This project represents and integrated approach for evaluating several molecular aspects of B lymphocyte function. The unifying theme of the program is the study of the two types of polymorphic molecules that serve as both receptors and recognition sites on the B cell membrane, immunoglobulin (Ig) and major histocompatibility complex-encoded class I and class II molecules. The program is composed of three research projects and a core facility, whose function is to provide various support services. In project I, Dr. Corley will analyze the antigenic and idiotypic diversity of the immunoglobulin repertoire specific for senescent erythrocytes. As a major component of this study, he will determine the number and sequences of the germ line genes encoding this response, and ask if somatic events alter the nature of the response to this endogenous autoantigen. Since the idiotypic profile of this response is controlled by Ir genes, this study should advance our understanding of the interrelationship between recognition of class II molecules and immunoglobulin expression. In project II, Dr. Argon will study the intracellular transport of class II and immunoglobulin molecules in cells of the B lineage, and identify the compartments in which post-translational modifications occur. The transport of these endogenous molecules will be compared with that of an exogenous viral glycoprotein in infected B cells. Dr. Argon is using a drug that reversibly inhibits the intracellular transport of membrane and secretory proteins. This work may provide ways to modulate the surface expression and secretion of various molecules. Dr. Cresswell, in project III, will complement these studies by evaluating the interactions between the intracellular transport pathways of class I and class II molecules, and the endocytic pathways taken by internalized ligands. The role of the class II antigen-associated invariant chain in class II transport will also be examined, using invariant chain-negative mutants of B cell lines. He will also antigens following lysosomal degradation. Results from these three projects will enhance our understanding of how B lymphocytes recognize, respond to, and process antigens.
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