The pathological features of Multiple Sclerosis (MS) encompass demyelination, focal disruption of the blood-brain barrier (BBB), recruitment of peripheral immune cells, neuronal and axonal damage, as well as activation of microglia and astrocytes. While the underlying causes of lesion formation in MS are still not fully understood, our research emphasizes brain-intrinsic processes that connect the loss of myelinating oligodendrocytes to the infiltration of cytotoxic immune cells. In this context, particular attention is given to the role of reactive astrocyte subpopulations and the mechanisms of primary oligodendrocyte loss.