The applicant has for some time been studying the antibody response to dsDNA that characterizes the autoimmune disease, systemic lupus erythematosus. She has shown that anti-dsDNA antibodies are encoded by somatically mutated variable region genes and are structurally similar to antibodies to foreign (bacterial) antigen. In a series of experiments performed in mice, a novel fusion partner, NSO bcl-2 that constitutively expresses the bcl-2 anti-apoptosis gene has been shown to rescue auto-reactive B cells that routinely arise by somatic mutation during the course of an immune response to the pneumococcal hapten phosphorycholine. The studies now proposed are designed to determine whether in the course of a human immune response to pneumococcus, B cells are generated which acquire dsDNA binding as a result of somatic mutation. The applicant will compare the splenic B cell response to pneumococcal polysaccharide of SLE patients and of non-autoimmune individuals. She will develop B cell geneologies to see when in the course of B cell activation, autospecificity is generated and when, in non-autoimmune individuals, DNA binding B cells are eliminated. In addition, she will study the pathogenicity of anti-dsDNA antibodies by analyzing the fine specificity differences among anti-dsDNA antibodies using peptide libraries to identify mimotopes for dsDNA. Using these peptides and in vivo assays of antibody deposition in the kidney, she will determine if there are correlations between fine specificity and pathogenicity. Analysis of peptide mimotopes may also provide clues to protein antigens that might be involved in either the activation or target organ binding of anti- dsDNA antibodies. These peptide mimotopes may constitute valuable new reagents that can be explored as therapeutics, both to block anti-dsDNA deposition in tissue and to induce tolerance in pathogenic B cells.
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