VIRAL ETIOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS

点击翻译按钮获取中文摘要

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-dsDNA antibodies. The etiology of SLE is unknown but it has been postulated that viruses may play a role. One virus that has frequently been implicated in SLE is Epstein-Barr virus (EBV), a B-cell trophic virus capable of establishing a latent infection. High titers of antibody to EBV are found in the sera of young SLE patients. DNA by itself is not immunogenic, but studies with the polyoma virus T antigen have shown that the binding of this viral DNA binding protein to host DNA can render it immunogenic, and trigger an anti-dsDNA response. The aim of this project is to determine whether an EBV, DNA binding protein such as EBNA-1 can elicit the production of anti-dsDNA antibodies after binding to host DNA. Since mice are not permissive for EBV infection, one way to express EBNA-1 will be to immunize mice intramuscularly with EBV based vectors that can express EBNA-1 in mouse cells. Sera from these mice will be assayed for the presence of antibodies to EBNA1. Mice with antibodies to EBNA-1 will be subsequently tested for antibodies to dsDNA. It is proposed that the binding of EBNA-1 to dsDNA is critical for anti-dsDNA antibody production. To demonstrate this, mutants will be constructed that lack the ability to bind DNA. Mice will be immunized with these mutants to determine if they loose their capacity to elicit anti-dsDNA antibodies. Mice transgenic for the EBNA-1 sequence will also be tested for the presence of anti-dsDNA antibodies. If transgenic mice are tolerant to EBNA-1 and EBNA-1-DNA complexes, then B-cells expressing the transgene will be transferred into wild type mice and sera from the recipients will be assayed for the production of anti-dsDNA antibodies.