Microglia are long-living resident immune cells of the brain, which secure a stable chemical and physical microenvironment necessary for the proper functioning of the central nervous system (CNS). ...These highly dynamic cells continuously scan their environment for pathogens and possess the ability to react to damage-induced signals in order to protect the brain. Microglia, together with endothelial cells (ECs), pericytes and astrocytes, form the functional blood–brain barrier (BBB), a specialized endothelial structure that selectively separates the sensitive brain parenchyma from blood circulation. Microglia are in bidirectional and permanent communication with ECs and their perivascular localization enables them to survey the influx of blood-borne components into the CNS. Furthermore, they may stimulate the opening of the BBB, extravasation of leukocytes and angiogenesis. However, microglia functioning requires tight control as their dysregulation is implicated in the initiation and progression of numerous neurological diseases. Disruption of the BBB, changes in blood flow, introduction of pathogens in the sensitive CNS niche, insufficient nutrient supply, and abnormal secretion of cytokines or expression of endothelial receptors are reported to prime and attract microglia. Such reactive microglia have been reported to even escalate the damage of the brain parenchyma as is the case in ischemic injuries, brain tumors, multiple sclerosis, Alzheimer's and Parkinson's disease. In this review, we present the current state of the art of the causes and mechanisms of pathological interactions between microglia and blood vessels and explore the possibilities of targeting those dysfunctional interactions for the development of future therapeutics.
Abstract Multiple sclerosis (MS), an autoimmune neurological disorder, is driven by self-reactive T helper (Th) cells. Research on the role of Th17 lymphocytes in MS pathogenesis has made significant ...progress in identifying various immunological as well as environmental factors that induce the differentiation and expansion of these cells, different subsets of Th17 cells with varying degrees of pathogenicity, and the role of the secreted effector cytokines. While approved therapies for MS offer significant benefit to patients, there remain unmet needs. Ongoing clinical trials aim to translate the advanced knowledge of Th17 cytokines to improved therapies. This review discusses the current status and future developments of research into the role of Th17 and related cytokines in MS pathogenesis and therapy.
The past decades have yielded major therapeutic advances in many autoimmune conditions – such as multiple sclerosis (MS) – and thus ushered in a new era of more targeted and increasingly potent ...immunotherapies. Yet this growing arsenal of therapeutic immune interventions has also rendered therapy much more challenging for the attending physician, especially when treating patients with more than one autoimmune condition. Importantly, some therapeutic strategies are either approved for several autoimmune disorders or may be repurposed for other conditions, therefore opening new curative possibilities in related fields. In this article, we especially focus on frequent and therapeutically relevant concomitant autoimmune conditions faced by neurologists when treating patients with MS, namely psoriasis, rheumatoid arthritis and inflammatory bowel diseases. We provide an overview of the available disease-modifying therapies, highlight possible contraindications, show pathophysiological overlaps and finally present which therapeutics can be utilized as a combinatory treatment, in order to ‘kill two birds with one stone’.
Beyond the major role of T cells in the pathogenesis of the autoimmune neuroinflammatory disorder multiple sclerosis (MS), recent studies have highlighted the impact of B cells on pathogenic ...inflammatory processes. Follicular T helper cells (Tfh) are essential for the promotion of B cell-driven immune responses. However, their role in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), is poorly investigated. A first step to achieving a better understanding of the contribution of Tfh cells to the disease is the consideration of Tfh cell localization in relation to genetic background and EAE induction method. Here, we investigated the Tfh cell distribution during disease progression in disease relevant organs in three different EAE models. An increase of Tfh frequency in the central nervous system (CNS) was observed during peak of C57BL/6 J EAE, paralleling chronic disease activity, whereas in relapsing-remitting SJL EAE mice Tfh cell frequencies were increased during remission. Furthermore, transferred Tfh-skewed cells polarized in vitro induced mild clinical symptoms in B6.Rag1
mice. We identified significantly higher levels of Tfh cells in the dura mater than in the CNS both in C57BL/6 and in SJL/J mice. Overall, our study emphasizes diverse, non-static roles of Tfh cells during autoimmune neuroinflammation.
OBJECTIVETo determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients.
METHODSIn ...this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19 cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years).
RESULTSPatients with a larger BSA had a higher probability to reach 1% CD19 cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19 B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time.
CONCLUSIONSB-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patientsʼ BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.
Background
Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis ...(MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders.
Objective
To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM.
Methods
After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters.
Results
Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment.
Conclusions
We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.
Frauke Zipp is a clinician scientist and expert in multiple sclerosis and other neurological disorders. In an interview with Neuron, she talks about her early work in neuroimmunology and how her ...lab’s research has advanced our understanding of the interplay between the immune and nervous systems in health and disease.
IL-17-producing CD8
(Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS ...by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8
T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.
The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is ...potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1
+/GFP
mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia became activated in the stroke penumbra and started to expand cellular protrusions towards adjacent blood vessels. All microglia in the penumbra were found associated with blood vessels within 24 h post reperfusion and partially fully engulfed them. In the same time frame blood vessels became permissive for blood serum components. Migration assays in vitro showed that blood serum proteins leaking into the tissue provided molecular cues leading to the recruitment of microglia to blood vessels and to their activation. Subsequently, these perivascular microglia started to eat up endothelial cells by phagocytosis, which caused an activation of the local endothelium and contributed to the disintegration of blood vessels with an eventual break down of the blood brain barrier. Loss-of-microglia-function studies using CX3CR1
GFP/GFP
mice displayed a decrease in stroke size and a reduction in the extravasation of contrast agent into the brain penumbra as measured by MRI. Potentially, medication directed at inhibiting microglia activation within the first day after stroke could stabilize blood vessels in the penumbra, increase blood flow, and serve as a valuable treatment for patients suffering from ischemic stroke.
Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by ...astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells (NPCs) through the histone deacetylase (HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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