Analysis of seroconversion following COVID-19 vaccination among multiple sclerosis patients treated with disease-modifying therapies in Poland.

CLINICAL RATIONALE FOR THE STUDY: The rapid spread of SARS-CoV-2 throughout the world has highlighted the importance of vaccinations to control the pandemic and to protect people at risk for severe disease courses. Disease-modifying therapies (DMT) in multiple sclerosis (MS), whether immunomodulatory or immunosuppressive, may affect the immune response. Therefore, the question arose as to whether these vaccinations would be effective. AIM OF THE STUDY: We planned a study to assess the immune response to SARS-CoV-2 vaccines by type of therapy. MATERIAL AND METHODS: Participants were recruited from 14 Polish MS centres. The data was obtained by neurologists using a questionnaire. We collected data on 353 MS patients (269 females, 84 males) who received complete primary SARS-CoV-2 vaccination. All persons with MS (PwMS) were treated with disease-modifying therapies. RESULTS: 305 out of 353 PwMS (86.4%) were positive for IgG Abs against SARS-CoV-2 S domain S1 Ag after vaccination. A strong immune response was noted in 129 PwMS (36.5%). The rate of seroconversion after SARS-CoV-2 vaccination in PwMS who received immunomodulatory DMTs (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab) was 91.5%, in PwMS receiving immune reconstruction therapy (alemtuzumab, cladribine) was 92%, and in immunosuppressive DMTs (fingolimod, ocrelizumab), the seroconversion rate was 59%. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that, in PwMS receiving immunomodulatory therapy, the immune response to vaccination is generally excellent. Even in immunosuppressive patients, seroconversion is satisfactory.

Astrocyte-Derived Exosomes Differentially Shape T Cells' Immune Response in MS Patients.

Astrocytes, the most abundant group of glia cells in the brain, provide support for neurons and indicate multiple various functions in the central nervous system (CNS). Growing data additionally describe their role in the regulation of immune system activity. They exert their function not only by direct contact with other cell types, but also through an indirect method, e.g., by secreting various molecules. One such structure is extracellular vesicles, which are important mediators of crosstalk between cells. In our study, we observed that the impact of exosomes derived from astrocytes with various functional phenotype differently affect the immune response of CD4+ T cells, both from healthy individuals and from patients with multiple sclerosis (MS). Astrocytes, by modulating exosome cargo, impacts the release of IFN-γ, IL-17A and CCL2 in our experimental conditions. Considering the proteins concentration in cell culture supernatants and the cellular percentage of Th phenotypes, it could be stated that human astrocytes, by the release of exosomes, are able to modify the activity of human T cells.

LC-MS/MS Determination of Modified Nucleosides in The Urine of Parkinson's Disease and Parkinsonian Syndromes Patients.

Epigenetic modifications play a key role in gene regulation and expression and are involved in numerous cellular processes. Due to the limited research on nucleosides in Parkinson's disease (PD), it is very important to consider epigenetic factors and their role in the development of PD. The aim of this study was to investigate and compare the levels of modified nucleosides, such as O-methylguanosine, N6-methyl-2'-deoxyadenosine, 1-methyladenosine, 1-methylguanine, 7-methylguanine, 3-methyladenine and 7-methylguanosine in the urine of Parkinson's disease (PD) patients and the control group, and to verify that the results obtained differ in a subgroup of patients with parkinsonian syndromes. The study group comprised 18 patients with diagnosed idiopathic Parkinson's disease and four parkinsonian syndromes. The control group consisted of 30 age- and sex-matched neurological patients without confirmation by neuroimaging brain damage and extrapyramidal symptoms. The levels of nucleosides were determined by validated liquid chromatography coupled with the mass spectrometry (LC-MS/MS) method using the multiple reaction monitoring (MRM) mode. Lower levels of O-methylguanosine, 3-methyladenine, 1-methylguanine, N6-methyl-2'-deoxyadenosine and a higher level of 7-methylguanine in the urine of 22 PD patients were observed. Moreover, elevated levels of 1-methyladenosine, 7-methylguanine, and O-methylguanosine were observed in the parkinsonian syndrome subgroup. These preliminary results may indicate that modified nucleosides describe metabolic disturbances in the metabolism of purine, which was the most severely affected pathway that mediated the detrimental effects of neuroinflammation on PD.

CCR6 blockade on regulatory T cells ameliorates experimental model of multiple sclerosis.

