Patients with systemic lupus erythematosus (SLE) develop multiple autoantibodies against nuclear antigens. Antibodies against the small nuclear ribonucleoproteins (snRNPs) are of special interest since these antibodies are specific for SLE(). It is therefore important to study events that lead to production of these antibodies, since they may provide clues to the etiology of this autoimmune disease. Although anti-snRNP antibodies in SLE and its animal model, MRL mice, seem to depend on T cell help, the nature of this T cell help and the specificity of the T cells have remained unclear and there is no direct evidence to show that antigen specific T cells are necessary for this auto-antibody response. In order to study the anti-snRNP antibody response we have developed a model of anti-snRNP antibody production in normal mice. We were able to show that auto-antigen-specific anti-snRNP T cells are present in the normal mouse repertoire. We have used this experimental approach to generate and analyze autoreactive T cell hybridomas against the mouse A protein. These autoreactive hybrids are CD3+, CD4+ and seem to target a restricted region of the mouse A protein. We propose to continue these studies and analyze a panel of these hybridomas for peptide specificity and TCR gene usage and, study peripheral control of such autoreactive T cells in TCR transgenic mice. We intend to isolate the TCR gene from one of these clones and make transgenic mice in which the vast majority of the T cells carry this specific TCR. We will then look at these T cells in the transgenic mice and analyze their state of tolerance, or activation, and search for different factors that control such an autoreactive T cell population. We will cross these mice into autoimmune MRL background, to see if there are any fundamental defects in the T cell selection in these mice. Although several TCR transgenic mouse models have been used to answer specific questions about either CD4 or CD8 T cells, the TCR genes used are not against intracellular autoantigens such as snRNP proteins. These mice will be used to study events that govern selection (both positive and negative) and peripheral control of T cells against intranuclear autoantigens, in normal and autoimmune mice. We will further examine to see if the intranuclear location of the mouse A protein has any role on selection of autoreactive T cells that specifically recognize it. This will be done by generating double transgenic mice expressing the mouse A outside of the nucleus. These studies will provide important clues to the initiation of anti-snRNP antibodies which are important targets of autoantibodies in SLE.
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| Fatenejad, S; Peng, S L; Disorbo, O et al. (1998) Central T cell tolerance in lupus-prone mice: influence of autoimmune background and the lpr mutation. J Immunol 161:6427-32 |
