Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS.

Figure 1

Tolerogenic dendritic cells play their tolerogenic role through promote regulatory T cells differentiation. The tolerogenic DCs regulate autoreactive T cells by inducing anergy, apoptosis, phenotypically skewing, and/or Treg cells or tolerogenic DCs can be induced through the induction of T regulatory cells, such as Tr1 and CD4+, CD25+, and Foxp3 cells.

Figure 2

Role of dendritic cells (DCs) in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). As professional antigen-presenting cells (APCs), DCs in the periphery could activate the T cells upon pathological stimulation resulting in secreting proinflammatory cytokines, aiding their entry through the endothelial blood-brain barrier (BBB) to the CNS; then these myelin-reactive T cells are reactivated upon encounter with resident APCs including DCs which present myelin-derived epitopes. Subsequently, these perivascular T cells will secrete proinflammatory cytokines which result in recruitment of other inflammatory cells. Consequently, this will lead to demyelination of axons accounting for the sensory and motor deficits of MS.

Figure 3

Dendritic cells (DCs) promote the differentiation of Th1 and Th17 cells. Mature DCs could induce the differentiation of naive CD4+ T cells into different types of T helper (Th) cells. Both Th1 and Th17 cells play pathogenic roles in the disease progression of MS mainly through their cytokines.

Figure 4

Effects of vitamin D on the immune system and immune responses. Vitamin D affects the immune responses including modulation of antigen-presenting cells (APCs), B, T, and NK cells. ↑ denotes induction or upregulation; ↓ denotes inhibition or downregulation. DCs: dendritic cells; iNOS: inducible nitric oxide synthase; IL: interleukin; IFN-γ: interferon gamma; Ig: immunoglobulin; Mφ: macrophage; MHC: main histocompatibility complex; NK cells: natural killer cells; TNF-α: tumor necrosis factor alpha; VDR: vitamin D receptor.