Regulatory T cells (Tregs) play a significant role in limiting damage of tissue affected by autoimmune process, which has been demonstrated in various experimental models for multiple sclerosis (MS) (mostly experimental autoimmune encephalomyelitis - EAE), rheumatoid arthritis, and type 1 diabetes. In this study, we demonstrated that Tregs increasingly migrate to central nervous system (CNS) during subsequent phases of EAE (preclinical, initial attack, and remission). In contrast, in peripheral tissues (blood, lymph nodes, and spleen), a significant accumulation of Tregs is mostly present during EAE remission. Moreover, an increased expression of CCR6 on Tregs in the CNS, blood, lymph nodes, and spleen in all phases of EAE was observed. The highest expression of CCR6 on Tregs from the CNS, lymph nodes, and spleen was noted during the initial attack of EAE, whereas in the blood, the peak expression of CCR6 was detected during the preclinical phase. The presence of Tregs in the CNS during EAE was confirmed by immunohistochemistry. To analyze additional functional significance of CCR6 expression on Tregs for EAE pathology, we modulated the clinical course of this MS model using Tregs with blocked CCR6. EAE mice, which received CCR6-deficient Tregs showed significant amelioration of disease severity. This observation suggests that CCR6 on Tregs may be a potential target for future therapeutic interventions in MS.

The use of functional magnetic resonance imaging techniques in the evaluation of patients with disorders of consciousness: a case report.

PURPOSE: The management of patients with disorders of consciousness (DOC) constitutes a challenge for clinicians. CASE REPORT: We present the case of a 66-year-old man who developed coma with subsequent DOC after a severe traumatic brain injury. Behavioural assessment constitutes the gold standard in the evaluation of patients with DOC. In the case presented herein the neuropsychological findings were ambiguous, and the patient underwent functional magnetic resonance imaging (fMRI) to determine whether he was in a vegetative state or minimally conscious state. Three paradigms: passive, active, and resting state fMRI were used to study the brain activity in our patient. CONCLUSIONS: fMRI provided reliable evidence of preserved minimal consciousness. The neuroimaging techniques used in our patient were vital for his further treatment.

sP- and sE-selectin in stroke patients with metabolic disorders.

BACKGROUND: Activation of platelets and endothelial cells plays an important role in the pathogenesis of atherosclerosis and thrombotic disorders. The aim of our study was to assess the relationship between the metabolic disorders and markers of platelet activity and vascular injury in patient with acute ischemic stroke. MATERIAL AND METHODS: The study group consisted of 84 patients with acute non-lacunar ischemic stroke divided into four subgroups with: (1) normolipidemia and normoglycemia, (2) normolipidemia and hyperglycemia, (3) hyperlipidemia and normoglycemia, (4) hyperlipidemia and hyperglycemia. 21 healthy subjects served as controls. We analyzed the concentration of adhesion molecules sP-selectin and sE-selectin in serum collected from all studied groups using ELISA method. RESULTS: We observed significantly higher sE- and sP-selectin concentration in patients with hyperglycemia and hyperlipidemia compared to both control subjects and patients with normolipidemia and normoglycemia. We did not observe additional effect of comorbid hyperlipidemia and hyperglycemia on studied markers. Soluble E- and P-selectin concentration correlated positively with LDL, TC and HbA1c level in all stroke patients. CONCLUSION: Soluble E- and P-selectin, blood markers of vascular injury and platelet activation, could be useful in the assessment of atherothrombotic properties of hyperglycemia and hyperlipidemia in stroke patients.

Interleukin 17A Promotes Lymphocytes Adhesion and Induces CCL2 and CXCL1 Release from Brain Endothelial Cells.

The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). Tumor necrosis factor alpha (TNF-α) or interleukin 17 (IL-17) stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express Vascular cell adhesion molecule 1 (VCAM-1), the receptor responsible for inflammatory cell adhesion, which binds very late antigen 4 (VLA-4) on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-α and IL-17 on the adherence of Th17 cells to bEnd.3. The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.

66034T/C polymorphism of the human pregnane X receptor (hPXR) as potential risk factor for drug resistance in epilepsy - Preliminary study.

