Plasmacytoid Dendritic Cells and Immunotherapy in Multiple Sclerosis

Felipe von Glehn; Leonilda M Santos; Konstantin E Balashov

Disclosures

Immunotherapy. 2012;4(10):1053-1061. 

In This Article

pDCs in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS.[74,75] pDCs have been given particular emphasis due to their importance in stimulating or inhibiting effector T cells in MS.[76] Cytokines, such as type I interferon, IL-6 and TNF-α produced by pDCs, have been implicated in MS pathogenesis. Type I interferon promotes Th1 polarization[46] and IFN-γ production;[47] IL-6 promotes myelin antigen-specific Th17 and Th1 responses in encephalomyelitis (EAE);[77] and TNF-α directly induces oligodendrocyte apoptosis[78] and mediates human neuronal injury after activation with TLR9 agonists.[79]

pDCs are present in the cerebrospinal fluid (CSF),[80] leptomeninges and demyelinating lesions of patients with MS[81] and their concentration is increased in the CSF of MS patients during an exacerbation.[82] Furthermore, the relative concentration (among all mononuclear cells) of pDCs is increased in the CSF in MS.[80] However, the concentration of pDCs in peripheral blood of patients with MS is comparable with healthy subjects.[83–85]

pDCs are difficult to study owing to their low concentration in peripheral blood. As a result, it is still not clear if pDCs play a predominantly pathogenic or protective role in MS (Figure 1). The ambivalent function of pDCs has also been observed in experimental autoimmune EAE, one of several animal models of human MS. It was suggested that pDCs promote priming of autoimmune Th17 in EAE, whereas depletion of pDCs prior to induction of the disease decreases its severity.[86] On the other hand, clinical signs of EAE were exacerbated considerably if pDCs were depleted during the peak period of the disease. pDC depletion enhanced CNS, but not peripheral, CD4-positive T-cell activation, as well as IL-17 and IFN-γ production.[76] pDCs also function as important APCs that regulate the priming phase of EAE.[87] EAE was exacerbated in chimeric mice lacking MHC class II expressed on pDCs. Compared to the wild-type mice, the chimeric mice had increased myelin oligodendrocyte glycoprotein-specific IFN-γ and IL-17 secretion by T cells, impaired Treg proliferation and decreased IL-10 production. No differences were observed in the production of type I interferons and other cytokines by pDCs, suggesting that the disease exacerbation was a result of the impaired antigen presentation by these cells.[87] The state of DC maturation affects antigen-presenting capabilities in humans as well.[88]

Figure 1.

Plasmacytoid dendritic cells in multiple sclerosis. Plasmacytoid dendritic cells can be activated with viral and bacterial DNA via TLR9. Activated pDCs promote generation of both Th1/Th17 cells [46,76,87,92] and Tregs [104,105]. IFN-β treatment decreases the ability of pDCs to produce IFN-α, IL-6, TNF-α and chemokines CCL3, CCL4 and CCL5 [90], as well as inhibiting TLR9 processing necessary for TLR9-mediated activation of pDCs [87]. INH-ODNs, also called TLR9 antagonists, block downstream signaling events in TLR9-mediated activation [97,98]. BDCA-2 and ILT-7 inhibit human pDC functions, attenuating TLR-induced production of type I interferon and other cytokines [36]. Induction of IDO in human pDCs is implicated in Treg generation [104,105]. Blocking chemokine receptors (e.g., CCR7 or ChemR23) would control activated pDC recruitment to the CNS.
IDO: Indoleamine 2,3-dioxygenase; INH-ODN: Inhibitory oligodeoxyribonucleotide;pDC: Plasmacytoid dendritic cell.

The role of pDCs in immune regulation in MS has been addressed in several studies. The expression of the costimulatory molecule CD86 was decreased[85] or not changed[84] in pDCs isolated from patients with relapsing remitting MS. Expression of CD83, a costimulatory molecule and DC maturation marker, was decreased in pDCs in primary progressive MS patients.[84] CD137 is a member of the TNF receptor family, with stimulatory effect on T cells. The expression of CD137 ligand (4-1BBL) and CD86 was decreased in untreated relapsing–remitting multiple sclerosis patients compared with healthy controls.[85] In this study, treatment with glatiramer acetate restored the expression of CD86.[85] Schwab et al. suggested that pDCs in human peripheral blood could be divided into two subsets. The first subset (BDCA-4+, CD123low) primes IL-17-secreting T cells. The second subset (BDCA-4+, CD123high) promotes generation of IL-10-secreting T cells.[89] Patients with MS had an increased ratio of CD123low pDCs compared with healthy controls, which was corrected after immunomodulatory therapy with IFN-β. However, one may hypothesize that, in fact, these two phenotypic subsets represent different stages of pDC maturation.

In untreated MS patients, TLR9 agonist-activated pDCs produced increased levels of IFN-α compared with healthy subjects and IFN-β- treated patients with comparable frequency of IFN-α-producing pDCs.[90,91] Furthermore, MS patients had increased production of CCL3, CCL4 and CCL5, chemokines that attract CCR5-positive Th1 cells, and upregulation of CCR7, the chemokine receptor that directs APCs to secondary lymph organs and possibly to sites of CNS inflammation. A recent gene expression microarray study revealed the complexity of disease-associated changes in pDCs. More than 1200 genes were differentially expressed in pDCs of untreated MS patients compared with healthy subjects. Expression of 60 genes was 'corrected' after treatment with IFN-β.[92]

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