Our belief is that autoimmune disorders are usually based upon infectious agents, the autoimmunity often depending upon molecular mimicry between virally-encoded proteins and normal tissue proteins. We will explore this concept in two diseases: infectious mononucleosis (IM) and rheumatoid arthritis (RA). In IM, we have already established that IgM autoantibodies are present, which react with numerous normal tissue proteins and also with the glycine-alanine repeat in the Epstein-Barr virus (EBV) encoded EBNA-1 protein. In the IgM -- greater than IgG isotype switch of anti-EBNA-1, which occurs in an unusually delayed time scale, the antibodies lose their cross reactivities with normal tissue proteins. We will attempt to define mechanisms for this loss of crossreactivity of the anti-EBNA-1 antibodies, exploring: 1) the possible role of anti-idiotypic antibodies; 2) the nature of the T cell reactivity with EBNA-1 synthetic peptides and with fusion proteins representing the tissue antigens; and 3) the phenotypes and functional potentials of the reactive T cells. In RA, we will explore T cell reactivities with EBV-encoded antigens for two purposes: 1) to discern any possible disposition of RA patients' lymphocytes as a group to react differently from control lymphocytes with the peptides studied; and 2) to discern whether B lymphocytes with given HLA Class II characteristics, defined by classical typing sera, monoclonal antibodies, or family studies, present the peptides differently from other B lymphocytes, e.g. autoantigenically. To determine whether T lymphocytes activated in vivo as part of the RA disease process exhibit anti-EBV (EBNA-1 or LYDMA) reactivity or autoimmune reactivity, we will grow out synovial T lymphocytes in interleukin-2 with intermittent anti CD3, clone them, and then examine them against autologous B cells or synovial cells with and without added EBV-associated peptides. The presence in synovial and salivary tissues of EBV encoded antigen or EBV DNA will be sought by immunoperoxidase staining and by in situ hybridization, respectively.
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