Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response

Abstract

Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-α compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-γ, TNF-α) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.

Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis

“…There is increasing evidence that the innate immune system contributes to MS pathogenesis. Vaknin-Dembinsky et al 28 have reported higher levels of the Th17 survival cytokine, IL23, in dendritic cells in MS. Huang et al 29 have reported that there are higher levels of dendritic cells secreting pro-inflammatory cytokines in RRMS, and recently, Karni et al 30 identified myeloid dendritic cells as drivers of the inflammatory response in RRMS and especially secondary progressive MS.…”

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…Peripheral DCs from patients with MS are more mature and polarize naive T cells to secrete higher levels of cytokines * This work was supported, in whole or in part, by National Institutes of Health when compared with DCs from healthy individuals (5). In addition to their key role in priming naive T cells in the periphery, CD11c…”

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

“…[60][61][62] Moreover, circulating cDCs in RRMS show increased expression of activation markers and chemokine (C-C motif) receptor 5 (CCR5) than healthy controls. 63,64 Interestingly, the expression of the CCR5 ligands chemokine (C-C motif) ligand 3 (CCL3) and CCL5 is increased in MS CNS lesions, 65 and CCR5 polymorphisms have been linked to changes in disease onset and activity, 66,67 suggesting that this pathway contributes to the recruitment of cDCs to the inflamed CNS of MS patients.…”