In toxic demyelination oligodendroglial cell death occurs early and is FAS independent

Oligodendroglial cell death is a frequent phenomenon of many neurological diseases, e.g. in demyelinating diseases such as multiple sclerosis (MS). The underlying mechanisms are largely unknown. Here, we demonstrate that in the toxic demyelination cuprizone model, oligodendroglial cell death and downregulation of myelin genes start days after initiation of the cuprizone diet and weeks before demyelination is obvious. In early – but not in later – stages, dying oligodendrocytes express activated caspase 3, suggesting a switch from classical apoptotic pathways to caspase 3-independent mechanisms during the course of the cuprizone diet. The expression level of FAS in the corpus callosum, a cel…

Expression of the G-protein coupled receptor EBI2 in T cells is highly regulated and confers pathogenicity to myelin specific Th17 cells

Cross-recognition of a myelin peptide by CD8+ T cells in the CNS is not sufficient to promote neuronal damage.

Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8+T cells are frequently found in multiple sclerosis lesions, their distinct role remains controversial because direct signs of cytotoxicity have not been confirmedin vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8+T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40–54 (MOG40–54) bothin vitroandin vivo. The aim of this study was to investigate whether such cross-recognizing CD8+T cells are capable of inducing CNS damagein vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, …

Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity

Abstract Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T…

Recovery from Toxic-Induced Demyelination Does Not Require the NG2 Proteoglycan

NG2 cells are defined as CNS cells expressing chondroitin sulfate proteoglycan nerve/glia antigen. The vast majority of NG2-positive cells also express platelet-derived growth factor receptor alpha (PDGFRα) and are oligodendroglial progenitors (OPC). In addition a subpopulation of pericytes expresses NG2, but is positive for PDGF receptor beta (PDGFRβ) [1]. NG2-positive OPC comprise approximately 5% of the cells in the CNS where they are evenly distributed in grey and white matter [2, 3]. NG2-positive OPC form synapses with neurons [4–6] and react to brain injury with proliferation, as has been shown in several animal models as well as in human demyelinating and degenerative diseases [7–9].…

Remyelinating strategies in multiple sclerosis.

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the CNS characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. In recent years, the importance of the neuronal compartment in the early pathology of multiple sclerosis has become increasingly clear. Direct axonal damage within the early stages of inflammation as well as neuronal injury as a result of chronic demyelination are essential factors for the development of long-term disability in patients. Viewing MS as both inflammatory and neurodegenerative has significant implications for treatment, with remyelination of denuded axons to protect neurons from dam…

EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7{alpha},25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7{alpha},25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1{beta}), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhan…