ENDOGENOUS RETROVIRUSES AS A CAUSAL MECHANISM IN LUPUS

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Endogenous retroviruses (ERV) are potential etiologic agents in human and murine autoimmunity. A class of ERV, Mpmv, is transcribed in thymuses of 5 lupus-prone but in none of 11 control mouse strains. In lupus-prone mice, thymus Mpmv RNA expression is abnormal from day one of life, suggesting that it may be closely linked to genes which predispose to autoimmunity. To determine whether the proteins encoded by Mpmv directly contribute to autoimmunity, their expression will be blocked in transgenic lupus mice. Our preliminary data and published reports from four different groups targeting other genes (including a retrovirus) indicate the potential utility of antisense RNA for manipulating Mpmv expression in transgenic mice. Using a T cell line that highly expresses Mpmv RNA and protein, we will test multiple constructs expressing antisense RNA to different Mpmv sequences under different promoters and enhancers. Initially, we will focus on the CMV-based vector previously used successfully in transgenic mice to protect against infectious retrovirus by expressing antisense RNA. The most promising vectors identified by stable transfection into the T cell line will be used to generate transgenic lupus-prone mice, which will then be studied to determine if the disease phenotype has been altered. Previous genetic studies using recombinant inbred and backcross mice have demonstrated that several autoimmune traits segregate independently. To determine whether thymus Mpmv RNA expression may cosegregate with a particular feature of autoimmunity, we will perform Northern analyses of well-characterized recombinant inbred lines between lupus-prone NZB and control SM/J mice. Finally, the present application will pursue our preliminary studies which indicate that Mpmv transcription results from a dysregulation of gene expression in lupus. The DNA sequences responsible for abnormal Mpmv transcription in lupus-prone mice will be identified and characterized. Since abnormal gene regulation in lupus is not well understood, studies of the regulation of Mpmv expression could lead to new insights into the molecular genetic defects of human and murine lupus.