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Umesh S. Deshmukh^*, Janet E. Lewis^*,, Felicia Gaskin, Carol C. Kannapell^*, Samuel T. Waters^*,, Ya-huan Lou^||, Kenneth S.K. Tung^,||, and Shu Man Fu^*,

From the ^* Division of Rheumatology, Department of Internal Medicine, the Department of Microbiology, the Departments of Psychiatric Medicine and Neurology, and the ^|| Department of Pathology, the University of Virginia School of Medicine, Charlottesville, Virginia 22908

Anti-Ro60 autoantibodies are found in a variety of autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren's syndrome, primary biliary cirrhosis, and active hepatitis. They are the most prevalent autoantibodies in normal individuals and in asymptomatic mothers of infants afflicted with neonatal lupus. In the present study, immune responses to recombinant human Ro60 (rhRo60) and recombinant mouse Ro60 (rmRo60) and selected Ro60 peptides in non–SLE-prone mice were investigated. Multiple T and B cell epitopes were identified in Ro60. Immunizations with either xenogeneic or autologous Ro60 induced autoantibodies to a diverse group of autoantigens. In addition to La and Ro52, proteins in the small nuclear ribonucleoprotein (snRNP) particles such as SmA, SmB, SmD, and 70-kD U1-RNP were unexpectedly identified as targeted antigens. In the studies involving synthetic Ro60 peptides, both human and mouse Ro60_316–335 peptides, which differ in three amino acids, were found to contain dominant cross-reactive T cell determinants. Immunizations with these peptides induced autoantibodies to Ro60, La, SmD, and 70-kD U1-RNP without autoantibodies to Ro52, SmA, or SmB. With human Ro60_316–335 as the immunogen, additional autoantibodies reactive with the Golgi complex were found. In contrast to the immunodominance of both human and mouse Ro60_316–335 peptides, the T cell determinant in human Ro60_441–465 was dominant, whereas that in the mouse peptide was cryptic. Immunization with human Ro60_441–465 induced primarily anti-peptide Abs. Mouse Ro60_441–465 failed to induce an antibody response. These results show that both the nature of the immunogen and the immunogenicity of the related endogenous antigen are important in determining the specificities of the autoantibodies generated. They have significant implications for proposed mechanisms on the generation of complex patterns of autoantibodies to a diverse group of autoantigens in SLE patients.

Key Words: systemic lupus erythematosus • determinant spreading • tolerance • autoimmunity • T and B cell epitopes

Abbreviations used: ANA, antinuclear antibody; DHFR, dihydrofolate reductase; LNC, lymph node cell; MAP, multiple antigenic peptides; rhRo60, recombinant human Ro60; rmRo60, recombinant mouse Ro60; SI, stimulation index; SLE, systemic lupus erythematosus; SS-A, Sjögren's syndrome-A; SS-B, Sjögren's syndrome-B; snRNP, small nuclear ribonucleoproteins.

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