The triggering of brain autoimmune disease

• Applicant: Professor Dr. Hartmut Wekerle
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225143297

We recently found that a myelin directed autoimmune response is triggered in the intestine following an interaction between the commensal bacterial microbiota and quiescent myelin-reactive T lymphocytes. The experimental paradigm used RR mice, transgenic SJL/J mice over-expressing a T cell receptor for myelin oligodendrocyte glycoprotein (MOG), which develop spontaneously a relapsing-remitting autoimmune inflammation of the central nervous system (CNS), similar to early human MS. We now postulate a three-step pathogenesis of MS: First, activation of myelin autoreactive T cells in the gut; second, recruitment of autoimmune B cells to the CNS draining lymph nodes; third, infiltration of the CNS by T and B cells resulting in demyelination and axonal degeneration. We propose to test this hypothesis in 4 project parts: 1) Identification of critical bacterial components and the mechanism of T cell activation (innate vs. mimicry); 2) Recruitment of B cells by activated T cells and CNS autoantigen exported from the CNS and determination of pathogenic B cell functions (autoantigen presentation, autoantibody production, cytokine production); 3) Tracking the fate/migration of activated T and B cells to and within the target organ; 4) Ultimately verification of the findings in clinical MS research (human microbiota vs. MS susceptibility; therapeutic/antibiotic/vaccination strategies).

• DFG Programme: Reinhart Koselleck Projects