INTRODUCTION AND OBJECTIVES: Recent research has suggested that genetic factors may play an important role in the development of drug resistance in epilepsy. It is not clear which gene loci are responsible for the drug-resistant phenotype. Studying certain nuclear receptors may be helpful in predicting drug response, as they regulate drug transporting proteins and enzymes involved in their metabolism. This study focuses on one of these receptors, the human pregnane X receptor (hPXR). The objective was to examine the link between selected single nucleotide polymorphisms (SNPs) 69789A/G rs 7643645 and 66034T/C rs 13059232 hPXR and the lack of response to epilepsy treatment. MATERIALS AND METHODS: 73 patients diagnosed with drug-resistant epilepsy were included in the study. The diagnoses were made according to the criteria published by The International League Against Epilepsy (ILAE) in 2010. The control group was comprised of a group of 122 healthy volunteers. Genetic material isolated from the peripheral blood of the participants was analyzed with TagMan Genotyping Assays in search of the selected hPXR polymorphisms. RESULTS: The distribution of genotypes of the 66034T/C rs 13059232 hPXR polymorphism was significantly different in the group with drug-resistant epilepsy and the control group. In the drug-resistant group the CC genotype was significantly more common compared to the control group (50.7% vs 35.2%) p=0.0339. The distribution of 69789 A/G rs 7643645 hPXR genotypes was comparable in both groups. CONCLUSIONS: There is potential association between hPXR and drug resistance but its relevance for the development of drug-resistant phenotype remains to be studied.

The impact of multiple sclerosis relapse treatment on migration of effector T cells--Preliminary study.

UNLABELLED: Migration of inflammatory cells from the blood to the central nervous system (CNS) is crucial for development of multiple sclerosis (MS). Inhibition of this process would allow to control disease activity. The first step confirming this approach would be the analysis of the impact of effective MS relapse therapy on migration of effector T cells. The aim of the study was to analyze the influence of methylprednisolone (MP) on the migratory activity of effector CD4+ T cells from MS patients. Moreover, to study the potential mechanism of this process we studied expression of chemokine receptors on migrating cells. MATERIAL AND METHODS: Peripheral blood samples were obtained from relapsing-remitting MS (RR-MS) patients during relapse (n=23) and from control group (n=23). After isolation CD4+ T cells were incubated with various concentrations of MP. Then they were stimulated in chemotaxis assay with chemokines CCL3 or CXCL10 or were used to CCR1 and CXCR3 expression analysis. RESULTS: CXCL10- and CCL3-stimulated migration of CD4+ T cells was significantly increased in MS. MP was able to reduce in vitro migration of effector T cells induced by CXCL10, but not by CCL3. Inhibition by MP was dose-dependent. Expression of analyzed chemokine receptors was unaltered after MP incubation. CONCLUSIONS: MP reduced CD4+ T cells migration induced by CXCL10 without affecting CXCR3 expression. These observations demonstrate one of the potential mechanisms of MP action in MS, distinct from inducing cell apoptosis, and suggests the new targets for development of more effective MS treatments.

Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background.

Multiple sclerosis is an autoimmune neurodegenerative disorder resulting in motor dysfunction and cognitive decline. The inflammatory and neurodegenerative changes seen in the brains of MS patients lead to progressive disability and increasing brain atrophy. The most common type of MS is characterized by episodes of clinical exacerbations and remissions. This suggests the presence of compensating mechanisms for accumulating damage. Apart from the widely known repair mechanisms like remyelination, another important phenomenon is neuronal plasticity. Initially, neuroplasticity was connected with the developmental stages of life; however, there is now growing evidence confirming that structural and functional reorganization occurs throughout our lifetime. Several functional studies, utilizing such techniques as fMRI, TBS, or MRS, have provided valuable data about the presence of neuronal plasticity in MS patients. CNS ability to compensate for neuronal damage is most evident in RR-MS; however it has been shown that brain plasticity is also preserved in patients with substantial brain damage. Regardless of the numerous studies, the molecular background of neuronal plasticity in MS is still not well understood. Several factors, like IL-1ß, BDNF, PDGF, or CB1Rs, have been implicated in functional recovery from the acute phase of MS and are thus considered as potential therapeutic targets.

Hemorrhagic stroke, cerebral amyloid angiopathy, Down syndrome and the Boston criteria.

A stroke, or a cerebrovascular accident (CVA) is a life-threatening condition which often results in permanent or significant disability in the adult population. Several classifications of CVAs exist, one of them being based on the mechanism of injury of brain tissue: ischemic (85-90%) and hemorrhagic (10-15%). In a hemorrhagic stroke an intercranial bleeding occurs, leading to the formation of a focal hematoma typically located in the basal ganglia of the brain (approx. 45% of cases). A common yet underestimated cause of intracerebral hemorrhage is cerebral small vessel disease with microhemorrhages, including the cerebral amyloid angiopathy (CAA). This condition is associated with the deposition of amyloid-beta in arterial walls (in soft meninges, subcortical areas and the cerebral cortex). Research has shown that causes of hemorrhagic changes in the brain include genetic disorders, such as Down syndrome. The association is caused by the so-called 'gene dosage effect', as the gene for the precursor protein for amyloid-beta is located in chromosome 21. We wish to present the case of a 60 year old patient with Down syndrome who suffered a hemorrhagic stroke without antecedent hypertension. Based on the history taken, diagnostic imaging and the source literature, a diagnosis of cerebral amyloid angiopathy as the source of the bleeding was made (however it must be noted that without a full post-mortem examination, the Boston criteria allow only for a 'probable cerebral amyloid angiopathy' diagnosis to be made). The authors hereby also report the need to modify the Boston criteria for cerebral amyloid angiopathy.

