RESUMO
BACKGROUND AND PURPOSE: Individuals with radiologically isolated syndrome (RIS) are at increased risk of converting to multiple sclerosis (MS). Early identification of later converters is crucial for optimal treatment decisions. The purpose of this study was to assess the predictive potential of optical coherence tomography (OCT) measures in individuals with RIS regarding conversion to MS. METHODS: This prospective observational cohort study included 36 individuals with RIS and 36 healthy controls recruited from two German MS centers. All individuals received baseline OCT and clinical examination and were longitudinally followed over up to 6 years. The primary outcome measure was the conversion to MS. RESULTS: During clinical follow-up of 46 (26-58) months (median, 25%-75% interquartile range), eight individuals with RIS converted to MS. Individuals converting to MS showed a thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the common ganglion cell and inner plexiform layer (GCIP) at baseline and during follow-up. Individuals with a pRNFL of 99 µm or lower or a GCIP of 1.99 mm3 or lower were at a 7.5- and 8.0-fold risk for MS conversion, respectively, compared to individuals with higher measures. After correction for other known risk factors, Cox proportional hazards regression revealed a hazard ratio of 1.08 for conversion to MS for each 1 µm decline in pRNFL. CONCLUSIONS: Reduction of the pRNFL might be a novel and independent risk factor for conversion to MS in individuals with RIS. OCT might be useful for risk stratification and therapeutic decision-making in individuals with RIS.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Doenças Desmielinizantes/diagnóstico por imagem , Humanos , Esclerose Múltipla/diagnóstico por imagem , Estudos Prospectivos , Retina/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
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 the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto/normas , Sociedades Médicas/normas , Europa (Continente) , HumanosRESUMO
BACKGROUND AND PURPOSE: Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. METHODS: Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. RESULTS: In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. CONCLUSIONS: Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections.
Assuntos
Infecções do Sistema Nervoso Central/diagnóstico , Infecções do Sistema Nervoso Central/virologia , Encefalite/diagnóstico , Infecções por Enterovirus/diagnóstico , Infecções por Herpesviridae/diagnóstico , Meningite Asséptica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções do Sistema Nervoso Central/epidemiologia , Encefalite/epidemiologia , Encefalite/virologia , Infecções por Enterovirus/epidemiologia , Feminino , Alemanha/epidemiologia , Infecções por Herpesviridae/epidemiologia , Humanos , Incidência , Masculino , Meningite Asséptica/epidemiologia , Meningite Asséptica/virologia , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.
Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Monitorização Imunológica/métodos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Humanos , Imunocompetência/efeitos dos fármacos , Imunocompetência/imunologia , Esclerose Múltipla/classificaçãoRESUMO
In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.
Assuntos
Alergia e Imunologia/normas , Imunossupressores/administração & dosagem , Imunoterapia/normas , Esclerose Múltipla/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Alemanha , Humanos , Imunossupressores/normas , Esclerose Múltipla/imunologiaRESUMO
During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.
Assuntos
Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , GravidezRESUMO
We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same "infusion group". The group consisted of four patients with relapsing-remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Leucoencefalopatia Multifocal Progressiva/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/transmissão , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/virologia , Natalizumab , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.
Assuntos
Antígenos Comuns de Leucócito/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Mutação Puntual , Sequência de Bases , Estudos de Casos e Controles , DNA/genética , Primers do DNA/genética , Éxons , Feminino , Variação Genética , Heterozigoto , Humanos , Masculino , Esclerose Múltipla/enzimologia , Linhagem , FenótipoRESUMO
Interferons-ß (IFN-ß) are the most widely used immunomodulatory drugs for treatment of multiple sclerosis (MS). The development of neutralizing antibodies (NABs) against IFN-ß is one of the main reasons for treatment failure. While formulation of the drug has a proven impact on the development of NABs, the genetic predisposition to develop antibodies is poorly understood. We performed genome-wide single-nucleotide polymorphism (SNP) genotyping in 362 MS patients of whom 178 had developed and 184 had not developed antibodies on IFN-ß therapy. Four candidate SNPs were validated in an independent cohort of 350 antibody-positive and 468 antibody-negative MS patients. One SNP within the human leucocyte antigen (HLA) region (rs9272105, P-value: 3.56 × 10⻹°) and one SNP in an intergenic region on chromosome 8q24.3 (rs4961252, P-value: 2.92 × 10â»8 showed a genome-wide significant association with the anti-IFN-ß antibody titers. We found no interaction between the genome-wide significant SNPs (rs9272105 and rs4961252) in our study and the previously described HLA-DR*0401 or *0408 alleles, indicating an additive effect of SNPs and HLA alleles. Testing for these SNPs and the HLA-DR*0401 or *0408 alleles allows to identify patients at risk to develop antibodies to IFN-ß and may provide helpful information for individual treatment decisions.
