Background: In Experimental Autoimmune Encephalomyelitis (EAE), the animal model for multiple sclerosis, the meninges represent a crucial checkpoint for disease initiation.
Hypothesis: We hypothesize that the meninges also represent a crucial checkpoint in the resolution phase of CNS inflammation, tipping the balance in favor of full tissue recovery or chronic damage.
Strategy: We will combine intravital-two-photon microscopy, super-resolution microscopy and gene-expression profile in a relapsing-remitting model of EAE.
The CNS is protected by three thin layers of tissue collectively referred to as the meninges. Far from being just a physical barrier, the meninges are increasingly appreciated as a site of immune activity, being capable of influencing CNS homeostasis and contributing to neurological disorders. This seems the case in multiple sclerosis (MS) where the occurrence of meningeal inflammation, both in the early and chronic phases of the disease, correlates with tissue damage and disease severity. In experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we could show that leptomeningeal vessels represent the entry point of autoreactive T cells. Moreover, within the leptomeningeal compartment the invading autoreactive T cells recognize their self-antigen presented by resident phagocytes. The T cell reactivation represents a crucial step for the establishment of the subsequent destructive autoimmune process within the parenchyma. The leptomeningeal milieu can also provide a niche for immune cells to persist within the CNS tissue. Lymph follicle-like structures can be formed which seem to be important for the perpetuation of the disease process. More recently, it has been proposed that the meninges play a critical role, not only for the initiation of the disease, but also in the recovery phase. This aspect, however, has not yet been clarified, an issue which we wish to address. Therefore, the focus of our project is to evaluate the role of the meninges during the resolution phase after an acute autoimmune lesion in detail. The goal of our study is the identification of checkpoints that allow either the resolution of the meningeal damage upon acute autoimmune attacks or contribute to the chronicity of the autoimmune process.