Neuroimmune interaction that operate in the development and progression of inflammatory demyelinating diseases: lessons from pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is considered an autoimmune chronic inflammatory disease of the central nervous system ( CN S) characterized b y demyelination and axonal damage. It is widely accepted that MS immune response compartmentalized within the CNS is mediated by autoreactive major histocompatibility complex (MHC) class II–restricted CD4+ T cells trafficking across the blood–brain barrier (BBB) after activation and secreting T helper 1 (Th1)-type pro-inflammatory cytokines. These cells seem to regulate a combined attack of both innate and acquired immune responses directed against myelin proteins, which includes macrophages, MHC class I–restricted CD8+ T cells, B cells, natural killer (NK) cells, and γδ T cells. This coordinated assault is also directed toward neurons and results in axonal loss. However, although the understanding of the mechanisms that orchestrate the development and the progression of the disease has recently received increasing attention, the sequence of events leading to myelin and axonal injury currently remains uncertain. Failure of peripheral immunologic tolerance is hypothesized to play a crucial role in the initiation of MS, but evidence for a single triggering factor is lacking. In addition, the different theories proposed to explain this crucial step, suggesting the involvement of an infectious agent, a dysfunction of regulatory pathways in the periphery and a primary neurodegeneration, are difficult to reconcile. On the other hand, the view of MS as a “two-stage disease,” with a predominant inflammatory demyelination in the early phase (relapsing–remitting MS form) and a subsequent secondary neurodegeneration in the late phase (secondary or primary progressive MS) of the disease, is now challenged by the demonstration that axonal destruction may occur independently of inflammation and may also produce it. Therefore, as CNS inflammation and degeneration can coexist throughout the course of the disease, MS may be a “simultaneous two-component disease,” in which the combination of neuroinflammation and neurodegeneration promotes irreversible disability