Assuntos
Anticorpos Neutralizantes/sangue , Cromossomos Humanos Par 8 , Antígenos HLA/genética , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , DNA Intergênico , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Fatores Imunológicos/imunologia , Interferon beta/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Fenótipo , Medição de Risco , Fatores de Risco , Falha de Tratamento , Adulto JovemRESUMO
BACKGROUND: Multiple sclerosis treatment options are increasing. Evidence-based patient information (EBPI) are therefore crucial to enable patient involvement in decision making. Based on earlier work on decision support, patient information handbooks on 8 MS immunotherapies were developed, piloted and evaluated with support from the German Clinical Competence Network MS and the German MS Society. METHODS: Handbooks were structured according to EBPI concepts. Drafts were commented by patient representatives and neurologists with an MS expertise. Executive boards of the German MS Society and the Competence Network as well as pharmaceutical companies' feedback was included. Handbooks were distributed among MS neurologists by the German MS Society. Evaluation followed applying a mixed methods approach with interviews, focus groups and surveys. One survey addressed persons with MS (pwMS) based on a questionnaire included in each handbook. Neurologists who received printed patient handbooks were invited to give feedback in a second survey. RESULTS: Eight handbooks were developed providing absolute and relative risk information in numbers and figures as well as monitoring needs and drug fact boxes. Despite the high amount of information and the display of low absolute risk reduction rates of treatments, handbooks were overall appreciated by pwMS (n=107) and mostly also by physicians (n=24). For more than 70% of the pwMS the information was new, understandable and supportive for decision making. But patients felt uncomfortable with relative risk information. However, response rates in the evaluation were low, exposing the challenges when implementing EBPI into clinical care. Therefore, conclusions must be considered preliminary. CONCLUSION: EBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.
Assuntos
Esclerose Múltipla , Grupos Focais , Humanos , Imunoterapia , Esclerose Múltipla/tratamento farmacológico , Neurologistas , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. METHODS: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. RESULTS: Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. CONCLUSION: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.
Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monossacarídeos/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Feminino , Testes Genéticos/métodos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Adulto JovemRESUMO
Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in infectious diseases, tumors and autoimmune diseases.
Assuntos
Epitopos/isolamento & purificação , Doença de Lyme/imunologia , Mimetismo Molecular/imunologia , Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Antígenos de Bactérias/genética , Antígenos de Bactérias/isolamento & purificação , Autoantígenos/genética , Autoantígenos/isolamento & purificação , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/isolamento & purificação , Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/imunologia , Células Clonais , Epitopos/genética , Humanos , Imunidade Celular , Técnicas In Vitro , Doença de Lyme/genética , Neuroborreliose de Lyme/genética , Neuroborreliose de Lyme/imunologia , Ativação Linfocitária , Masculino , Mimetismo Molecular/genética , Polimorfismo Conformacional de Fita SimplesRESUMO
OBJECTIVE: To examine the dynamics of intracranial venous flow patterns in patients with idiopathic intracranial hypertension (IIH). METHODS: Nonrandomized controlled trial analyzing the difference in cerebral perfusion in 13 IIH patients and 12 healthy controls using contrast-enhanced duplex sonography. In patients, an additional 3D gradient echo magnetic resonance venography (MRV) using a new technique was performed to quantify stenosis of the cerebral sinus. The cerebral perfusion parameters, including cerebral transit time (CTT) and time to peak (TTP), were analyzed. RESULTS: IIH patients had a higher BMI (29.3 [95% CI 26.4, 32.2] vs. 23.3 [95% CI 20.7, 25.9], p = 0.003) and an increased prevalence of headache, but all other clinical characteristics were comparable. The CTT did not differ significantly. The TTP was significantly longer in IIH patients compared to controls (8.5 [95% CI 7.6, 9.4] vs. 7.3 s [95% CI 6.3, 8.1], p = 0.04). Twelve of 13 (92%) IIH patients showed stenosis of the cerebral sinus. CONCLUSIONS: Our study is the first to report an altered cerebral venous flow in IIH patients compared to controls using a dynamic ultrasonographic technique. A simplified MRV technique confirms the high prevalence and reliable detection of venous stenosis in IIH patients.
Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Pseudotumor Cerebral/diagnóstico por imagem , Pseudotumor Cerebral/fisiopatologia , Adulto , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Cavidades Cranianas/patologia , Cavidades Cranianas/fisiopatologia , Feminino , Hemodinâmica/fisiologia , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Flebografia/métodos , Pseudotumor Cerebral/patologia , Ultrassonografia Doppler DuplaRESUMO
Fingolimod and natalizumab are approved disease-modifying drugs in relapsing-remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Cloridrato de Fingolimode/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Natalizumab/uso terapêutico , Estudos RetrospectivosRESUMO
PURPOSE: Through analysis of T1-weighted (T1w) images this study investigated gadolinium (Gd) deposition in the brain after administration of a linear (gadopentetic acid) and a cyclic (gadoteric acid) gadolinium-based contrast agent (GBCA) in patients with multiple sclerosis (MS), a disorder frequently requiring magnetic resonance imaging (MRI) scans over years. METHODS: A total of 3233 T1w images (unenhanced with respect to the same scanning session) of 881 MS patients were retrospectively analyzed. After spatial normalization and intensity scaling using a sphere within the pons, differences of all pairs of subsequent scans were calculated and attributed to either linear (nâ¯= 2718) or cyclic (nâ¯= 385) or no GBCA (nâ¯= 130) according to the first scan. Regional analyses were performed, focusing on the dentate nucleus, and whole brain analyses. By 1sample ttests, signal intensity increases within conditions were searched for; conditions were compared by 2sample ttests. Furthermore, recent hypotheses on the reversibility of GBCA deposition were tested. RESULTS: In the dentate nucleus, a significant increase was observed only after administration of linear GBCA even after a single GBCA administration. This increase differed significantly (pâ¯< 0.001) from the other conditions (cyclic and no GBCA). Whole brain analyses revealed T1w signal increases only after administration of linear GBCA within two regions, the dentate nucleus and globus pallidus. Additional analyses did not indicate any decline of Gd deposition in the brain. CONCLUSION: The data point towards Gd deposition in the brain after administration of linear GBCA even after a single administration.
Assuntos
Esclerose Múltipla , Compostos Organometálicos , Meios de Contraste , Feminino , Gadolínio , Gadolínio DTPA , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Estudos RetrospectivosRESUMO
Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27+ memory, and CD27-IgD- double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.
Assuntos
Linfócitos B/efeitos dos fármacos , Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Adolescente , Adulto , Idoso , Linhagem da Célula/efeitos dos fármacos , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células B de Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Adulto JovemRESUMO
CD4+ class II-restricted T cells specific for self antigens are thought to be involved in the pathogenesis of most human autoimmune diseases and molecular mimicry between foreign and self ligands has been implicated as a possible mechanism for their activation. In this report we introduce combinatorial peptide libraries as a powerful tool to identify cross-reactive ligands for these T cells. The antigen recognition of a CD4+ T cell clone (TCC) specific for myelin basic protein peptide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the libraries for each position of the antigen, artificial peptides were found that induced proliferative responses at much lower concentrations than MBP(86-96). In addition stimulatory ligands derived from protein sequences of self and microbial proteins were identified, some of them even more potent agonists than MBP(86-96). These results indicate that: (a) for at least some autoreactive CD4+ T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC represents only a suboptimal ligand for the TCC; (c) a completely random and unbiased approach such as combinatorial peptide libraries can decrypt the spectrum of stimulatory ligands for a T cell receptor (TCR).
