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1.
PLoS One ; 15(2): e0228380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32012202

RESUMO

BACKGROUND: Treatment with fingolimod reduces inflammation in multiple sclerosis (MS) by inhibiting lymphocyte egress from lymph nodes. We aimed to map, in detail, the alterations in peripheral blood lymphocyte subpopulations in relation to clinical outcome in MS patients treated with fingolimod. METHODS: Paired blood samples from relapsing-remitting MS patients (n = 19) were collected before and after one year of treatment with fingolimod (0.5 mg/day). Absolute counts and relative proportions of a broad set of T- B- and NK-cell subsets were analyzed by flow cytometry. Blood samples from 18 healthy controls were used for baseline comparisons. RESULTS: Treatment with fingolimod markedly decreased the absolute numbers of all major lymphocyte subsets, except for NK cells. The reduction was most pronounced within the T helper (Th) and B cell populations (p<0.001). By phenotyping differentiation status of T cells, dramatic reductions within the naïve and central memory (CM) cell populations were found (p<0.001), while a less pronounced reduction was observed among effector memory (EM) cells (p<0.001). The numbers of regulatory T cells (Tregs) were also decreased (p<0.001), but to a lesser extent than other T cell populations, resulting in a relative preservation of Tregs with a memory phenotype (p = 0.002). CONCLUSIONS: Our results confirm that fingolimod therapy markedly reduces lymphocyte counts in peripheral blood of MS patients. Subgroup analysis of T cells showed that naïve and CM Th cells were the most profoundly affected and that memory Tregs were relatively preserved.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Subpopulações de Linfócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
2.
BMC Bioinformatics ; 20(Suppl 6): 623, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822261

RESUMO

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed. RESULTS: In this paper we propose a new methodology for studying RRMS, which we implemented in GreatSPN, a state-of-the-art open-source suite for modelling and analyzing complex systems through the Petri Net (PN) formalism. This methodology exploits: (a) an extended Colored PN formalism to provide a compact graphical description of the system and to automatically derive a set of ODEs encoding the system dynamics and (b) the Latin Hypercube Sampling with PRCC index to calibrate ODE parameters for reproducing the real behaviours in healthy and MS subjects.To show the effectiveness of such methodology a model of RRMS has been constructed and studied. Two different scenarios of RRMS were thus considered. In the former scenario the effect of the daclizumab administration is investigated, while in the latter one RRMS was studied in pregnant women. CONCLUSIONS: We propose a new computational methodology to study RRMS disease. Moreover, we show that model generated and calibrated according to this methodology is able to reproduce the expected behaviours.


Assuntos
Simulação por Computador , Esclerose Múltipla Recidivante-Remitente , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Gravidez , Recidiva
3.
BMC Neurol ; 19(1): 231, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558148

RESUMO

BACKGROUND: Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. CASE PRESENTATION: We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. CONCLUSIONS: Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution.


Assuntos
Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Adulto , Feminino , Humanos , Esclerose Múltipla Recidivante-Remitente/sangue
4.
Nat Commun ; 10(1): 3081, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300673

RESUMO

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Monócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , NADPH Oxidases/genética , Adulto , Metilação de DNA/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
5.
Mult Scler Relat Disord ; 34: 92-99, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31272071

RESUMO

BACKGROUND: Glatiramer acetate (GA) is a drug for Multiple Sclerosis (MS) treatment. However, its administration induces anti-drug antibodies (ADA). This research evaluated the sex differences in humoral response against GA in RR-MS patients METHODS: We analyzed 69 RR-MS patients, 43 treated with GA and 26 treated with IFN-ß. In all cases, the serum concentration of IgG antibodies was determined by UPLC, whereas the levels of IgG subclasses (1-4) of anti-GA antibodies and the concentration of IL-6 were detected by Multiplex and IL-10, and IFN-γ were detected by ELISA. RESULTS: The total concentration of IgG antibodies in patients did not differ between treatments, whereas the IgG levels of ADA were higher in male and female patients treated with GA (P ≤ 0.0001). The subclasses of IgG anti-GA antibodies were as follows: IgG4>>IgG3>IgG1>IgG2. Statistical analysis showed differences in the IgG2 (P ≤ 0.01) and IgG4 (P ≤ 0.0001) subclasses by sex in RR-MS patients. Levels of IgG1 subclass in male patients correlated positively with the circulatory levels of IL-6 (rs = 0.587, P ≤ 0.04) and IFN-γ (rs = 0.721, P ≤ 0.001), while IgG2 subclass levels in female patients correlated with serum levels of IFN-γ (rs = 0.628, P ≤ 0.0006). Statistical analysis did not detect correlations between the levels of IgG (1-4) subclasses of anti-GA antibodies and the evaluated clinical parameters. CONCLUSION: This study showed differences in the levels of IgG2 and IgG4 subclasses of ADA between male and female RR-MS patients. Further studies are necessary to take advantage of the clinical potential of this finding.


