Mycoplasma arthritides superantigen (MAM) is one of several secreted microbial toxins termed superantigens in reference to their potent activation of subsets that share expression of certain TCR V gene products. Dr. Posnett chose to work with MAM because it derives from a microbe that causes an autoimmune-like arthritis in rodents and that can also infect humans. In preliminary studies, a monoclonal antibody (MAb) specific for a TCR V gene product identified a T cell population that was expanded in cultures exposed to MAM. L cells transfected with human DR, but not those transfected with human DQ MHC molecules were able to present MAM to T cell. The current application pursues these results in order to complete the information on MAM-reactive TCR and MHC molecules in human system. The four specific aims are 1) to define all MAM-reactive TCR V gene products, 2) to produce MAb specific for these V gene products, 3) to define MHC isotopes and alleles that may present MAM to MAM-reactive T cells and to determine the contact site(s) for MAM on MHC, and 4) to define the TCR site(s) reactive with the MAM-MHC complex. The latter two aims will require the production of hybrid TCR and MHC molecules by PCR using overlap extension and also site-directed mutagenesis studies. While the functional significance of superantigens is not yet clear, he and others have postulated roles for superagtigens in autoimmunity. It might therefore be useful to understand the exact specificity of a potentially pathogenic superantigen, since vaccines based on the TCR sequences involved could be produced in the future.
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