The structure of antigen has profound effects on its perception by the immune system. Antigen valence, affinity, and size as well as association with ligands for accessor receptors are critical to its ability to induce important functional effects in B cells, including tolerance, activation (signal 1), proliferation and efficient antigen presentation to helper T-cells. Any such functional effects of antigen structure must reflect the quality or quantity of the signal transmitted through membrane immunoglobulin and its associated Ig-alpha and Ig-beta subunits, which comprise the B cell's receptor for antigen (BCR). Compelling evidence indicate that this signal is negatively modulated by immune complex coligation of BCR and CR2. The goal of this project is to identify how the B-cell perceives and interprets structural differences in antigens through its BCR and accessory receptors for IgG and C3d. To address these questions we have chosen to use immunoglobulin gene transgenic mice as a source of antigen-specific B-cells. Using a combination of heavy and light chain genes that encode antibody of defined specificity, mice can be designed which produce a large, homogeneous population of normal B-cells of predetermined specificity and affinity. This property of immunoglobulin gene transgenic mice facilitates a number of in vivo and in vitro studies by eliminating the extreme variability and heterogeneity of B-cell specificity of the normal immune system. B-cells from these transgenic mice will be challenged with synthetic polymers substituted with various amounts and densities of small haptens or peptides that are recognized by the antigen combining site of the transgenic B- cell's sIg receptors. In some cases these polymers will be modified with antibodies or antibody plus complement. In producing these antigenic conjugates, we will take advantage of the most modern techniques in conjugate design, production, and quality control. We will systematically analyze conjugates of different structure both for immunogenic and tolerogenic effects and then determine how these different functional effects correlate with early activation and signal transduction events. We seek to define the molecular mechanisms by which unique, structure determined signals are transduced. The long term goal is to apply this knowledge to the design of immunogenic and tolerogenic vaccines and to the development pharmacologic agents for immunological intervention in immunodeficiency and autoimmunity.
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