Assuntos
Acetato de Glatiramer/uso terapêutico , Imunoglobulina G/sangue , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/terapia , Caracteres Sexuais , Adulto , Feminino , Humanos , Interferon gama/sangue , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue
6.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181776

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. The cause of multiple sclerosis is unknown but there are several evidences that associate the genetic basis of the disease with environmental causes. An important association between viral infection and development of MS is clearly demonstrated. Viruses have a strong impact on innate immune cells. In particular, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), are able to respond to viruses and to activate the adaptive immune response. METHODS: In this study we mimic viral infection using synthetic single-strand RNA, Resiquimod, and we compared the response of both DC subsets derived from healthy donors and MS patients by characterizing the expression of costimulatory molecules on the DC surface. RESULTS: We found that pDCs from MS patients express higher levels of OX40-L, HLA-DR, and CD86 than healthy donors. Moreover, we found that blood cells from MS patients and healthy donors upon Resiquimod-stimulation are enriched in a subpopulation of pDCs, characterized by a high amount of costimulatory molecules. CONCLUSION: Overall, these results indicate that activation of pDCs is enhanced in MS, likely due to a latent viral infection, and that costimulatory molecules expressed on pDCs could mediate a protective response against the viral trigger of autoimmunity.


Assuntos
Células Dendríticas/efeitos dos fármacos , Imidazóis/farmacologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Células Dendríticas/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Ligante OX40/genética , Ligante OX40/metabolismo
7.
Cells ; 8(6)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167379

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-ß, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-ß, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.


Assuntos
Esclerose Múltipla Recidivante-Remitente/patologia , Células Th17/metabolismo , Adulto , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucinas/metabolismo , Linfotoxina-alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Células Th17/citologia
8.
Cells ; 8(6)2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212712

RESUMO

The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro-inflammatory T cell functions in relapsing-remitting MS (RRMS) patients. We show that CD28 up-regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c-myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3-kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS.


Assuntos
Antígenos CD28/metabolismo , Glicólise , Inflamação/patologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Linfócitos T/imunologia , Regulação para Cima , Adulto , Idoso , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Humanos , Metabolômica , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/metabolismo
9.
Mult Scler Relat Disord ; 34: 29-37, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228713

RESUMO

BACKGROUND: Fingolimod, an oral therapy for patients with relapsing Multiple Sclerosis (MS), traps CC chemokine receptor type 7 (CCR7)-expresssing lymphocytes within lymphoid tissues in the periphery, thereby supposedly reducing the infiltration of pathogenic cells into the central nervous system. Additional immunomodulatory effects of Fingolimod, involving cell function, B and T cells interactions and cross-regulation, have scarcely been studied. The objective of this study was to assess how Fingolimod therapy affects B cells functions, namely cell migration, immunoglobullin production and T cell stimulation. METHODS: B cells from 36 patients with relapsing MS were obtained before and after 3 months Fingolimod therapy, while CD4 T cells were collected pre-treatment. Clinical follow-up was performed for 1 year. For in-vitro validation, Lymphoblastoid cell-lines from 16 patients were cultured with Fingolimod. B cell migration towards C-X-C Motif Chemokine Ligand 12 (CXCL12) was assessed using a transwell system. C-X-C chemokine receptor 4 (CXCR4) expression was assessed by flow cytometry and western blot. Plasma immunoglobullins and Brain-derived Neurotrophic Factor (BDNF) were assessed by ELISA or RT-PCR. Drug effect on interacting co-cultured B and T cells on cytokine profiles and T cell proliferation was explored by flow cytometry. RESULTS: Lymphocyte count reduction did not predict clinical response of patients. Fingolimod therapy reduced CXCR4 expression and B cell migration towards CXCL12. No effect was found on immunoglobulins and BDNF. B cells from Fingolimod-treated patients induced a reduction in pro-inflammatory cytokines in T cells, while increased transforming growth factor beta (TGFß)+ B and T cells, and downregulated IL2-secretion from proliferative T cells. CONCLUSIONS: Fingolimod promotes anti-inflammatory cytokine profiles of B and T cells, through induction of regulatory B cells. Reduced B cell migration capacity in Fingolimod-treated patients leading to decreased cerebral inflammatory infiltration, may be part of the mechanism by which Fingolimod reduces disease activity in MS.


