Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis

Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing-remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions-as frequently claimed-or is the atrophy stronger correlated to "silent" (nonlesional) microstructural thalamic alterations? One-hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic vol…

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune…

Dietary salt promotes ischemic brain injury and is associated with parenchymal migrasome formation

Sodium chloride promotes vascular fibrosis, arterial hypertension, pro-inflammatory immune cell polarization and endothelial dysfunction, all of which might influence outcomes following stroke. But despite enormous translational relevance, the functional importance of sodium chloride in the pathophysiology of acute ischemic stroke is still unclear. In the current study, we show that high-salt diet leads to significantly worse functional outcomes, increased infarct volumes, and a loss of astrocytes and cortical neurons in acute ischemic stroke. While analyzing the underlying pathologic processes, we identified the migrasome as a novel, sodium chloride-driven pathomechanism in acute ischemic …

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.

The potassium channels TASK2 and TREK1 regulate functional differentiation of murine skeletal muscle cells.

Two-pore domain potassium (K2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca2+-concentration [Ca2+]i. While the physiological importance of K2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis includin…

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis.

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 w…

PML risk stratification using anti-JCV antibody index and L-selectin

Background: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters. Objective: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification. Methods: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patient…

Cytosolic RIG-I–like helicases act as negative regulators of sterile inflammation in the CNS

The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 s…

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Background/aims Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca2+ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods We tested t…

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis

ObjectiveTo determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).MethodsSerum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing–remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we re…

Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration

Background: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. Objective: To detect microstructural cerebellar tissue alterations in early MS patients with a “normal appearing” cerebellum using diffusion tensor imaging (DTI). Methods: A total of 68 patients with relapsing–remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolu…

A novel automated segmentation method for retinal layers in OCT images proves retinal degeneration after optic neuritis.

Aim The evaluation of inner retinal layer thickness can serve as a direct biomarker for monitoring the course of inflammatory diseases of the central nervous system such as multiple sclerosis (MS). Using optical coherence tomography (OCT), thinning of the retinal nerve fibre layer and changes in deeper retinal layers have been observed in patients with MS. Here, we first compare a novel method for automated segmentation of OCT images with manual segmentation using two cohorts of patients with MS. Using this method, we also aimed to reproduce previous findings showing retinal degeneration following optic neuritis (ON) in MS. Methods Based on a 5×5 expansion of the Prewitt operator to efficie…

14-3-3 Proteins regulate K2P5.1 surface expression on T lymphocytes

K2P5.1 channels (also called TASK-2 or KCNK5) have already been shown to be relevant in the pathophysiology of autoimmune disease since they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14-3-3 proteins as novel binding partners of K2P5.1 channels. We show that a non-classical 14-3-3 co…

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis.

Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs = tolDCs) and are potential targets for the treatment of MS. While the immunogenic potential of DCs in fighting infection and cancer has been well established, approaches that exploit their tolerogenic features to promote transplantation tolerance and autoimmunity have emerged only more recently. TolDCs usually maintain antigen-specific T-cell tolerance either directly by inducing anergy, apoptosis, or phenotype skewing or indirectly by induction of …

Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by imbalanced immune regulatory networks, and MS patient-derived T effector cells are inefficiently suppressed through regulatory T cells (Treg), a phenomenon known as Treg resistance. In the current study we investigated T cell function in MS patients before and after interferon-beta therapy. We compared cytokine profile, responsiveness for Treg-mediated suppression ex vivo and evaluated reactivity of T cells in vivo using a humanized mouse model. We found that CD4+ and CD8+ T cells of therapy-naive MS patients were resistant to Treg-mediated suppression. Treg resistance is associated with an augmented IL-6 product…

The quality of cortical network function recovery depends on localization and degree of axonal demyelination

AbstractMyelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced…

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

Abstract Background We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. Methods In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. Findings Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (R…

Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity

Objective: Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity. Methods: Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing–remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of …

Gut-CNS-Axis as Possibility to Modulate Inflammatory Disease Activity-Implications for Multiple Sclerosis.

