The role of the adaptive immune system in the initiation and persistence of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) in which complex networks of interacting immune cells initiate and sustain the disease. The pathogenesis of relapsing MS is driven by adaptive immune cells that become activated outside the CNS compartment and then migrate into the CNS to initiate a presumably autoimmune inflammatory process. Recent technological advances, particularly single-cell analyses, have revealed substantial heterogeneity in T and B cells involved in this stage of the disease. Disease progression involves different mechanisms, with compartmentalized inflammation and chronic activation of CNS-resident cells becoming predominant features. The contribution of tissue-resident adaptive immune cells to the pathology of progressive MS, including tissue-resident CD8⁺ T cells and B cells in the meningeal compart, is increasingly debated. Here, we will discuss concepts of how adaptive immune cells might initiate and maintain autoimmune inflammation in the CNS, while the responses to autoimmune inflammation of CNS intrinsic cells, including astrocytes, oligodendrocytes, and neurons, are described elsewhere [1], [2], [3], [4], [5] and will not be a particular focus of this overview. Finally, it is the aim of this review to conceptualize the grounds for efficient therapeutic interventions targeting players of the adaptive immune system in relapsing but also in progressive MS.