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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Oregon Health and Science University
Schools of Medicine
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Chan, S C; Reifsnyder, D; Beavo, J A et al. (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol 91:1179-88
Hanifin, J M; Lloyd, R; Okubo, K et al. (1992) Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis. J Invest Dermatol 98:100S-105S
Barker, A F; Hirshman, C A; D'Silva, R et al. (1991) Airway responsiveness in atopic dermatitis. J Allergy Clin Immunol 87:780-3
Hanifin, J M (1990) Phosphodiesterase and immune dysfunction in atopic dermatitis. J Dermatol Sci 1:1-6
Trask, D M; Chan, S C; Sherman, S E et al. (1988) Altered leukocyte protein kinase activity in atopic dermatitis. J Invest Dermatol 90:526-31
Ebertz, J M; Hirshman, C A; Kettelkamp, N S et al. (1987) Substance P-induced histamine release in human cutaneous mast cells. J Invest Dermatol 88:682-5
Austin, D R; Chan, S C; Hanifin, J M et al. (1987) Cyclic nucleotide function in trachealis muscle of dogs with and without airway hyperresponsiveness. J Appl Physiol 63:2309-14
Ebertz, J M; Hermens, J M; McMillan, J C et al. (1986) Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release. Agents Actions 18:455-62
Holden, C A; Chan, S C; Hanifin, J M (1986) Monocyte localization of elevated cAMP phosphodiesterase activity in atopic dermatitis. J Invest Dermatol 87:372-6
Cooper, K D; Chan, S C; Hanifin, J M (1985) Lymphocyte and monocyte localization of altered adrenergic receptors, cAMP responses, and cAMP phosphodiesterase in atopic dermatitis. A possible mechanism for abnormal radiosensitive helper T cells in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 114:41-7

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