Response in the immune system involves one of the most complex genetic and physiological series of activities that are known in eukaryotes. One of the primary components, which acts as both a receptor and an effector, is the immunoglobulin molecule. My objectives are to understand how and when structural diversity in these antibody molecules originates and how this structural diversity translates into functional (binding site) diversity. We are also interested in the biological significance of this functional diversity. We use the immune response to the natural hapten, phosphocholine (PC) as a model since considerable information about the families of responding antibodies, their conservation and diversification in mice, the structure of their heavy and light chains, and encoding gene families is known. Additional monoclonal (hybridoma) antibodies will be sequenced, especially in the DH region, in order to determine the extent of diversity and patterns that occur. Functional diversity will be measured in binding assays for both hapten and neighboring carrier determinants using a battery of PC analogues and natural PC-antigens. The biological relevance of anti-PC antibodies will be assessed in protection experiments in mice receiving hybridoma antibodies and infected with two pathogens. Streptococcus pneumoniae and Proteus morganii. Using selected monoclonal anti-idiotopes we will follow the ontogeny of antibody specificities (individual idiotypes) in normal mice and their expression following immunization with structurally different PC antigens. These studies are in part designed as a prelude to the development of monoclonal anti-PC antibodies which may be used in immunotherapy against human pathogens. Finally, we will study diversification mechanisms at the DNA level for two anti-PC light chains. We are particularly interested in determining the basis for a genetic polymorphism in VK22, how many members of this L chain gene family contribute to anti-PC antibodies and what role JK plays in VK24 L chains.
Showing the most recent 10 out of 11 publications
