PHOSPHODIESTERASE STUDIES IN ATOPIC DERMATITIS

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Atopic dermatitis (AD) is a chronically recurrent cutaneous inflammatory disease which may affect up to 10% of the population. The condition is part of the atopic triad which also includes asthma and allergic rhinitis. These diseases have strong hereditary patterns but the genetics is unclear. AD is characterized by a variety of immunologic and pharmacologic abnormalities, and evidence from transplant studies indicates that the basic abnormality is expressed in bone marrow cells. Defects such as increased basophil histamine release and high spontaneous IgE production by B lymphocytes imply defective cellular regulation. Abnormalities of cyclic nucleotide metabolism have been demonstrated in AD and elevated cAMP-phosphodiesterase (PDE) activity with resultant low intracellular cAMP levels may have a net permissive effect on immune and inflammatory responses. Chromatofocusing studies of abnormal PDE have demonstrated two distinctly abnormal cytosolic fractions of PDE activity in monocytes and lymphocytes. The recent development of monoclonal antibodies to PDE's now provides us with the means to characterize and isolate abnormal enzyme forms. We will expand upon preliminary evidence for phosphorylation as a mechanism of PDE activation and study proteolytic effects on enzyme structure and activity. We will use immunodetection assays for predictive screening of atopic individuals and for identifying specific leukocyte subsets. Another major effort will be directed at induction of leukocyte activation markers and abnormal PDE mononuclear leukocytes by immune effector factors produced by AD leukocyte cultures and potentially by specific cytokines. Finally we intend to study cord blood leukocytes for elaboration of activation factors and for abnormal PDE activity as predictors of atopy and bronchopulmonary dysplasia. These studies are directed at determining primary events leading to atopy, to provide biochemical markers of disease and to clarify abnormal biochemical and immunological mechanisms associated with increased PDE in atopic dermatitis.