| Virginia Commonwealth University |
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Research Interests : Approximately one third of the U.S. population suffers from IgE-mediated allergic disease. The high incidence of IgE-mediated allergic disease in man has lead to a strong commitment to understanding the basic mechanisms involved in IgE-mediated conditions with the objective of developing new methods for alleviation or even elimination of human allergy. My laboratory is thus, interested in investigating agents that regulate IgE production. One of our newest findings is that agents that activate protein kinase C, such as bryostatin and PMA, have a specific inhibitory action on IgE production. The mechanism of this activity is currently under investigation. As the lead in indicates, the laboratory is especially interested in the structure and function of CD23, which has as one of its main roles, regulation of IgE synthesis. CD23 is a member of the calcium dependent animal lectin family and the lectin "cassette" is located in the carboxy terminal region of the molecule. CD23 acts as a low affinity receptor for IgE and this capacity led to its initial discovery. CD23 exists as a homotrimer at the cell surface and as the picture indicates, interacts with IgE in a divalent manner - two of the lectin head groups interacting with specific (but different) sites on the Ce3 domain of IgE. The stalk region of the molecule, which is the part between the lectin head and the membrane surface, is thought to interact as a coiled-coil structure - and this interaction leads to the homotrimer formation. CD23 is cleaved by an as yet unidentified metalloprotease - the arrows in the diagram show the approximate sites of the two cleavages. This results in a monovalent CD23, since there is not sufficient stalk left to make a stable coiled-coil. The homotrimeric structure can be further stabilized by the addition of a modified isoleucines zipper to the amino terminus of the stalk. This allows a soluble CD23 with full IgE binding capacity to be produced. The affinity - or a better term would be avidity - of the chimeric CD23 is sufficient to block binding of IgE to the high affinity mast cell IgE receptor. We are currently determining the minimum amount of stalk that is necessary to make the isoleucines zipper chimera that has full IgE binding activity. CD23 is induced to higher level expression by the same cytokines that induce IgE production, namely IL-4 and IL-13, indicating that these cytokines both induce IgE as well as a controlling agent for the same. Strong evidence for a role for CD23 in regulating IgE synthesis comes from the analysis of CD23 transgenic mice, which exhibit reduced levels of IgE production in a number of model systems. The mechanism via which CD23 exerts these functions is currently under investigation, however, initial studies point to a role of CD23 expression on follicular dendritic cells as being an important in this activity. In addition, the trimeric structure of CD23 is important in the regulatory activity. This is shown with recent studies involving antibodies against the stalk region of CD23, which both block the trimerization and enhance IgE synthesis in animal models.
Current Projects and Responsible Personnel:
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