Fig. 1
Roles of dendritic cells in the pathogenesis of multiple sclerosis and impacts of disease-modifying therapies. Immune tolerance invalidation is thought to play an important role in the pathogenesis of MS. DCs and B cells capture and process CNS-releasing myelin protein-derived antigens, migrate to secondary lymphoid organs and tissues, and present the self-antigens to T cells to induce myelin-reactive TH1 and TH17 cells. The activated T cells, B cells and DCs travel across the blood brain barrier (BBB). DCs drastically accumulate in the CNS, invade the parenchyma, and prime myelin-specific T cell responses. Once in the perivascular space, the DC-activated T cells from the peripheral draining lymph nodes encounter CNS-derived antigen–MHC complexes presented by local antigen-presenting cells (APCs) especially cDCs, followed by T cell reactivation. These autoreactive immune cells as well as pro-inflammatory mediators then migrate into CNS parenchyma. Ectopic lymphoid follicles containing T cells, B cells, plasma cells and follicular DCs are detected along the meninges in SPMS patients. The dual capacity of DCs to drive immunity and to confer antigen-specific T cell tolerance makes them a potential therapeutic target for MS by either inhibiting their immunogenicity or enhancing their tolerance. Current DMT drugs exert direct or indirect effects on DCs. IFN-β, sphingosine 1-phosphate receptor (S1PR) modulators, dimethyl fumarate (DMF), teriflunomide and glatiramer acetate reduce the polarization of pro-inflammatory TH1 and/or TH17 cells by influencing the maturation, antigen presentation and/or cytokine expression profiles of DCs. DMF, natalizumab and alemtuzumab are capable to induce tolerogenic DCs (tolDCs) conducing to the genesis of regulatory T cells (Tregs), thereby promoting the restoration of tolerogenic networks. Glatiramer acetate and IFN-β can also exert immunomodulatory effects through induction of Tregs. In addition, glatiramer acetate, daclizumab and cladribine might shift the cytokine synthesis pattern of human DCs toward an anti-inflammatory TH2 profile. Mitoxantrone and cladribine have non-specific effects, but also affect antigen presentation and cytokine production of DCs. S1PR modulators, IFN-β, DMF, teriflunomide and natalizumab can block the transit of DCs and autoreactive lymphocytes across the BBB. In the CNS, S1PR modulators exert beneficial effects on microgliosis and astrogliosis, alleviating demyelination. TolDCs, Tregs and TH2 cells generated in the periphery also modulate TH1 and TH17 cell production and microglial activity in the CNS