In the last decade the role of environmental factors as modulators of disease activity and progression has received increasing attention. In contrast to classical environmental modulators such as exposure to sun-light or fine dust pollution, nutrition is an ideal tool for a personalized human intervention. Various studies demonstrate a key role of dietary factors in autoimmune diseases including Inflammatory Bowel Disease (IBD), rheumatoid arthritis or inflammatory central nervous system (CNS) diseases such as Multiple Sclerosis (MS). In this review we discuss the connection between diet and inflammatory processes via the gut–CNS-axis. This axis describes a bi-directional communication syst…

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of…

Vaccination in multiple sclerosis patients treated with highly effective disease-modifying drugs: an overview with consideration of cladribine tablets

Infectious diseases are an important consideration in autoimmune conditions such as multiple sclerosis. Infective episodes may trigger relapses and significantly deteriorate the course of the disease. Some immunotherapies may cause increased rates of infection-related adverse events. Thus, infection and vaccine-related issues should be included in the individualized patient-specific treatment strategy and counseling before starting therapy and regularly on treatment. Clinical and epidemiological studies as well as pharmacovigilance data repeatedly demonstrated the safety of the great majority of vaccines in multiple sclerosis patients. Moreover, studies have shown that vaccinations with kil…

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing-remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-beta inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad…

Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responsesin vitro

Human tumors frequently escape immune destruction, despite the presence of cytotoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumor-specific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on fr…

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been repor…

Ocrelizumab initiation in patients with MS

ObjectiveTo provide first real-world experience on patients with MS treated with the B cell–depleting antibody ocrelizumab.MethodsWe retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed.ResultsWe could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5–5.5; range 0–8). Twenty-six percent of these patients had a pr…

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. …

Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.

ObjectiveTo evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.MethodsIn our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).ResultsThree hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09–13.07] weeks). Three months after the last ocrelizumab in…

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…

Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor+ Regulatory T Cells

SummaryMature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c+ DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction o…

Covarying patterns of white matter lesions and cortical atrophy predict progression in early MS

ObjectiveWe applied longitudinal 3T MRI and advanced computational models in 2 independent cohorts of patients with early MS to investigate how white matter (WM) lesion distribution and cortical atrophy topographically interrelate and affect functional disability.MethodsClinical disability was measured using the Expanded Disability Status Scale Score at baseline and at 1-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Covarying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel independent component analysis. Predictive power of covarying patterns for disability progression was tes…

UVB light attenuates the systemic immune response in CNS autoimmunity

Treatment choices and neuropsychological symptoms of a large cohort of early MS

ObjectiveTo assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS.MethodsThe German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms.ResultsOf 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06–40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded …

Low frequency and rare coding variation contributes to multiple sclerosis risk

AbstractMultiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including &gt;230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independe…

MSJ763541_supplementary_material – Supplemental material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

Supplemental material, MSJ763541_supplementary_material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis by Christiane Graetz, Adriane Gröge, Felix Luessi, Anke Salmen, Daniela Zöller, Janine Schultz, Nelly Siller, Vinzenz Fleischer, Barbara Bellenberg, Achim Berthele, Viola Biberacher, Joachim Havla, Michael Hecker, Reinhard Hohlfeld, Carmen Infante-Duarte, Jan S Kirschke, Tania Kümpfel, Ralf Linker, Friedemann Paul, Steffen Pfeuffer, Philipp Sämann, Gerrit Toenges, Frank Weber, Uwe K Zettl, Antje Jahn-Eimermacher, Gisela Antony, Sergiu Groppa, Heinz Wiendl, Bernhard Hemmer, Mark Mühlau, Carsten Lukas, Ralf Gold, Chri…

A human post-mortem brain model for the standardization of multi-centre MRI studies

Multi-centre MRI studies of the brain are essential for enrolling large and diverse patient cohorts, as required for the investigation of heterogeneous neurological and psychiatric diseases. However, the multi-site comparison of standard MRI data sets that are weighted with respect to tissue parameters such as the relaxation times (T1, T2) and proton density (PD) may be problematic, as signal intensities and image contrasts depend on site-specific details such as the sequences used, imaging parameters, and sensitivity profiles of the radiofrequency (RF) coils. Water or gel phantoms are frequently used for long-term and/or inter-site quality assessment. However, these phantoms hardly mimic t…

