Plasmacytoid dendritic cells in multiple sclerosis: Chemokine and chemokine receptor modulation by interferon-beta

Abstract

Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, leptomeninges and demyelinating lesions in patients with multiple sclerosis (MS). The ability of pDCs to produce chemokines and express the chemokine receptor CCR7 in MS is not known. We studied pDCs in MS patients and healthy subjects. The ability of pDCs to up-regulate CCR7 was significantly increased in untreated MS patients as compared to healthy subjects. IFN-beta treatment significantly inhibited TLR9 agonist-specific secretion of chemokines, which are ligands for CCR5-positive Th1 cells (CCL3, CCL4, and CCL5), and impaired TLR9 agonist-induced up-regulation of CCR7 and IFN-alpha in MS patients. This finding represents a new immunomodulatory effect of IFN-beta in patients with multiple sclerosis.

Multiple sclerosis-linked and interferon-beta-regulated gene expression in plasmacytoid dendritic cells

“…However, neither the frequency of IFN-alpha producing pDCs nor the total amount of IFN-alpha produced upon stimulation with TLR9 agonists were decreased in patients with MS based on our studies (Aung et al, 2010, Balashov et al, 2010). The gene expression levels of IFN-alpha were not significantly changed in pDCs of MS patients based our microarray results (data not shown).…”

“…IFN-beta impairs maturation of pDCs (Lande et al, 2008) and affects TLR9 processing and TLR9-mediated production of cytokines and chemokines (Aung et al, 2010, Balashov et al, 2010). …”

Plasmacytoid Dendritic Cells and Immunotherapy in Multiple Sclerosis

“…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.…”

“…The effect of immunomodulatory therapy on pDC phenotype and function has been reported [85–91,92]. Treatment with glatiramer acetate seems to restore the impaired maturation and altered regulatory function of pDCs in MS [85].…”

“…Treatment with glatiramer acetate seems to restore the impaired maturation and altered regulatory function of pDCs in MS [85]. Activated pDCs had decreased ability to produce IFN-α, IL-6, TNF-α and the chemokines CCL3, CCL4 and CCL5 in IFN-β-treated patients compared with untreated patients [91,92]. This effect may potentially lead to decreased migration of activated pDCs to the CNS and, afterwards, attraction of CCR5 + Th1 lymphocytes, which would diminish formation of new demyelinating lesions [38,92].…”