Assuntos
Autoantígenos/química , Autoimunidade/imunologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Células Clonais , Humanos , Ligantes , Ativação Linfocitária , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/imunologia , Peptídeos/imunologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The proposed predictive value of serum anti-myelin antibodies for the development of multiple sclerosis after a first clinically isolated syndrome was recently challenged. OBJECTIVE: To investigate myelin autoantibodies before first disease manifestation using different detection methods. METHODS: Patients with multiple sclerosis who had donated blood at a time prior to development of clinically isolated syndrome were identified via the German National Multiple Sclerosis Society. Control sera were obtained from age- and gender-matched blood donors. IgG-/IgM-antibodies against the extracellular part of native, cell surface-expressed myelin oligodendrocyte glycoprotein were detected by flow cytometry. Antibodies against linear epitopes were identified by immunoblot using recombinant myelin oligodendrocyte glycoprotein (aa1-125) and human myelin basic protein preparations. RESULTS: Fifty eight serum samples from 25 patients covering an interval of 7.3 years-2 months prior to disease onset were available. Longitudinal investigations were performed in 19 patients (2-14 samples per patient, 7 years-2 months prior to disease onset). No significant differences in the prevalence or titres of anti-myelin antibodies were detected between sera of preclinical individuals and healthy donors by either flow cytometry or immunoblot. There was no correlation between interval before clinically isolated syndrome and autoantibody status. Occurrence of antibodies was not associated with symptomatology/severity of clinically isolated syndrome. CONCLUSION: Neither anti-myelin autoantibodies against cell surface-expressed native myelin oligodendrocyte glycoprotein nor against linear epitopes have a predictive or discriminative role during the preclinical disease phase for developing clinically isolated syndrome or multiple sclerosis later in life.
Assuntos
Anticorpos/análise , Esclerose Múltipla/imunologia , Glicoproteína Associada a Mielina/imunologia , Adulto , Biomarcadores/análise , Western Blotting , Progressão da Doença , Epitopos , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/análise , Imunoglobulina M/análise , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina , Glicoproteína Associada a Mielina/química , Glicoproteína Mielina-Oligodendrócito , Valor Preditivo dos Testes , Conformação Proteica , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Despite numerous studies suggesting a relationship between paradoxical embolism from a patent foramen ovale (PFO) and stroke, the role of PFO as a risk factor for cerebral ischaemia remains controversial. We therefore sought to determine the association between a RLS detected by contrast-enhanced transcranial Doppler ultrasonography (c-TCD) and recurrent stroke in an unselected population sample. METHODS: We analyzed the records of 763 patients with diagnosis of cerebral ischaemia at our institution. All patients had undergone TCD-based detection of RLS. Embolic signals have been measured both under resting conditions and after performing a Valsalva maneuver. For follow-up, all patients were contacted by mail, which included a standardized questionnaire. Endpoints of follow-up were defined as recurrence of cerebral ischaemia, occurrence of myocardial infarction or death from any cause. RESULTS: Follow-up data were available in 639 patients (83.7%). At baseline, a RLS was detected in 140 (28%) men and in 114 (42%) women. Ten shunt-carriers (1.6%) and 32 patients (5.0%) without RLS had suffered a recurrent stroke. After adjustment for age, sex, and atrial fibrillation, the hazard ratio of RLS for stroke recurrence was 0.86 (95% CI 0.41-1.79). The condition of RLS at rest adjusted for age, sex, stroke subtype, and cardiovascular risk factors was not found to increase the risk of stroke substantially (HR 1.16 [95% CI 0.41-3.29]) CONCLUSION: Our data suggest that the risk of recurrent stroke in subjects with PFO is not significantly increased in comparison with subject without it.
Assuntos
Forame Oval Patente/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/etiologia , Exame Neurológico , Inibidores da Agregação Plaquetária/uso terapêutico , Modelos de Riscos Proporcionais , Recidiva , Síndrome das Pernas Inquietas/complicações , Síndrome das Pernas Inquietas/etiologia , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Ultrassonografia Doppler Transcraniana/métodosRESUMO
BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.