Mechanisms underlying lesion development and lesion distribution in CNS autoimmunity.

Abstract

It is widely accepted that development of autoimmunity in the central nervous system (CNS) is triggered by autoreactive T cells, that are activated in the periphery and gain the capacity to migrate through endothelial cells at the blood-brain barrier (BBB) into the CNS. Upon local reactivation, an inflammatory cascade is initiated, that subsequently leads to a recruitment of additional immune cells ultimately causing demyelination and axonal damage. Even though the interaction of immune cells with the BBB has been in the focus of research for many years, the exact mechanisms of how immune cells enter and exit the CNS remains poorly understood. In this line, the factors deciding immune cell entry routes, lesion formation, cellular composition as well as distribution within the CNS have also not been elucidated. The following factors have been proposed to represent key determinants for lesion evaluation and distribution: (i) presence and density of (auto) antigens in the CNS, (ii) local immune milieu at sites of lesion development and resolution, (iii) trafficking routes and specific trafficking requirements, especially at the BBB and (iv) characteristics and phenotypes of CNS infiltrating cells and cell subsets (e.g. features of T helper subtypes or CD8 cells). The heterogeneity of lesion development within inflammatory demyelinating diseases remains poorly understood until today, but here especially orphan inflammatory CNS disorders such as neuromyelitis optica spectrum disorder (NMOSD), Rasmussen encephalitis or SUSAC syndrome might give important insights in critical determinants of lesion topography. Finally, investigating the interaction of T cells with the BBB using invitro approaches or tracking of T cells invivo in animals or even human patients, as well as the discovery of lymphatic vasculature in the CNS are teaching us new aspects during the development of CNS autoimmunity. In this review, we discuss recent findings which help to unravel mechanisms underlying lesion topography and might lead to new diagnostic or therapeutic approaches in neuroinflammatory disorders including multiple sclerosis (MS).