Assuntos
Linfócitos B/imunologia , Movimento Celular/imunologia , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/terapia , Receptores CXCR4/metabolismo , Adulto , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células , Quimiocina CXCL12/metabolismo , Feminino , Seguimentos , Humanos , Inflamação/imunologia , Inflamação/terapia , Interleucina-2/metabolismo , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
10.
Life Sci ; 229: 116-123, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31082401

RESUMO

AIMS: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. MAIN METHODS: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. KEY FINDINGS: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. SIGNIFICANCE: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.


Assuntos
Biomarcadores/sangue , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Inflamação/sangue , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla/sangue , Adulto , Estudos de Casos e Controles , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/imunologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia
12.
Neurology ; 92(15): e1724-e1738, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30918100

RESUMO

OBJECTIVE: To assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis. METHODS: Using peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed. RESULTS: In DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses. CONCLUSIONS: DMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients. TRIAL REGISTRATION NUMBERS: EUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Linfócitos/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/sangue , Adulto , Linfócitos B/efeitos dos fármacos , Relação CD4-CD8 , Estudos Transversais , Preparações de Ação Retardada , Fumarato de Dimetilo/efeitos adversos , Fumarato de Dimetilo/farmacologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Estudos Longitudinais , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Medição de Risco , Linfócitos T/efeitos dos fármacos
13.
Iran J Allergy Asthma Immunol ; 18(1): 108-113, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30848579

RESUMO

 Invasion of auto-reactive CD4+ T cells especially Th17 into central nervous system (CNS) is an underlying pathogenic mechanism in multiple sclerosis (MS). CD4+ T cells release exosomes which are enriched in microRNAs, reflective of cell's physiological or pathological condition. Thus exosomes could be potent agents to provide quantitative and qualitative information about involved cells in MS. We investigated the expression of pathogenic microRNAs in T cells-derived exosomes of MS patients or healthy controls. Conventional T cells (Tconv) derived from relapsing-remitting (RR) MS patients (n=10) and healthy controls (n=10) were purified and cultured for 3 days by soluble anti-CD3/CD28. Exosomes were purified from cultured-T cells supernatants. The expression levels of exosomal miR-146a, miR-29a, miR-155, and miR-326 were quantified by real-time PCR. A statistically significant increased expression of miR-326 in Tconv-derived exosomes was observed in RRMS patients as compared with controls (7.5±1.88vs 2.51±0.9 p=0.03), On the contrary, no differences were found in the expression levels of miR-155, miR-146a, and miR-29a, in Tconv-derived exosomes of  patients as compared with controls (p>0.05). Our results point to altered expression in exosome-derived microRNAs. MiR-326 was previously shown to play a role in the immunopathogenesis of MS by inducing TH17 differentiation and maturation. Therefore, miR-326 containing exosomes might also be a potential clinical target in course of MS. Moreover, the deregulation of this miRNA in exosomes may serve as a diagnostic and prognostic biomarker.


Assuntos
Exossomos , MicroRNAs , Esclerose Múltipla Recidivante-Remitente/genética , Linfócitos T , Adulto , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia
14.
BMC Neurol ; 19(1): 37, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849952

