Systemic lupus erythematosus, Sjogren's syndrome, and congenital complete heart block are unified by the presence of autoantibodies binding to Ro/SSA in a variable but substantial proportion (20% to 8O%) of patients with these diagnoses. Ro/SSA is an RNA-protein complex composed of a 60 kD peptide noncovalently bound to one of four small uridine rich RNAs. The sponsor's laboratory is dedicated to understanding the features of this autoantibody-autoantigen system from clinical and autoimmune response relationships to basic structural and antigenic characterization. Overlapping octapeptides have identified a major epitope of 60 kD Ro/SSA which is bound by greater than 50% of anti-Ro/SSA positive SLE patients. This epitope has an unexpected 7 of 8 amino acid sequence identity with the nucleocapsid (N) protein of the vesicular stomatitis virus (VSV). More unexpectedly, RO/SSA and the VSV N protein sequences share a total of six regions of short sequence identity. A reference anti-Ro/SSA serum binds five of the six regions (p=0.001), while 11 additional sera bind four of these six (p=0.003). This is the first known example of possible multiple site molecular mimicry between an autoantigen and a foreign protein. The project is designed to evaluate the fine specificity of the anti-Ro/SSA response and test the hypothesis that this response is immunologically related to VSV N protein. Overlapping peptides of both RO/SSA and VSV N will be prepared. Then the relative binding of anti-Ro/SSA and control sera will be appraised. VSV and related rhabdoviral strains will be used in antibody neutralizing assays and in Western blot assays in an effort to identify the virus most closely related to the anti-Ro/SSA response. Messenger RNA from patients and normal donors will be evaluated for the presence of rhabdovirarl sequences by the polymerase chain reaction and Southern blotting or by the direct evaluation of mRNA in Northern blots. These experiments have the potential to develop independent evidence for the presence of rhabdovirus in patients with anti-Ro/SSA autoantibodies. This project has the potential to at least preliminarily identify a pathogenic stimulus for the anti-Ro/SSA antibody.
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