Role of Epidermal Keratinocytes as Key Initiators of Contact Dermatitis Due to Allergic Sensitization and Irritation

Abstract

Traditionally, dermatologists have attempted to clinically distinguish between contact dermatitis due to allergic sensitization/ellicitation versus irritation. Investigative immunodermatologists interested in the similarities/differences of these common clinical problems, have previously focused primarily on epidermal Langerhans cells and T lymphocytes. The epidermal keratinocyte was never seriously considered to actively participate either in the genesis or perpetuation of contact dermatitis reactions. This oversight has led to a view (which is more of a myth) of the keratinocyte as an inert collection of keratins and lipids. In this presentation, data is presented from the author's laboratory, and that of others, which clearly demonstrate that keratinocytes in vitro and in vivo possess the capacity to directly respond to a wide variety of pro-inflammatory and immunologic exogenous stimuli, by producing highly potent primary cytokines, mononuclear cell chemotaxins, and adhesion molecules. Indeed, a compelling case can be made that instead of viewing the keratinocyte as the least important constituent of the skin immune system, that it can be designated as a key cutaneous immunocyte. Moreover, returning to the practical problem of distinguishing between irritant and allergic contact reactions, we propose that many of the overlapping clinical and histological characteristics are directly related to the remarkable versatility of the keratinocytes to initiate a common pathophysiological cascade of molecular events that influence adjacent resident and recruited cells. In other words, the activation of keratinocytes is a critically important cellular link shared by both irritant and allergic contact dermatitis reactions of highly diverse etiologies. One of our principal challenges for the future will be to understand how the keratinocyte can convert such a wide variety of exogenous stimuli (ie, urushiol, sodium lauryl sulfate, croton oil, ultraviolet irradiation, etc) into a final common pathway of cytokines, chemotaxins, and adhesion molecules. Given the resourcefulness of keratinocytes as reviewed in this article, it is understandable why nature has selected this particular cell type to occupy greater than 90% of the epidermal compartment. By directly interfacing with the external milieu the keratinocytes as a functional unit can subserve an “environmental protection function,” to maintain the constancy of the internal milieu despite a perpetual onslaught of exogenous noxious stimuli.