Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

Abstract

Many studies have demonstrated the role of the adaptive immune system in the pathogenesis of multiple sclerosis (MS). Recent data suggest that dendritic cells (DCs), which are innate immune cells, also contribute to the pathogenesis of MS. In patients with MS, DCs are abundantly present in brain lesions, and display an altered phenotype and/or function as compared with this in healthy controls. DCs are thus in the position to pathologically influence the effector function of (auto-reactive) T and B cells. Interestingly, current first-line immunomodulating therapies for MS have been shown to restore DC phenotype and function, albeit in a non-specific manner. To date, clinical trials using agents specifically targeting DC function are ongoing. Moreover, several studies worldwide are currently investigating possible strategies to develop tolerogenic DCs. This review focuses on the phenotypic and functional alterations of conventional DCs and plasmacytoid DCs in patients with MS. Furthermore, we discuss how existing immunomodulating therapies for MS patients affect DC function and address future perspectives in the development of immunotherapies specifically targeting DCs.

Immunomodulatory activity of interferon‐beta

“…TLRs are pattern recognition molecules that are constitutively expressed, primarily on APCs and, to a lesser extent, on lymphocytes 3. A subtype of dendritic cells, myeloid dendritic cells, expresses TLR2, which responds to microbial products and induces dendritic cells to secrete IL-12p70 to stimulate T cells 13,14. Plasmacytoid dendritic cells express TLR7 and TLR9 (which respond to microbial nucleic acids) and secrete type I interferon when activated 13,14.…”

“…A subtype of dendritic cells, myeloid dendritic cells, expresses TLR2, which responds to microbial products and induces dendritic cells to secrete IL-12p70 to stimulate T cells 13,14. Plasmacytoid dendritic cells express TLR7 and TLR9 (which respond to microbial nucleic acids) and secrete type I interferon when activated 13,14. Elevated type I interferon induces Treg phenotypes and Th1 cells 13,15…”

Cell-specific effects in different immune subsets associated with SOCS1 genotypes in multiple sclerosis

“…DCs are crucial to MS onset and development 22 and SOCS1 plays an important role in DC function. 23,24 Hence, we investigated the association between rs423674 and expression and moDC differentiation and maturation.…”

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…68 Thus, it is possible that deficits in pDCs contribute to disease pathology. Of note, however, several findings on pDC in MS have not always been replicated by independent groups, and it has been suggested that specific pDC subpopulations (e.g., pDC1 versus pDC2) are affected in MS. 69 …”

“…IFN-b treatment decreases the numbers of circulating cDC in RRMS, without affecting pDCs. 69 At the functional level, monocyte-derived DCs show decreased IL12p70 production and produced increased amounts of IL-10 following treatment with IFN-b. 76 In addition, IFN-b treatment induces an antiinflammatory phenotype in pDCs, characterized by the upregulation of PDL1 and IL-10 expression.…”