Search results for "Sclerosis"

Polyvascular disease: A narrative review of current evidence and a consideration of the role of antithrombotic therapy.

2020

Abstract Background and aims Polyvascular disease (PVD) affects approximately 20% of patients with atherosclerosis and is a strong independent risk factor for ischemic outcomes. However, guidelines do not address screening or treatment for PVD, and there have been no PVD-specific trials. We reviewed subgroup analyses of large randomized controlled trials of more intense antithrombotic therapy to determine whether increased intensity of therapy improved ischemic outcomes in patients with PVD. Methods MEDLINE, MEDLINE in-Process, EMBASE, and the Cochrane Library were queried for randomized controlled trials larger than 5000 patients evaluating secondary prevention therapies in patients with c…

Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology?

2016

Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important fie…

Immunomodulatory effects of stem cells: Therapeutic option for neurodegenerative disorders.

2017

Stem cells have the capability of self-renewal and can differentiate into different cell types that might be used in regenerative medicine. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) currently lack effective treatments. Although stem cell therapy is still on the way from bench to bedside, we consider that it might provide new hope for patients suffering with neurodegenerative diseases. In this article, we will give an overview of recent studies on the potential therapeutic use of mesenchymal stem cells (MSCs), neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent…

Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK‐CHOP branch of the unfolded protein response

2017

Human neutrophil elastase impacts on atherosclerotic plaque stability by inducing apoptosis in endothelial cells. Our aim was to investigate the proapoptotic mechanism of elastase on endothelial cells and to evaluate the presence of elastase in human plaque material. Human endothelial cells were treated with purified human neutrophil elastase. Apoptosis was assayed by capsase-3/7 activation, TUNEL, and sub-G1 assay. Activation of unfolded protein response (UPR) effector molecules binding Ig protein, soluble X-binding protein-1, protein kinase RNA-like ER kinase (PERK), and C/EBP-homologous protein (CHOP) was analyzed by RT-PCR, immunocytochemistry, and Western blot. Genetic silencing of CHO…

2021

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated v…

Balanced Bcl-3 expression in murine CD4+T cells is required for generation of encephalitogenic Th17 cells

2017

The function of NF-κB family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IκB family. By using a murine model of conditional Bcl-3 overexpression specifically in T cells, we observed impairment in the development of Th2, Th1 and Th17 cells. High expression of Bcl-3 promoted CD4+ T-cell survival, but at the same time suppressed proliferation in response to TCR stimulation, resulting in reduced CD4+ T-cell expansion. As a consequence, T cell specific overexpression of Bcl-3 led to reduced inflammation in the small intestine of mice applied with anti-CD3 in a model of gut inflammation. Moreover, impaired Th17-cell develop…

Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice.

2016

This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr-/- Rag1-/- mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr-/- Rag1-/- Il2rg-/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western ty…

Time to activin on pathogenic T cells

2020

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic t…

Characterizing microstructural tissue properties in multiple sclerosis with diffusion MRI at 7 T and 3 T: The impact of the experimental design

2019

The recent introduction of advanced magnetic resonance (MR) imaging techniques to characterize focal and global degeneration in multiple sclerosis (MS), like the Composite Hindered and Restricted Model of Diffusion, or CHARMED, diffusional kurtosis imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI) made available new tools to image axonal pathology non-invasively in vivo. These methods already showed greater sensitivity and specificity compared to conventional diffusion tensor-based metrics (e.g., fractional anisotropy), overcoming some of its limitations. While previous studies uncovered global and focal axonal degeneration in MS patients compared to healthy contr…

Disease-Specific and Common HLA and Non-HLA Genetic Markers in Susceptibility to Rheumatoid Arthritis, Type 1 Diabetes Mellitus and Multiple Sclerosis

2016

Autoimmune diseases cause numerous health and social problems throughout the world. The common spectrum of autoimmune diseases affect the majority of tissues within the body, including pancreatic beta cells in type 1 diabetes (T1DM), myelin surrounding nerve axons in Multiple sclerosis (MS) and synovial joint antigens in Rheumatoid Arthritis (RA). The diseases are likely caused by a complex interaction between multiple HLA- and non- HLA related genes and environmental factors. The well documented co-clustering of autoimmune diseases within families and individuals, together with apparent sharing of number risk genes between the diseases suggests at least some common mechanisms of autoimmune…