PHOSPHODIESTERASE STUDIES IN ATOPIC DERMATITIS

Atopic dermatitis is an inflammatory skin disease that comprises, along
with asthma and allergic rhinitis, the triad of conditions known as the
atopic diseases. These conditions are hereditary and are common causes of
social and occupational morbidity. Disease mechanisms are uncertain and
there are no satisfactory means of prevention or cure. Diagnosis is
imprecise due to lack of distinct laboratory tests. Atopic dermatitis has
the most pronounced immunologic and pharmacologic aberrancies and we have
studied these abnormalities for clues as to basic causative factors. Our
long-term objectives are to delineate the basic pathologic mechanisms and
to identify a discrete laboratory indicator of the disease. Our studies have compared atopic and normal blood leukocytes. The latter
show biochemical similarities to atopioc cells after exposure to mediators
such as histamine, prostaglandin E1 and isoproterenol. This model led to
our observation of abnormally high cyclic AMP-phosphodiesterase (PDE) in
leukocytes of patients with atopic dermatitis and other atopic conditions.
This project is focused upon biochemical characterization of the abnormal
PDE in atopic leukocytes and on comparative studies of the PDE in normal
lymphocytes and monocytes stimulated with histamine and other mediators.
This model should provide a means for evaluating the role of
phosphorylation and other mechanisms which may lead to abnormal PDE enzyme
forms. Studies with inhibitors may provide insight into new pharmacologic
modalities for treating atopic dermatitis. Recent investigations have
utilized chromatofocusing as a novel means of biochemical identification
and have shown two distinct abnormal fractions of PDE activity in atopic
leukocytes. Future extensions of these studies should allow clarification
of the exact cell source of these enzyme forms and whether they are
identical with those in histamine stimulated cells. Collaborative studies
of the Basenji-Greyhound dog model of asthma have shown leukocyte cyclic
nucleotide abnormalities and elevated PDE similar to atopic humans.
Biochemical identification of abnormal PDE along with newly developed
specific antibodies to various PDE forms may provide a means of precise
diagnostic, and predictive epidemiologic and genetic studies of atopic
dermatitis and the other atopic diseases. Cyclic GMP synthesis and
metabolism in these cells will be assessed to evaluate the possibility of
imbalanced cyclic nucleotide regulation as an alternate cause of functional
defects in atopy.