[Chemokine CC receptors in the nervous system]. / Receptory chemokin z motywem CC w ukladzie nerwowym.

Chemoattractant cytokines (chemokines) are traditionally known as the important mediators of inflammatory processes, however, recently, is also given to their other functions in the body. Acting through specific receptors belonging to the G proteins they regulate immune processes in the body. About 20 chemokine receptors have been identified so far, and 10 of them bind chemokines CC, i.e. having in amino-terminal domain 2 adjacent molecules of cysteins. An increasing number of data indicates that chemokines and their receptors play an important role in the nervous system by acting as trophic factors, increasing the neurons survival, neural migration and synaptic transmission. Special role chemokine receptors play primarily in the diseases of the nervous system, because due to damage of the blood-brain barrier and the blood cerebrospinal fluid barrier, infiltration of leukocytes results in development of inflammation. Chemokine CC receptors has been shown to participate in Alzheimer's disease, multiple sclerosis, dementia associated with HIV infection, stroke or some type of cancers.

Interactions between neutrophils, Th17 cells, and chemokines during the initiation of experimental model of multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation. In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain. Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed. Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed. Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks. Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE. Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE. Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells.

Neurologic and functional long-term outcome after carotid endarterectomy.

BACKGROUND: The aim of this research was to assess the neurologic status of patients a year after endarterectomy with the use of National Institutes of Health Stroke Scale (NIHSS) and the degree of disability using the modified Rankin Scale (mRS) and to examine the patients' subjective evaluation of their health. METHODS: One hundred two patients with symptomatic internal carotid artery stenosis who underwent endarterectomy and attended a 1-year follow-up examination were enrolled in the study. The material comprised 72 (70.6%) men and 30 (29.4%) women. Before the surgery, the patients' neurologic status was assessed according to the NIHSS, and their functional status was rated with the mRS. Additionally, the patients were asked to assess their life quality on a 10-point Likert scale. RESULTS: The mean NIHSS score before the operation was 2.76 points (SD 2.47), whereas a year after it was 2.05 points (SD 1.84) (P < .0001). The NIHSS scores that improved significantly a year after endarterectomy were level of consciousness-questions and commands, motor leg, and sensory (P < .05). CONCLUSIONS: The patients' neurologic status assessed with the NIHSS improved significantly 1 year after carotid endarterectomy mostly because of the improvement in their verbal and motor communication ability, physical condition and agility, and reduction in sensory disturbances. The observed changes in the neurologic status were reflected in the functional status and subjective life quality assessment, which appeared to be significantly better a year after the surgical treatment.

CXCL1 as a Potential Biomarker of Plaque Instability in Carotid Stenosis. Preliminary Report.

Biomarkers of atherosclerotic plaque instability are needed. This study aimed to evaluate the level of chemokine CXCL1 (CXC motif ligand 1) in plasma and atherosclerotic plaques in patients with carotid stenosis and correlate that with plaque morphology. The study group included 82 patients (30 women and 52 men) aged 50-90 years (mean 68.1 ± 8.9) who underwent elective carotid endarterectomy. The obtained atherosclerotic plaques were macroscopically and microscopically assessed according to the American Heart Association (AHA) classification. Fifty-one (62.2%) and 31 (37.8%) of the plaques were unstable and stable, respectively. The mean concertation of CXCL1 in plaques in asymptomatic and symptomatic patients was 0.00 (±0.00) vs 88.90 (±95.19) pg/ml, respectively (P = 0.000). The mean plasma concentration of CXCL1 in the study group was 42.40 (±85.79) pg/ml, while in the control group (healthy volunteers without lesions in the carotid arteries) it was 0.00 pg/mL (±0.00) (P = 0.000). The mean plasma CXCL1 concertation in asymptomatic and symptomatic patients was 22.08 (±49.13) versus 67.72 (±107.91) pg/ml, respectively (P = 0.031). Significantly higher CXCL1 concentration in atherosclerotic plaques and plasma in symptomatic patients compared with asymptomatic patients probably resulted from unstable lesions in the carotid arteries.

The Role of Neutrophils in Multiple Sclerosis and Ischemic Stroke.

