Current Status of the Immunomodulation and Immunomediated Therapeutic Strategies for Multiple Sclerosis

Figure 2

Multiple sclerosis immunopathogenesis and therapeutic targets. Immature dendritic cells (DCs) are central players in the innate immune response and are involved in the maintenance of peripheral tolerance by promoting the suppressor Treg and anti-inflammatory Th2-cell responses. Abnormally activated (mature) antigen-presenting DCs can be found in patients with multiple sclerosis (MS). This activation results in the increased production of proinflammatory cytokines, which lead to the aberrant activation of Th1 and Th17 proinflammatory responses. Activated encephalitogenic adaptive immune effectors (such as Th1 cells, Th17 cells, CD8⁺ cells, and B cells) express surface molecules that allow them to penetrate the blood-brain barrier and to enter the central nervous system (CNS). The presence of autoreactive immune effectors, together with abnormally activated CNS astrocytes and microglia, leads to the increased production of reactive oxygen species, excitotoxicity, autoantibody production, and direct cytotoxicity, which are all involved in the demyelination and axonal and neuronal damage that is present in patients with MS. Potential therapeutic interventions at different levels of the immunopathological cascade are shown in the filled yellow boxes (cytotoxic T lymphocytes [CTL]; interferon γ [IFNγ]; IL2 receptor [IL2R]; major histocompatibility complex class II [MHC II]; matrix metalloproteinases [MMPs]; nitric oxide [NO]; oligodendrocyte [ODG]; sphingosine 1-phosphate receptor [S1PR]; transforming growth factor β [TGFβ]; tumor necrosis factor [TNF]; regulatory T cells [Treg]; vascular cellular adhesion molecule 1 [VCAM1]; very late antigen 4 [VLA-4] (This figure was adapted and partly revised from [55].).