Mechanisms in allergic contact dermatitis

During the past few decades, our understanding of why, where, and when allergic contact dermatitis (ACD) might develop has rapidly increased. Critical discoveries include the identification of T-cells as mediators of cell-mediated immunity, their thymic origin and recirculation patterns, and the molecular basis of their specificity to just one or a few allergens out of the thousands of allergens known. Progress has also resulted from the identification of genes that determine T-cell function, and the development of monoclonal antibodies that recognize their products. Moreover, the bio-industrial production of large amounts of these products, e.g., cytokines and chemokines, and the breeding of mice with disruptions in distinct genes (knock-out mice) or provided with additional genes of interest (transgenic mice), have allowed in-depth analysis of skin-inflammatory processes, such as those taking place in ACD. Although humoral antibody-mediated reactions can be a factor, ACD depends primarily on the activation of allergen-specific T-cells [1], and is regarded as a prototype of delayed hypersensitivity, as classified by Turk [2] and Gell and Coombs (type IV hypersensitivity) [3]. Evolutionarily, cell-mediated immunity has developed in vertebrates to facilitate eradication of microorganisms and toxins. Elicitation of ACD by usually nontoxic doses of small-molecular-weight allergens indicates that the T-cell repertoire is often slightly broader than one might wish. Thus,ACD can be considered to reflect an untoward side-effect of a well-functioning immune system. Subtle differences can be noted in macroscopic appearance, time course, and histopathology of allergic contact reactions in various vertebrates, including rodents and humans [4].Nevertheless, essentially all basic features are shared. Since both mouse and guinea pig models, next to clinical studies, have greatly contributed to our present knowledge of ACD, both data sets provide the basis for this chapter. In ACD, a distinction should be made between induction (sensitization) and effector (elicitation) phases [5] (Fig. 1). The induction phase includes the events following a first contact with the allergen and is complete when the individual is sensitized and capable of giving a positive ACD reaction. The effector phase begins upon elicitation (challenge) and results in clinical manifestation of ACD. The entire process of the induction phase requires at least 3 days to several weeks,whereas the effector phase reaction is fully developed within 1-2 days. Main episodes in the induction phase (steps 1-5) and effector phase (step 6) are: □Binding of allergen to skin components. The allergen penetrating the skin readily associates with all kinds of skin components, including major histocompatibility complex (MHC) proteins. These molecules, in humans encoded for by histocompatibility antigen (HLA) genes, are abundantly present on epidermal Langerhans cells (LC). □Hapten-induced activation of allergen-presenting cells. Allergen-carrying LC become activated and travel via the afferent lymphatics to the regional lymph nodes, where they settle as so-called interdigitating cells (IDC) in the paracortical T-cell areas. □Recognition of allergen-modified LC by specific T-cells. In nonsensitized individuals the frequency of T-cells with certain specificities is usually far below 1 per million.Within the paracortical areas, conditions are optimal for allergen-carrying IDC to encounter naive T-cells that specifically recognize the allergen-MHC molecule complexes. The dendritic morphology of these allergen-presenting cells strongly facilitates multiple cell contacts, leading to binding and activation of allergen-specific T-cells. □Proliferation of specific T-cells in draining lymph nodes. Supported by interleukin-1 (IL-1), released by the allergen-presenting cells, activated T-cells start producing several growth factors, including IL-2. A partly autocrine cascade follows since at the same time receptors for IL-2 are up-regulated in these cells, resulting in vigorous blast formation and proliferation within a few days. □Systemic propagation of the specific T-cell progeny. The expanded progeny is subsequently released via the efferent lymphatics into the blood flow and begins to recirculate. Thus, the frequency of specific effector T-cells in the blood may rise to as high as 1 in 1000, whereas most of these cells display receptor molecules facilitating their migration into peripheral tissues. In the absence of further allergen contacts, their frequency gradually decreases in subsequent weeks or months, but does not return to the low levels found in naive individuals. □Effector phase. By renewed allergen contact, the effector phase is initiated, which depends not only on the increased frequency of specific T-cells, and their altered migratory capacities, but also on their low activation threshold. Thus, within the skin, allergen-presenting cells and specific T-cells can meet, and lead to plentiful local cytokine and chemokine release. The release of these mediators, many of which have a pro-inflammatory action, causes the arrival of more T-cells, thus further amplifying local mediator release. This leads to a gradually developing eczematous reaction that reaches its maximum after 1848 h and then declines. In the following sections, we will discuss these six main episodes of the ACD reaction in more detail. Furthermore, we will discuss local hyper-reactivity, such as flare-up and retest reactivity, and hyporeactivity, i.e., upon desensitization or tolerance induction.