GENETICS AND REGULATION OF THE IG VH REGION

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This study represents a continuation of basic research on the genetics and regulation of immunoglobulin production with emphasis on the variable region (VH) of the heavy chain. The rabbit is used in these studies due to its well defined genetically-determined VH allotypes and the unique characteristics of antibody against these allotypes. The relationship between the VH allotypes and immunoglobulin idiotypes will be investigated from two perspectives. In one project the relationship between VH subgroups will be probed by assaying for the occurrence of crossreactive idiotypes between and within Ig populations expressing the VH subgroups. Anti-idiotype antisera will be raised against antibody to a simple and a complex antigen. The occurrence of crossreactive idiotypes in these experiments would support theories involving network regulatory interactions and might be indicative of shared genetic elements between distantly related VH subgroups. Alternatively, the presence of idiotypes which are restricted to a given subgroup may be revealed. In a second series of experiments, VH allotypes will be used as an antigen to induce anti-allotype antibody. This antibody has already been shown to express a remarkably high proportion of crossreactive idiotype in all rabbits tested. These observations have lead to speculation that the anti-allotype repertoire of the rabbit is highly conserved with the implication that it serves an important role in regulating allotype expression. It has been further suggested that the allotype, anti-allotype, anti-idiotype network is generated as a result of sequential negative and positive steric images (internal images). We propose to test these assumptions by comparing the immunobiological and immunochemical characteristics of antibody preparations raised in the rabbit to those raised in other non-rabbit species. The comparisons will be carried out using conventional serological methods (radioimmunoassay, affinity chromatography, isoelectric focusing) as well as by the use of allotype and idiotype suppression, monoclonal antibodies and immunoelectron microscopy. Regulation of immunoglobulin-production has important implications with regard to certain types of immunodeficiency diseases as well as myelomas and leukemias.