The applicant seeks a research project grant (RO1) to elucidate the mechanisms of B lymphocyte tolerance. The long-term goal of the project is to understand how autospecific B-cells are controlled, to determine if autoimmune-prone mouse strains have intrinsic B-cell tolerance defects, and, if so, to localize the genes involved. As a basis for this study, mice transgenic for functionally rearranged anti-H-2Kk IgM/IgD antibody genes have been generated. In these mice B- cells are tolerized in the presence of the appropriate class I antigens.
The Specific Aims of this proposal are as follows: 1. To determine the mechanisms of peripheral tolerance in autospecific B-cells. We will follow up the results we obtained in our initial grant with the analysis of tolerance to peripherally-expressed antigen. To do this we will analyze tolerance to membrane autoantigen that is not expressed in the bone marrow, where B-cells develop in the adult mouse, but on the surfaces of cells found in other organs, such as the liver, skin and pancreas. In this analysis we will take advantage of existing transgenic mice, produced by others, that target the expression of the low affinity ligand Kb to these peripheral tissues. This approach works because the antibody encoded by the transgenes has a low, but physiologically significant affinity for the Kb antigen. 2. To determine the influence of autoimmune-prone genetic background on self-tolerance to peripheral membrane antigen. We have already established that in at least one transgenic line expressing Kb in the periphery, autospecific anti-H-2K B-cells are tolerized by deletion. We will cross these transgenes onto autoimmune-prone strains of mice to determine if they manifest a B-cell tolerance defect to Kb antigen in this double transgenic system. 3. To begin the chromosomal mapping of a background gene of MRL strain mice that appears to favor the breaking of self-tolerance in the B-cells of MRL/lpr/3-83 transgenic backcross mice. We will use the most modern technique in classical genetic mapping, including taking advantage of polymorphic DNA microsatellite polymerase chain reaction markers. In this process we will determine if the transgenic system provides advantages of speed and accuracy to the mapping of genes that affect autoimmunity.
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