The presence of autoantibodies has led investigators to conclude that systemic lupus erythematosus is an autoimmune disease. Indeed, systemic lupus erythematosus in man is probably caused by autoantibodies. Specific autoantibodies are associated with particular clinical manifestations of lupus and in some clinical settings very powerful evidence supports the conclusion that specific autoantibodies induce tissue injury and are responsible for clinical manifestations. Anti-Sm and anti-nRNP are commonly found at extraordinary concentrations in the sera of lupus patients. The Sm and nRNP autoantigens have been identified as components of the spliceosome complex which provides cells with the capacity to remove introns from heteronuclear RNA. The anti-Sm portion of this anti-spliceosome response is thought by many to be especially specific for lupus patients. The goals of this proposal are simple. We hereby request the resources to identify the components of the anti-spliceosome response in human lupus patients, to determine the degree to which the anti-Sm and anti-nRNP responses of human lupus patients can be imitated by animal models, to test theories of the immune mechanism of autoimmunity, and to explore the sequence variations which permit anti-spliceosomal autoimmunity in animals. We conclude that this project is directly relevant to the goals of RFA: AR-93-005 and has the potential to reveal important, previously unappreciated Causal Mechanisms in Systemic Lupus Erythematosus.
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