IRRITANTS EFFECTS ON EPIDERMAL ANTIGEN PRESENTATION

点击翻译按钮获取中文摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) Irritant contact dermatitis (ICD) is a common and clinically important type of inflammatory skin disorder, and is thought to be the result of non-immunologic inflammation resulting from chemical injury to the skin. This is in contrast to allergic contact dermatitis (ACD), in which hapten specific CD4+ T-lymphocytes are thought to be critical in the immunopathogenesis of this type of dermatitis. However, previous clinical, histologic and immunologic research studies comparing irritant to allergic contact dermatitis indicated that in most assays, these two types of dermatitis are similar, if not identical. We hypothesize that irritant and allergic contact dermatitis share common pathways of immune-mediated skin damage, resulting in the common phenotype of the two kinds of contact dermatitis. Irritants and allergens damage the epidermis, resulting in the release of self-antigens. We hypothesize that these self-antigens are presented to auto-reactive T-lymphocytes by epidermal antigen presenting cells (APC), which are central to the pathogenesis of both irritant and allergic contact dermatitis. To test our hypothesis, we will study the direct effects of irritants on human keratinocytes (KC) and Langerhans cell (LC)-like dendritic cells (DC) in their expression of adhesion molecules and cytokines that are known to be critical for regulating APC-functions or T-lymphocyte growth. Antigen presentation by normal or irritant-treated epidermal KC or LC-like DC cells to skin homing T-lymphocyte populations will be studied. The autologous mixed lymphocyte reaction will be used a model for presentation of self-antigens to autoreactive T-lymphocytes by irritant-stressed epidermal APC. The following T-lymphocyte populations will be studied for autoreactivity against irritant-treated APC: Skin homing T-cell populations (Cutaneous leukocyte antigen+) (CLA) derived from the peripheral blood; T-lymphocytes that infiltrate into irritant skin challenge sites; or non-classical T-lymphocytes (CD4-CD8-, T-cell receptor y/8 bearing) derived from normal human epidermis. These studies will define novel immunologic mechanisms of ICD, and will lead to a better understanding of the effects of irritants on the regulation of APC function and the subsequent interactions with skin homing T-lymphocytes. Some of these assays may be useful as an in vitro to identify individuals at risk for irritancy. Since ICD can be a debilitating skin problem that potentially affects millions of Americans, the identification of individuals at risk for irritancy using in vitro tests would be of utility in preventing this common and potentially disabling condition.