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In many T cell-mediated autoimmune diseases including multiple sclerosis (MS) there is currently only an incomplete understanding, which is/are the most important autoantigen/s in the context of those HLA-class II molecules that confer most of the genetic risk. Furthermore and directly related, the knowledge about environmental triggers, e.g. viruses, of autoimmune diseases and MS is only limited. While myelin antigens are considered relevant autoantigens in MS, and Epstein Barr virus (EBV) is a known environmental risk factor of MS, we believe that the search for autoantigens and foreign triggers in MS has been too hypothesis-driven in the past, i.e. the focus was almost entirely put on myelin proteins. This narrow focus probably in part explains, why antigen-specific tolerization has not been successful so far in MS, and therefore, we propose here to employ a combination of methods to identify disease-relevant autoantigens and foreign triggers in MS. In brief, we will examine the antigen specificity of CD4+ and CD8+ T cells that are clonally expanded within the brains of MS patients, expand these T cell clones and test them with two broad-based and largely hypothesis-free approaches: a) combinatorial peptide libraries in the positional scanning format (ps-SCL), and b) lentiviral expression libraries using large numbers of cDNAs from MS brain tissue, which will be used to transduce antigen-presenting cells. These studies will likely lead to important insights about the target antigens in MS, possibly to new biomarkers and hopefully also provide a basis for future treatments by antigen-specific tolerization.