Repertoire and antigen recognition of brain-infiltrating immune cells in progressive MS

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Cells from the immune system (lymphocytes, for example T cells and B cells/plasma cells) are found in the brains of patients with multiple sclerosis (MS), located in areas where myelin sheaths are destroyed and where neurons degenerate. Moreover, these cells are found in MS brains at the very beginning of the disease, in the relapsing-remitting stage, and also in the progressive phase of the disease. Do these cells belong just to a few clones gone awry, or to many different ones?What do they recognize?Do immune cells found in the brain of very early MS recognize the same antigens as immune cells found later, in the progressive phase of the disease?Studies to find answers for these questions have not been done yet for patients with progressive MS where suitable material is extremely rare and often formaldehyde-fixed and paraffin-embedded (FFPE) deemed useless for further analysis. However, we have such precious samples, and we have the expertise to use FFPE tissue for molecular studies. Studies of pathogenic lymphocytes within the tissue require sophisticated techniques like next generation sequencing to learn more about their repertoire (which is, to learn how different their antibodies and T cell receptors are, and whether they belong to few or many different clones). Over the last years, also these techniques have been adjusted to FFPE samples. Disease-relevant cells are typically expanded within the tissue. Therefore, we will next clone and express the most abundant antibodies and T cell receptors identified in the progressive MS brains to find out what these molecules recognize. And finally, when we know this, we will go back to pathology to find out when and where this recognition occurs. Answers to these questions could help to better understand the driving forces of MS, and perhaps even to find better therapies for MS.It can be easily envisaged that such a demanding and important project will only be successful when specialists for all these steps jointly work together. In our case, the technical know-how needed to achieve this goal is complementarily distributed between two groups, on of them located in Vienna, Austria (Monika Bradl and Hans Lassmann), the other one located in Munich, Germany (Klaus Dornmair). Therefore, we propose a joint binational project of our two groups under the DACH lead agency action. Such a joint project has an especially important point of added value since we will be able to directly compare our data and antigens from progressive MS to those obtained from samples with relapsing remitting MS and with very early MS (data currently obtained in a project supported by DFG, proposal CRC TR 128 A5).