Autoantibodies that react with cellular components occur in high frequency in patients with systemic rheumatic diseases. The basis for this phenomenon is unknown. The autoantigen, La, a conserved cellular phosphoprotein, is the target for immunological response in a significant number of patients with Sjogren's syndrome-sicca complex (60% of cases) and with systemic lupus erythematosus (approx. 10% of cases). One hypothesis suggests that molecules normally sequestered intracellularly become """"""""neoantigens"""""""" by virtue of complexing with foreign molecules such as viral products, and become immunogenic in certain individuals when released from damaged tissue. La antigen binds RNA and interacts directly with small RNAs encoded by adenovirus, Epstein-Barr virus, and vesicular stomatitis virus. La protein functions in the stabilization and/or transport of cellular, (as well as viral), small RNAs with 3' U-rich termini. We propose to (1) obtain the amino acid sequence of the epitopes in La protein that are recognized by patient anti-La antibodies using techniques in protein biochemistry and immunology (SDS-PAGE, amino acid sequence analysis, immunoblotting); (2) characterize the RNA-binding site for adenovirus VA RNA I on purified La protein using our RNP """"""""reconstitution"""""""" assay, VA RNAs transcribed in vitro, cross-linking with U.V. irradiation, and protein and RNA PAGE; and (3) study the genetics of La antigen by (a) isolating the La gene(s) from a mouse genomic library using our La cDNA clones as probes for DNA hybridization, and (b) characterizing our La clones at the DNA level by recombinant cloning, DNA sequencing, Southern and Northern hybridization. The study of La protein antigenicity, RNA-binding function (a property shared with several other antoantigens), and genetics might help to elucidate its role in human autoimmune disease.
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