Search results for "experimental autoimmune encephalomyelitis"
showing 10 items of 88 documents
New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis
2015
Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system, which is thought to be triggered by environmental factors in genetically susceptible individuals leading to activation of autoreactive T lymphocytes. Large multi-centre genome-wide association studies have identified multiple genetic risk loci in multiple sclerosis. In this study, we investigated T cell transcriptomic changes in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We correlated these findings with the multiple sclerosis risk genes postulated by the most recent Immunochip analysis and found that multiple sclerosis susceptibility genes were significant…
Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis.
2011
Abstract Cannabinoid CB1 receptors (CB1Rs) regulate the neurodegenerative damage of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R stimulation exerts protective effects is still unclear. Here we show that pharmacological activation of CB1Rs dampens the tumor necrosis factor α (TNFα)-mediated potentiation of striatal spontaneous glutamate-mediated excitatory postsynaptic currents (EPSCs), which is believed to cogently contribute to the inflammation-induced neurodegenerative damage observed in EAE mice. Furthermore, mice lacking CB1Rs showed a more severe clinical course and, in parallel, exacerbated alterations of sEPSC duration af…
In Vivo Imaging of Partially Reversible Th17 Cell-Induced Neuronal Dysfunction in the Course of Encephalomyelitis
2010
SummaryNeuronal damage in autoimmune neuroinflammation is the correlate for long-term disability in multiple sclerosis (MS) patients. Here, we investigated the role of immune cells in neuronal damage processes in animal models of MS by monitoring experimental autoimmune encephalomyelitis (EAE) by using two-photon microscopy of living anaesthetized mice. In the brainstem, we detected sustained interaction between immune and neuronal cells, particularly during disease peak. Direct interaction of myelin oligodendrocyte glycoprotein (MOG)-specific Th17 and neuronal cells in demyelinating lesions was associated with extensive axonal damage. By combining confocal, electron, and intravital microsc…
Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity
2018
Significance In spite of TNF involvement in the pathogenesis of multiple sclerosis (MS), systemic TNF neutralization in MS patients was not successful. One of the possible reasons is that TNF possesses both pathogenic and protective features that may be related to TNFR1 versus TNFR2 receptor engagement. This study uncovers one of such protective functions of TNF mediated by intrinsic TNFR2 signaling in Treg cells. In mice bearing humanized TNF and TNFR2 genetic loci, TNFR2 ablation restricted to Treg cells led to reduced capacity to control Th17 cell responses, exacerbated experimental autoimmune encephalomyelitis (EAE) development, and affected the maintenance of Treg cells. These findings…
Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists
2014
The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing…
Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.
2007
The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher…
Role of Sortilin in Models of Autoimmune Neuroinflammation
2015
Abstract The proneurotrophin receptor sortilin is a protein with dual functions, being involved in intracellular protein transport, as well as cellular signal transduction. The relevance of the receptor for various neuronal disorders, such as dementia, seizures, and brain injury, is well established. In contrast, little is known about the role of sortilin in immune cells and inflammatory diseases. The aim of our study was to elucidate the distribution of sortilin in different immune cell types in mice and humans and to analyze its function in autoimmune CNS inflammation. Sortilin was expressed most profoundly in murine and human macrophages and dendritic cells and to a much lesser extent in…
Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function.
2009
Background: The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinicopathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains …
OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.
2019
Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell‐intrinsic mechanism governing astrocyte function during MS and EAE. Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE. Mice with astrocyte‐specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1‐deficient astrocytes were hy…
Molecular mechanisms linking neuroinflammation and neurodegeneration in MS.
2013
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) and one of the leading causes of neurological deficits and disability in young adults in western countries. Current medical treatment mainly influences disease progression via immunomodulatory or immunosuppressive actions. Indeed, MS research has been foremost focused on inflammation in the CNS, but more recent evidence suggests that chronic disability in MS is caused by neurodegeneration. Imaging studies show an early involvement of neurodegeneration as brain atrophy and gray matter lesions can be observed at disease onset. Thus, neuroprotective treatment strategies and the eluc…