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Functional Role of the HLA-DR15 Haplotype in Multiple Sclerosis

Final Report Summary - HLA-DR15 IN MS (Functional Role of the HLA-DR15 Haplotype in Multiple Sclerosis)

The “HLA-DR15 in MS” ERC project aimed at a better understanding how the most important genetic risk factor of multiple sclerosis (MS), that is the HLA DR15 molecules DRB1*15:01 and DRB1*01:01, contributes to causing and maintaining this prototypic autoimmune disease of young adults. MS is the first autoimmune disease, for which an association with certain HLA molecules had been discovered in 1973, but until now it is not clear yet, how the presence of the gene, which is frequent in the Northern European population, translates into an autoimmune disease damaging the brain and spinal cord. In the “HLA-DR15 in MS” project a number of approaches were integrated that bridged expertises from cellular immunology to biochemistry, peptide- and protein chemistry, virology, and clinical neurology to examine how peptides presented by the MS-associated DR15 alleles generate a T cell repertoire, which carries the risk of mounting an overshooting immune response against nervous system antigens. Several interesting and novel observations were made during these studies. Based on the findings, presentation of DR molecule-derived self-peptides appears to select T helper cells (CD4+) in the thymus, which are then maintained in the peripheral immune system. Here, they can be activated by MS-associated infectious agents like Epstein Barr virus and certain gut microbiota and also recognize MS autoantigens. Following migration into the brain, these autoreactive CD4+ T cells are probably the main mediators of the autoimmune damage in the target organ. Further, the project outlined how B lymphocytes indirectly contribute to MS by activating autoreactive T cells, which in turn explains how the most effective treatment of MS, the depletion of B cells by anti-CD20 antibodies, works. The observations provided very important and novel insights about the contribution of HLA molecules to a prototypic organ-specific autoimmune disease. In the future, the findings not only open the path for novel treatments of MS, but also how similar associations between HLA molecules and autoimmune diseases like rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, celiac disease, vitiligo, thyroid disease and many others can be studied.