Current information suggest that eosinophils have, in addition to anthelminthic properties, a proinflammatory role in disease. Prior observations showed extensive deposition of a toxic, cationic eosinophil granule protein, the major basic protein, in atopic dermatitis and a relative paucity of intact eosinophils. These results indicate that eosinophil degranulation occurs in atopic dermatitis. The long-term goal of this proposal is understanding the role of the eosinophil in atopic dermatitis. First, the inflammatory reaction and the mechanisms of the inflammatory reaction in atopic dermatitis will be studied by: (a) testing whether eosinophil granule protein deposition occurs in all the various morphologic lesions of atopic dermatitis and in all stages of the disease and whether eosinophil degranulation, as judged by granule protein deposition in tissue and granule protein elevation in blood, is associated with disease activity; (b) testing the hypothesis that eosinophil degranulation occurs through both IgE- mediated mechanisms and IgE-independent responses including the study of atopic dermatitis patients with low levels or absent serum IgE as an """"""""experiment of nature""""""""; and (c) testing whether neutrophil elastase deposition discriminates between the inflammatory reaction in atopic dermatitis and the urticarias. Preliminary studies indicate that neutrophil elastase deposition is striking in the IgE-mediated late phase reaction and the physical urticarias but is essentially absent in atopic dermatitis. Second, because high concentrations of toxic eosinophil granule proteins are deposited in the skin, the effects of granule proteins on epithelium and mast cells will be analyzed by: (a) testing the effect of eosinophil granule proteins on keratinocyte proliferation and differentiation, (b) testing the proteins for their ability to stimulate mast cell histamine release, and (c) testing whether exposure of mast cells to major basic protein induces synthesis of this granule protein. The information derived from these studies is important for understanding and, thus, for development of new therapeutic approaches to this vexing disease.
