genes, suggesting their increased survival potential in patients with AD.