(from the application): Autoantibodies are universally found in patients suffering from systemic lupus erythematosus. The presence of the antibodies has led investigators to conclude that SLE is an autoimmune disease. Indeed, lupus in man is probably caused by autoantibodies. In some clinical settings powerful evidence supports the conclusion that specific autoantibodies induce tissue injury and are responsible for clinical manifestations. Anti-Sm and anti-nRNP autoantibodies are commonly found at extraordinary concentrations in the sera of lupus patients. When these autoantibodies are found concomitantly they are associated with renal disease and a poor disease prognosis. Anti-nRNP autoantibodies in the absense of Sm are associated with a more limited form of lupus. Antibodies against Sm are so specific for SLE that they are considered a diagnostic criterion. This proposal sets forth to explain the development of autoimmunity in SLE. Through our previous work studying the fine specificity of autoantibodies binding to the spliceosome, we have identified over 90 peptide epitopes, 40 of which tend to be shared among patients. Using this methodology we have found that the fine specificity progresses from a small number to as many as 86 different antigenic regions from an individual patient serum. In preliminary studies, patients with anti-Sm antibodies appear to initially bind the structure defined by PPPGMRPP. This response evolves by epitope spreading to other structures of the antigen. Immunization with this peptide has led to a novel model of lupus complete with spliceosomal autoimmunity, anti-double stranded DNA antibodies, renal disease, thrombocytopenia, and seizures. Immunization with the closely related PPPGRRP sequence, which is found in a virus and which is bound by some of the autoantibodies that bind Sm, also induces anti-spliceosomal lupus autoimmunity. We suspect that there are a number of different initial epitopes that are bound by autoantibodies. We request the resources to identify the initial target epitopes of anti-Sm and anti-nRNP autoantibodies in SLE sera. We will find peptides from the environment (and, especially, from microorganisms) which are similar to the initial target epitopes and will determine if the initial target peptide epitopes from the spliceosome (and their structurally similar peptides from the environment) are cross reacting antigens. We will determine whether the peptides from the spliceosome or environment induce lupus autoimmunity after peptide immunization. This project is directly relevant to the goals of RFA: AR-97-001 and has the potential to reveal important, previously unappreciated, mechanisms of pathogenesis and to contribute toward establishing the etiology of SLE.
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