TRANSGENIC MODEL FOR B-CELL TOLERANCE AND AUTOIMMUNITY

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The goal of this study is to examine the development and expression of B cells specific for a disease-associated self-antigen, DNA, in nonautoimmune and autoimmune mice. We have developed a transgenic (TG) model system using multiple sets of TGs: the Vh3H9 heavy chain-only TG, which when paired with endogenous light chains generates a spectrum of anti-DNA and non-Dna binding antibodies; the Vh3H9 heavy chain TG mated to a Vkappa8 light chain TG resulting in an essentially monospecific anti-single strand (ss)DNA repertoire; and the Vh3H9 heavy chain TG mated to either a Vlambda1 or a Vlambda2 light chain TG, both of which when paired with the Vh3H9 heavy chain bind ss and double strand (ds)DNA, but with different affinity. Tolerance to DNA is manifested in different ways in these TGs. In the Vh3H9/Vkappa8 TGs the anti-ssDNA B cells dominate the repertoire yet they are functionally silent, they are tolerized. We will investigate what the cellular basis preventing anti- DNA expression is in these mice. The Vh3H9 TGs extend the model to show that different mechanism of B cell tolerance operate in normal mice on B cells with anti-dsDNA specificity: anti-dsDNA B cells are deleted or have drastically down regulated their surface immunoglobulin (Ig). The fate of the anti-dsDNA B cells in normal versus autoimmune animals will be studied. We have evidence that the Vh3H9/Vkappa8 TGs are expressed when in an autoimmune genetic background. What is not clear is what changes lead to their expression. The extent and the clonality of the TG anti-DNA expression will directly address the etiology of autoimmunity. We want to know why tolerance to DNA is manifested in different ways. How the detailed specificity and avidity of the anti-DNA antibodies influence the way a B cell is regulated will be addressed using the various combinations of TG heavy and light chain TGs. The anti-DNA antibodies generated from these TGs are heterogeneous with respect to the form of DNA they recognize, the extent of reactivity with structurally related molecules, and the avidity they have for DNA. We are in a position to determine which of these parameters are significant in determining the fate of a B cell in normal mice. The direct relationship between expression of certain kinds of anti-DNAs and pathology is controversial. It is not at all established which ant- DNA antibodies are present in normal animals and which are present and contribute to disease in autoimmune animals. The potential range of anti-DNA antibodies that can be expressed by the TGs may provide an opportunity to correlate the expression of particular anti-DNA antibodies with disease. The ultimate goal of this research is to be able to cure autoimmunity. Through the use of the enriched population of anti-DNA antigen presenting cells (APC) we may learn the nature of the in vivo antigen and eventually design methods to interfere with the anti-DNA/self interaction.