What Guides Peripheral Immune Cells into the Central Nervous System?

Multiple sclerosis (MS), an immune-mediated demyelinating disease of the central nervous system (CNS), initially presents with a relapsing-remitting disease course. During this early stage of the disease, leukocytes cross the blood–brain barrier to drive the formation of focal demyelinating plaques. Disease-modifying agents that modulate or suppress the peripheral immune system provide a therapeutic benefit during relapsing-remitting MS (RRMS). The majority of individuals with RRMS ultimately enter a secondary progressive disease stage with a progressive accumulation of neurologic deficits. The cellular and molecular basis for this transition is unclear and the role of inflammation during the secondary progressive disease stage is a subject of intense and controversial debate. In this review article, we discuss the following main hypothesis: during both disease stages, peripheral immune cells are triggered by CNS-intrinsic stimuli to invade the brain parenchyma. Furthermore, we outline the different neuroanatomical routes by which peripheral immune cells might migrate from the periphery into the CNS.