CD4+ T cells mediate autoimmune disease in a new transgenic murine model induced by U1 RNA and U1-70kD ribonucleoprotein self antigens (130.4)

Abstract

Abstract C57BL/6 mice transgenic (Tg) for the human major histocompatibility complex gene HLA-DR4 were immunized with U1 RNA and a fusion protein spanning the RNA binding domain of the U1-70kD polypeptide, control fusion protein, with or without U1-RNA, or saline. Complete serologic and histologic analyses were performed on all mice. CD4+ T cells and APCs were isolated from immunized mice using immunoaffinity columns and tested for proliferation. Either freshly isolated CD4+ T cells from immunized mice or T cell lines were adoptively transferred to unmanipulated HLA-DR4 Tg or RAG−/− mice. Freshly isolated CD4+ T cell from immunized DR4 Tg mice proliferated in response to U1-70kD and to synthetic peptides from the RNA binding domain region of the protein in the presence of irradiated autologous APCs. We found that CD4+ T cells specific for U1-70kD were able to transfer disease to unmanipulated syngeneic mice. Furthermore, using purified CD4+ T cells or T cell lines specific for U1-70kD we were able to transfer disease to RAG−/− mice in the absence of detectable B cells or autoantibodies. In conclusion, we have developed a new model of systemic autoimmunity that is induced following a single exposure to U1-RNA and its associated RNA binding protein. Anti-U1-70kD autoantigen-specfic CD4+ T cells appear to medicate pathogenesis of disease in this model and can do so in the absence of detectable B cells or autoantibodies. This work was supported by NIH award AR43308 (RWH), the Lupus Foundation of American (RWH) and Department of Veterans Affairs Merit Review awards (RWH & ELG).