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

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).

Repertoire and antigen recognition of brain-infiltrating immune cells in progressive MS 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? To address these questions, we studied the repertoire of immune cells in the tissue. We could show that CD8+ T cells are the dominating T cell population in the brain, at each timepoint in the MS course. At least some of these CD8+ T cells proliferate in active inflammatory lesions, and locally differentiate to tissue resident memory cells with the potential for re-activation. We could also show that the brains of MS patients in the relapsing/remitting disease stage contain more B lymphocytes, which further differentiate in the disease course to plasmablasts found then in higher numbers in MS patients in the progressive stage of their disease. Both T and B cells/plasmablasts contain several-many different cell clones, which hampered the identification of disease-relevant cells, their receptors or antibodies, and the recognized target structures in the brain. However, we could achieve a major break-through with a tissue sample which displayed all characteristic pathological features of MS, but derived from a patient who underwent an experimental therapy for Parkinsons disease some 60 years ago. In the course of this treatment, the patient was injected with homogenized brain tissue, and as a result of it, died due to massive brain inflammation. Similar disease courses have been observed before as a complication of historic rabies vaccination, and it turned out then that the vaccine was contaminated with brain tissue. Historically, these complications have been taken as evidence for an autoimmune genesis of MS. By using high-end molecular and pathological technologies, we found out that the patient of our tissue sample produced autoantibodes against myelin/oligodendrozyte-glycoprotein (MOG), and that the correct diagnosis of his condition should be MOG-antibody-associated disease (MOGAD), and not MS. Our results raise profoung doubts about the historical evidence for an autoimmune genesis of MS.