Cooperation of autoreactive B cells and Th17 cells in the development and progression of CNS autoimmunity

• Applicant: Dr. Anneli Peters
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 350913910

The goal of the proposed project is to investigate the nature of T:B cell collaboration in CNS autoimmunity taking into account the different B cell effector functions that may play a role in the pathogenesis of multiple sclerosis (MS). These include production of autoreactive antibodies, presentation of autoantigen to T cells and production of proinflammatory cytokines both in the periphery and in the CNS. To model those different B cell effector functions, we are employing and have developed different experimental autoimmune encephalomyelitis (EAE) models, each suited to answer specific questions that are still unresolved in the field: (1) Where and how do CNS-reactive B cells evolve during disease development and are disease-associated repertoire changes pathogenic? This question can be addressed in the spontaneous EAE model, the RR mouse, in which myelin-specific B cells are recruited from the endogenous repertoire and required for disease development. We could identify disease-associated changes in the repertoire in this model and can now determine the relevance of these changes for disease manifestation. (2) What functions do B and T cells fulfill in meningeal ectopic lymphoid follicles? We have established the Th17 transfer EAE model featuring large and numerous meningeal eLFs and characterized eLF B cells to be highly activated, poised for germinal center reactions, and engaged in long-lasting contacts with T cells resulting in reactivation of proinflammatory T cells in eLFs. Using our transcriptomic dataset, we are now in the unique position to determine whether similar B cell subpopulations exist in MS patients and thus gain insight into eLF function in MS. (3) What are the cellular sources of the pathogenic cytokine IL-23 and does it also have intrinsic effects on T and B cell pathogenicity? In our novel B cell-driven transfer EAE model, we found that IL-23p19 expression enhances B cell pathogenicity without affecting the T cell or myeloid response and in addition, IL-23p19 deficient T cells failed to transfer EAE. Thus, IL-23p19 may intrinsically affect T and B cell pathogenicity, in addition to the known function of APC-produced IL-23 of promoting terminal differentiation of pathogenic Th17 cells. We have generated IL-23p19fl/fl mice and can now analyze the mechanism of action of IL-23p19 in relation to cellular source in depth.

• DFG Programme: Independent Junior Research Groups