IMMUNOPATHOGENESIS OF RUBELLA VIRUS ASSOCIATED AUTOIMMUNE DYSFUNCTION

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Complications of natural rubella infection or immunization with attenuated rubella vaccine in adult women include transient and chronic arthritic symptoms. Because 25% of adult RV vaccinations result in acute or chronic arthritis in adult females, it would be useful to understand the events leading to these complications. Potentially this would lead to improvements in RV vaccination. In order to understand the molecular mechanisms underlying RV-associated disease, we have been studying the mechanism of RV replication. We have identified the cis-acting elements, stem-loop structures present at the 5' and 3' terminus of RV RNA, necessary for virus replication. Further, we have characterized the host-encoded proteins which interact with these elements. The 5' (+) SL RV RNA binding protein is a homologue of the Ro/SS-A antigen, whereas the 3' (+) SL RV RNA binding protein is a homologue of human calreticulin. Further, characterization of the Ro-SSA autoantigen binding to the 5' end of RV RNA, identified it as the La autoantigen by immunoprecipitation using mono-specific La human sera and a rabbit serum raised against recombinant La. Specific interaction of La with the RV 5' (+) SL RNA was demonstrated both in vitro and in vivo. The importance of the 5' (+) SL RV RNA in translation was also demonstrated in vivo using Lucifersae reporter RNA. The interaction of both La antigen and calreticulin with RV RNA is of clinical interest because antibodies to these proteins have been found in many autoimmune diseases. We have investigated whether human serum from individuals suffering from various autoimmune dysfunctions could recognize the cellular proteins associated with the RV RNAs. A subset of sera from individuals with Sjogren's syndrome (SS) or Systemic Lupus Erythematosus (SLE) immunoprecipitated the RV RNA-protein complexes. The reactivity of the sera with RV 5' and 3' (+) SL RNA-protein complexes correlated with the ability of the sera to recognize either the La or the Ro and La autoantigens. We also observed a significant anti-La activity in RV infected individuals 2 years post-infection. The association of cellular antigens with the RV cis-acting elements and antibody response to such complexes in autoimmune patients, suggest that similar events may occur at the initiation of autoimmunity in chronic RV infections following natural infections or immunization. Currently, the role of both the La antigen and calreticulin in understanding the etiology of chronic rubella virus vaccine-associated arthropathy is being investigated.Publication:Pogue, G. P., Hofmann, J., Duncan, R. D., Best, J. M., Etherington, J., Sontheimer, R. D., Nakhasi, H. L. (1996) J. Virol. 70, 6269-6277.