Somatic mutations leading to CD8+ T cell proliferation contribute to the pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults, affecting around 10,000 people in Belgium and leading to important physical as well as cognitive disability. MS is characterized by three hallmarks: inflammation, demyelination and neuronal loss. During our previous FWO project, we identified >200 genetic factors for susceptibility to MS as well as a different set of genetic factors explaining important heterogeneity between patients. We unravelled how these factors point to primary role of the immune system. As these established MS risk factors explain <50% of the variation in MS risk between individuals, the current next key challenge is: what triggers whether an individual with a certain load of common genetic risk factors does or does not get MS? In this project, we propose an entirely novel explanation: mutations that are not inherited from the parents but that have arisen newly in a subset of cells of the patient (somatic mutations). Such mutations are known to be important in cancer and are used in the choice between cancer treatments, and our project would extend this to diseases like MS. Preliminary data from our group as well as recent data from the literature, confirm as a “proof of principle” the presence of somatic mutations in immune cells in autoimmune or neurological diseases. In this project, we will build on this and investigate whether and how somatic mutations contribute to the pathogenesis of MS.