FIGURE 1 | The immune response dichotomy in multiple sclerosis.

a | A key step in early disease — entry of self-reactive lymphocytes (adaptive immune effectors) into the central nervous system (CNS) — initiates an abnormal immunopathogenic cascade, which leads to relapsing focal damage. b,c | Disease progression may relate to an immune balance shift that is characterized by abnormal activation of innate immune effectors — such as dendritic cells, resident CNS microglia, macrophages and natural killer cells — and astrocytes together with upregulated production of pro-inflammatory cytokines and toxic molecules — tumour necrosis factor- (TNF-), interferon- (IFN-), T-cell immunoglobulin mucin 3 (TIM3; also known as HAVCR2), galectin 9 (GAL9; also known as LGALS9), glutamate, and reactive oxygen species (ROS) and reactive nitrogenous species (RNS). c | An additional element that is implicated in the progression of multiple sclerosis may be the presence of ectopic meningeal B-cell follicles. Abnormally activated B cells present in these structures produce chemokines that further attract other immune effectors. The events described in (b,c) and (d), either in conjunction or independently, may perpetuate diffuse CNS inflammation and neurodegeneration. CCL2, chemokine (C-C motif) ligand 2; CXCL13, chemokine (C-X-C motif) ligand 13; iNOS, inducible nitric oxide synthase; IL10, interleukin 10; RRMS, relapsing–remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; TGF-, transforming growth factor-; T_H1 cell, T helper 1 cell; T_Reg cell, regulatory T cell.

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