Key pathological processes within blood and central nervous system (CNS) during EAE and MS. (1) Danger associate molecular patterns (DAMP) and Pathogen-Associated molecular patterns (PAMP) released into the peripheral blood activate inflammatory myeloid and T cells that migrate into the CNS after blood-brain barrier (BBB) breakdown. (2) Infiltrating monocytes and neutrophils release IL-1β that activates γδ T cells to secrete IL-17, IL-21 and blood-brain barrier (TNF), which amplifies Th17 responses. In addition, activation of inflammatory myeloid cells releases granulocyte-macrophage colony stimulating factor (GM-CSF) that amplifies Th17 cell activation (3) IFN-γ and GM-CSF released from Th1 cells, and IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF) released from activated Th17 cells activate microglia. (4) T cell re-activation by presented myelin antigens. (5) Clonal expansion of T effector (Teff) cells. (6) Activation of infiltrating and resident cells results in the release of inflammatory mediators by Th1 and Th17 cells (IL-17, GM-CSF, IFN-γ, TNF) and production of reactive oxygen and nitrogen species, cytotoxic products and proteases that promote the destruction of myelin around axons (7) and oligodendrocytes (8), which are responsible for axonal remyelination, resulting in a toxic inflammatory response that leads to neuronal death and neurological deficits. Adapted from McGinley et al.