UnmetMS - Unraveling the immune etiology of multiple sclerosis

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults and if untreated leads to irreversible and severe disability. Although distinct subtypes of the disease exist with regard to clinical and imaging presentation as well as neuropathological appearance, there is general agreement that an autoimmune inflammatory process is the driving force behind tissue injury in MS. A large body of mechanistic insight into the autoimmune pathogenesis of MS has been derived from the CD4+ T cell-mediated animal model, experimental autoimmune encephalomyelitis (EAE). However, EAE dos not mimic the full picture of MS neuropathology as a number of anti-inflammatory treatments that were highly effective in EAE, have failed in MS trials. In addition, although immunomodulatory treatments are effective in the treatment of early stages of MS, they are no longer once patients have entered the progressive phase of disease development. These observations suggest that the autoimmune pathogenesis underlying MS is much more complex as previously thought and cannot be modeled in its entire complexity in available animal models. There is therefore an unmet need for a detailed phenotypic and functional analysis of disease-relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. The Sinergia UnmetMS brings together the 3 Swiss laboratories of Roland Martin/Mireia Sospedra Ramos (Zürich), Britta Engelhardt (Bern) and Federica Sallusto/Antonio Lanzavecchia (Bellinzona), which combine their unique expertises in clinical MS research, human T and B cell immunology, neuroimmunology, vascular biology and CNS immune cell invasion for the first time with the aim to develop a better understanding for the temporo-spatial contribution of specific subsets of adaptive immune cells in MS pathogenesis as a pre-requisite to further unravel the immune etiology of MS. To achieve this overall goal Sinergia UnmetMS will make use of unique samples of T and B cells isolated from brains, cerebrospinal fluid (CSF) and peripheral blood of patients with different subtypes of MS to perform a concerted in-depth analysis of the phenotype, gene expression profile, antigen specificity and functional characteristics of these patient-derived and thus disease-relevant T and B cell subsets. The ability of these T and B cell subsets to enter specific CNS compartments will be studied using novel models of the human blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB) and to be established patient-derived in vitro BBB models by nuclear reprogramming of fibroblasts. Further, the role of citrullination of CNS proteins as adaptive immune targets will be examined in detail for the first time. Sinergia UnmetMS has a strong commitment to provide novel insights into the cellular and molecular mechanism of the immune etiology underlying the diverse subtypes of MS. Results obtained in the proposed collaborative effort will improve our knowledge on the complex etiology of MS and set the stage to explore novel therapeutic targets for developing treatments for those MS patients who have not benefited to date. Sinergia UnmetMS will therefore aim at providing major advances towards understanding the immune etiology of MS and potential novel strategies for improving this disabling disease. The overall research goal of Sinergia UnmetMS can only be achieved in the proposed combination of expertises and experimental setups available within the 3 partner laboratories and progress will be achieved in a step-by-step process, in which results obtained within one laboratory will directly influence experimentation in the others. Last-but not least with a female applicant involved in each partner's laboratory the Sinergia UnmetMS will provide an environment for junior scientists that beyond the added value of network research provides female role models which will specifically help the advancement of women in science in Switzerland.