Inflammation plays an important role in numerous central nervous system (CNS) disorders. Its role is ambiguous-it can induce detrimental effects, as well as repair and recovery. In response to injury or infection, resident CNS cells secrete numerous factors that alter blood-brain barrier (BBB) function and recruit immune cells into the brain, like neutrophils. Their role in the pathophysiology of CNS diseases, like multiple sclerosis (MS) and stroke, is highly recognized. Neutrophils alter BBB permeability and attract other immune cells into the CNS. Previously, neutrophils were considered a homogenous population. Nowadays, it is known that various subtypes of these cells exist, which reveal proinflammatory or immunosuppressive functions. The primary goal of this review was to discuss the current knowledge regarding the important role of neutrophils in MS and stroke development and progression. As the pathogenesis of these two disorders is completely different, it gives the opportunity to get insight into diverse mechanisms of neutrophil involvement in brain pathology. Our understanding of the role of neutrophils in CNS diseases is still evolving as new aspects of their activity are being unraveled. Neutrophil plasticity adds another level to their functional complexity and their importance for CNS pathophysiology.

Chemokines and neurodegeneration in the early stage of experimental ischemic stroke.

Neurodegeneration is a hallmark of most of the central nervous system (CNS) disorders including stroke. Recently inflammation has been implicated in pathogenesis of neurodegeneration and neurodegenerative diseases. The aim of this study was analysis of expression of several inflammatory markers and its correlation with development of neurodegeneration during the early stage of experimental stroke. Ischemic stroke model was induced by stereotaxic intracerebral injection of vasoconstricting agent endothelin-1 (ET-1). It was observed that neurodegeneration appears very early in that model and correlates well with migration of inflammatory lymphocytes and macrophages to the brain. Although the expression of several studied chemotactic cytokines (chemokines) was significantly increased at the early phase of ET-1 induced stroke model, no clear correlation of this expression with neurodegeneration was observed. These data may indicate that chemokines do not induce neurodegeneration directly. Upregulated in the ischemic brain chemokines may be a potential target for future therapies reducing inflammatory cell migration to the brain in early stroke. Inhibition of inflammatory cell accumulation in the brain at the early stage of stroke may lead to amelioration of ischemic neurodegeneration.

MicroRNAs as novel regulators of neuroinflammation.

MicroRNAs are relatively recently discovered class of small noncoding RNAs, which function as important regulators of gene expression. They fine-tune protein expression either by translational inhibition or mRNA degradation. MicroRNAs act as regulators of diverse cellular processes, such as cell differentiation, proliferation, and apoptosis. Their defective biogenesis or function has been identified in various pathological conditions, like inflammation, neurodegeneration, or autoimmunity. Multiple sclerosis is one of the predominated debilitating neurological diseases affecting mainly young adults. It is a multifactorial disorder of as yet unknown aetiology. As far, it is suggested that interplay between genetic and environmental factors is responsible for MS pathogenesis. The role of microRNAs in this pathology is now extensively studied. Here, we want to review the current knowledge of microRNAs role in multiple sclerosis.

The Influence of Conventional and Innovative Rehabilitation Methods on Brain Plasticity Induction in Patients with Multiple Sclerosis.

Physical rehabilitation and physical activity are known non-pharmacological methods of treating multiple sclerosis. Both lead to an improvement in physical fitness in patients with movement deficits while improving cognitive function and coordination. These changes occur through the induction of brain plasticity. This review presents the basics of the induction of brain plasticity in response to physical rehabilitation. It also analyzes the latest literature evaluating the impact of traditional physical rehabilitation methods, as well as innovative virtual reality-based rehabilitation methods, on the induction of brain plasticity in patients with multiple sclerosis.

Dietary Polyphenols Decrease Chemokine Release by Human Primary Astrocytes Responding to Pro-Inflammatory Cytokines.

Astrocytes are considered to be the dominant cell fraction of the central nervous system. They play a supportive and protective role towards neurons, and regulate inflammatory processes; they thus make suitable targets for drugs and supplements, such as polyphenolic compounds. However, due to their wide range, knowledge of their anti-inflammatory potential remains relatively incomplete. The aim of this study was therefore to determine whether myricetin and chrysin are able to decrease chemokine release in reactive astrocytes. To assess the antioxidant and anti-inflammatory potential of polyphenols, human primary astrocytes were cultured in the presence of a reactive and neurotoxic astrocyte-inducing cytokine mixture (TNF-α, IL-1a, C1q), either alone or in the presence of myricetin or chrysin. The examined polyphenols were able to modify the secretion of chemokines by human cortical astrocytes, especially CCL5 (chrysin), CCL1 (myricetin) and CCL2 (both), while cell viability was not affected. Surprisingly, the compounds did not demonstrate any antioxidant properties in the astrocyte cultures.