Cellular and molecular mechanisms of formation and function of ectopic lymphoid follicles in CNS autoimmunity

• Applicant: Dr. Anneli Peters
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576148600

Multiple Sclerosis (MS) is an autoimmune disease driven by self-reactive T helper (Th) cells, particularly Th1 and Th17 effector subsets, which promote tissue inflammation, demyelination and axonal damage in the central nervous system (CNS). In addition, B cells play an important role in pathogenesis, as demonstrated by the efficacy of B cell-depleting therapies. However, the mechanisms of how B cells contribute to pathogenesis and progression are not completely understood. In about half of the people with MS, B cells can be detected to accumulate in ectopic lymphoid follicles (eLFs) in the CNS. Presence of meningeal eLFs is linked to relapse-independent progression activity, correlates with more aggressive disease courses, and with severe cortical pathology in the neighboring tissue, supporting the hypothesis that eLFs fuel inflammatory and tissue-destructive processes in the CNS. In order to gain mechanistic insight into the cellular processes ongoing in eLFs, we employ the Th17 adoptive transfer experimental autoimmune encephalomyelitis (Th17-AT-EAE) model, which features formation of large and numerous B cell-rich eLFs under the meninges. Our work over the last years has shown that T and B cells engage in long-lasting contacts in eLFs, which leads to both activation and maturation of B cells, but also to reactivation of autoreactive T cells and maintenance of their proinflammatory cytokine profile. Our data further indicate that Th17 cells initiate the formation of eLFs in the meninges, where they interact with both tissue cells and immune (non-B) cells, which then results in the recruitment and organization of B cells into maturing eLFs, where T and B cells intensely interact and become activated. After defining these important cornerstones, we can now begin to answer key open questions regarding the mechanisms of eLF formation and function. More specifically, we will employ our Th17-AT-EAE model to investigate the cellular and molecular mechanisms involved in eLF formation and organization over time. We will characterize the types of antigens presented by different cell types in eLFs, the mechanism of autoreactive T cell activation, and the specificities and clonal expansion of autoreactive lymphocytes in eLFs. To determine the translatability of our results to human disease, we will analyze eLF-positive MS-derived CNS tissue via a combined imaging and spatial transcriptomics approach. The proposed research program will provide mechanistic insight into how eLFs propagate autoimmune inflammation in the CNS both in the mouse model and in human disease, and will identify pathways that could be therapeutically targeted in the future to interfere with activation of autoreactive lymphocytes in these structures.

• DFG Programme: Research Grants