The overall objective is to identify immunological mechanisms that lead to myelin damage using animal models of autoimmune demyelinating disease. Studies currently focus on the use of the mouse model, experimental allergic encephalomyelitis (EAE). EAE is an experimental disease that is characterized by inflammatory lesions of the central nervous system followed by demyelination. The disease model used in these studies involves the adoptive immunization of naive animals using T cells derived from animals immunized with myelin, myelin proteins or portions of these proteins that are know to be encephalitogenic. The course of the disease studied in this project is relapsing-remitting. In addition to examining mechanisms of damage, studies also examine treatments that can modify the disease process. Recent studies have examined mechanisms that can lead to the generation of autoreactive T cells. It is thought that diseases such as multiple sclerosis are due to the occurrence of autoreactive t cells but it has been unclear how these cells are generated. One mechanism that has been considered is that the autoreactive T cells are generated in response to environmental antigens such as viruses. Considerable progress has been made in defining the molecular requirements for cross reactivity or molecular mimicry. It is now clear that even limited sequence homology can allow cross-reactivity if the amino acids(aa) necessary for binding to the MHC and those important for T cell receptor recognition are identical or similar between the native peptide and another antigen. Using these criteria antigens that cross-react with encephalitogenic portions of MBP such as the 88-99 region have been identified. However, it has been uncertain if cross reactivity can actually lead to T cells that have biological properties similar to those derived with the encephalitogenic peptides and, specifically, if they can induce disease. To test the concepts of molecular mimicry, the ability of T cells selected with peptides predicted to cross-react with an encephalitogenic portion of MPB, aa 87-99, were studied. Previous studies have demonstrated that a peptide derived from human papillomavirus 12 can be recognized by MBP-specific T cells clones from humans. In addition, a peptide derived from EBV that has also predicted to cross-react with MBP 87-99 was studied. Lymph node cells derived from animals were immunized with the papillomavirus peptide and then stimulated in vitro with MBP were encephalitogenic when transferred to naive mice. Further, when different doses of the papillomavirus peptide was used, it was found that lower doses were more effective at generating cross-reactive clones. Similar experiments with the EBV peptide failed to generate T cells able to transfer disease. However, when T cells were generated with MBP, EBV peptide could be used to expand these cells in vitro prior to transferring disease.These results support the hypothesis that environmental antigens can contribute to the generation or activation of autoreactive T cells. The results also indicate that the selection of autoreactive T cells can depend on the dose of the foreign antigen. While preliminary, these results indicate that the potential for molecular mimicry as a mechanism for driving autoimmunity exists. - Autoimmunity, multiple sclerosis, T cell, Experimental allergic encephalomyelitis
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