Neurons as targets for T cells in the nervous system

International audience; Accumulating evidence shows that T cells penetrate the central nervous system (CNS) parenchyma in several autoimmune, infectious, and degenerative neurological diseases. The structural and functional consequences for CNS neurons of their encounter with activated T cells have been investigated in several experimental systems, including ex vivo co-cultures, electrophysiology, and in vivo imaging. Here, we review the modalities of neuron/T cell interactions. We substantiate the contention that T cells are directly responsible for neuronal damage in a large number of neurological diseases and discuss mechanisms of neuronal damage mediated by distinct T cell subsets, the …

Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells.…

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or…

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatri…

The metalloproteinase-disintegrin ADAM10 is exclusively expressed by type I muscle fibers.

ADAM10 (Kuzbanian) is a member of a recently discovered family of membrane-anchored metalloproteinases with a complex and conserved domain structure. In part, these metalloproteinases have been implicated in muscle formation. Herein the expression pattern of ADAM10 in human skeletal muscle was studied. ADAM10 was found to be present in human myoblasts and to be exclusively expressed in type I fibers, suggesting that it may be critical in muscle fiber differentiation.

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis

Objective White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increa…

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

AbstractBackgroundMultiple sclerosis (MS) disease risk is associated with reduced sun exposure. This study assessed the relationship between measures of sun-exposure (vitamin D (vitD), latitude) and MS disease severity, the mechanisms of action, and effect-modification by medication and sun-sensitivity associated MC1R variants.MethodsTwo multi-center cohort studies (nNationMS=946, nBIONAT=991). Outcomes were the multiple sclerosis severity score (MSSS) and the number of Gd-enhancing lesion (GELs). RNAseq of four immune cell populations before and after UV-phototherapy of five MS patients.ResultsHigh serum vitD was associated with reduced MSSS (PNationMS=0.021; PBIONAT=0.007) and reduced ris…

Is APOE ε4 associated with cognitive performance in early MS?

ObjectiveTo assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).MethodsThis multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memo…

Substance P Saliva Reduction Predicts Pharyngeal Dysphagia in Parkinson's Disease

Introduction: Although patients with Parkinson's disease (PD) often suffer from oropharyngeal dysphagia, knowledge about the underlying pathophysiological mechanisms is limited. Substance P (SP) is a localization-independent neurotransmitter of the entire nervous system. Reduced levels of SP were found in saliva of patients with impaired cough reflex and in advanced stages of PD. The aim of the study was to investigate SP in PD patients in order to gain further insights into the underlying pathophysiology of PD-related dysphagia and to evaluate the potential of SP as a biomarker for early dysphagia. Methods: Flexible endoscopic evaluation of swallowing (FEES) was used to objectively assess …

High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients

Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration. Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk. Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiol…

The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in inflammatory myopathies

Inflammatory cell invasion and cytokine activation are important steps in the pathogenesis of immune-mediated diseases of muscle. Metalloproteinase-disintegrins (ADAMs) are considered to play a critical role in leukocyte migration by promoting cellular adhesion, cleavage of molecules of the extracellular matrix and shedding of membrane bound cytokines. Here, we report the expression patterns of ADAM8, ADAM9, ADAM10, ADAM12, ADAM17 and ADAM19 in cultured human myoblasts and peripheral blood mononuclear cells (PBMCs) in vitro, as well as in biopsies from patients suffering from polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and non-inflammatory controls. We observed an…

Identification of inflammatory neuronal injury and prevention of neuronal damage in multiple sclerosis: hope for novel therapies?

Importance Although multiple sclerosis (MS) has long been considered the prototype for an inflammatory, demyelinating disease of the central nervous system, modern histopathology and imaging techniques show that significant damage to neuronal structures already start occurring in the earliest stages of the disease. As the disease progresses, the extent of neuronal pathology accumulates. Therapeutic progress in terms of the prevention of increased disability has only just begun. Objective To review possible diagnostic improvements of neuronal compartment pathology as well as direct therapeutic interventions based on reports from the last decade and outline clinical results from studies and p…

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

Background and purpose: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in…