Atopic dermatitis is a cutaneous inflammatory condition which usually occurs in persons with a personal or family history of one or more atopic diseases (i.e., asthma, allergic rhinitis or atopic dermatitis). Each of these conditions may show evidence of immunologic and pharmacologic dysfunction, but such aberrancies tend to be most pronounced in topic dermatitis. This project is focused on the molecular basis of immunologic and pharmacologic interactions. These studies have utilized mononuclear leukocytes which manifest a number of immunologic abnormalities in atopic dermatitis. Our studies have also demonstrated abormalities of cyclic nucleotide metabolism in patients' cells. Cyclic AMP-phosphodiesterase activity is elevated and membrane beta-adrenegic receptor binding is altered in atopic leukocytes. Similar changes are induced in normal mononuclear leukocytes exposed to low concentrations of histamine. It seems probable that these changes have a common origin and identifying the basic molecular site of alteration may lead to an understanding of pathomechanisms in atopic disease. Histamine causes changes in mononuclear leukocytes and provides a useful probe for delineating molecular defects in atopy and for clarifying the effects of the inflammatory mediator on immune-associated cells. The action of histamine on receptor binding, adenylate cyclase activity, protein kinase activity and cyclic AMP turnover will be determined, thus providing comprehensive assessment of various steps in the cyclic nucleotide pathway. Comparisons with mononuclear leukocytes of patients with atopic dermatitis will be made at each step to confirm the usefulness of the histamine model. In addition, pertussis toxin, recently shown to act on a specific subunit of the adenylate cyclase regulatory unit, will be evaluated for similarities to hisatmine-induced and atopic cellular abnormalities. This toxin has long been known to induce atopic characeristics in animals. The above studies relate to the adenylate cyclase linked receptor system. In addition, recent studies show a second major class of receptors linked to inositol phospholipid metabolism. Preliminary evidence indicates involvement of this pathway in atopic and histamine-treated normal mononuclear leukoycytes. Further investigations of inositol phospholipid metabolism will allow evaluation of abnormalities and relationships with1the cyclic nucleotide system in atopic dermatitis.
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