RESUMO

BACKGROUND: Studies have shown positive effects of therapeutic exercise on motor- and cognitive function as well as on psychosocial outcomes in persons with multiple sclerosis (MS). A reduction of inflammatory stress through physical exercise has been suspected as one key mechanism, mediating the positive effects of exercise in the context of MS. The primary objective of this trial is to investigate the acute and chronic effects of different exercise modalities on (anti-)inflammatory immune signalling as well as on cognitive and functional capacity in persons with MS. METHODS: A two armed single-blind randomized controlled design will investigate 72 persons with relapsing remitting or secondary progressive MS (EDSS 3.0-6.0), during 3 weeks of inpatient rehabilitation. Participants will be randomized into either a high-intensity interval training (HIIT) or a moderate continuous training group; the latter represents the local standard therapy (ST). Both groups will exercise 3x per week. The HIIT group will perform 5 × 1.5-min high-intensive exercise bouts at 95-100% of their maximum heart rate (HRmax) followed by active breaks of unloaded pedalling (60% HRmax) for 2 min. In contrast, the ST group will exercise for 24 min continuously at 65% of HRmax. The proportion of circulating regulatory T-cells will be measured as primary outcome. Secondary outcomes comprise numbers and proportions of further immune cells including Th17-cells, soluble factors ((anti-) inflammatory cytokines, tryptophan metabolites), endurance capacity, cognitive performance, processing skills for activities of daily living, fatigue, depression and healthcare-related quality of life. Outcomes will be assessed before (T0) and after (T3) the 3-week exercise intervention program. Blood samples of T0 will be taken immediately before the first exercise session. Additionally, blood samples for the soluble factors will be collected immediately after (T1) and three hours (T2) after the first exercise session of each group. DISCUSSION: This study will be the first to investigate both acute and chronic effects of aerobic exercise on immune function and disease associated biomarkers in persons with MS. Combining biological analyses with cognitive and functional capacity assessments may contribute to a better understanding of responses to rehabilitative training, needed to improve exercise recommendations for persons with MS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT03652519 ; 29 August 2018).


Assuntos
Cognição , Terapia por Exercício/métodos , Treinamento Intervalado de Alta Intensidade , Esclerose Múltipla Crônica Progressiva/reabilitação , Esclerose Múltipla Recidivante-Remitente/reabilitação , Atividades Cotidianas , Adulto , Biomarcadores/sangue , Citocinas/sangue , Tolerância ao Exercício , Fadiga/etiologia , Fadiga/prevenção & controle , Humanos , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/psicologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Qualidade de Vida , Método Simples-Cego , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fatores de Tempo , Resultado do Tratamento , Triptofano/sangue
15.
Mult Scler Relat Disord ; 31: 38-40, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901703

RESUMO

BACKGROUND: Multiple sclerosis (MS) and psoriasis vulgaris (PV) are two disorders with autoimmune pathophysiology and a supposed altered T helper (TH) cell response. OBJECTIVE: To report a case of concomitant relapsing remitting MS and PV treated with different immunomodulatory medications, particularly secukinumab and rituximab. METHODS: Case report. RESULTS: In a 68-year-old woman diagnosed with MS and PV, secukinumab alleviated the dermatological condition, but could not control neuroinflammation. Rituximab treatment halted MS activity, but led to a flare-up of dermatological inflammation. CONCLUSION: The presented case suggests that the pathomechanisms of MS and PV differ regarding involvement of TH and B cells with implications for therapeutic approaches.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Psoríase/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Feminino , Humanos , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/imunologia , Psoríase/complicações , Psoríase/imunologia , Resultado do Tratamento
16.
Isr Med Assoc J ; 21(3): 151-157, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30905097

RESUMO

BACKGROUND: Glatiramer acetate (GA, Copaxone®, Copolymer1, Cop 1) is an approved drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy in reducing the frequency of exacerbations and its safety profile establish it as a first-line therapy for MS. Evidence from the animal model experimental autoimmune encephalomyelitis (EAE) and from MS patients indicate that GA affects various levels of the innate and the adaptive immune response, inducing deviation from the pro-inflammatory to the anti-inflammatory pathways. This includes mainly the induction of Th2/3 and T-regulatory cells, and down-regulation of both Th1 and Th17 cells. The immune cells induced by GA reach the CNS and secrete in situ anti-inflammatory cytokines, alleviating the pathological processes. In addition to its immunomodulatory activities, GA promotes neuroprotective repair processes such as secretion of neurotrophic factors, remyelination and neurogenesis, indicating that repair process in the CNS can be up-regulated by therapy.


Assuntos
Acetato de Glatiramer/uso terapêutico , Imunomodulação/efeitos dos fármacos , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Israel , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia
17.
J Neuroimmunol ; 328: 94-97, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30610966

RESUMO

Multiple Sclerosis (MS) is thought to be an autoimmune disease of the central nervous system (CNS), in which the immune system becomes activated, cross the blood-brain barrier (BBB), and cause neuroinflammation and neurodegeneration. Fingolimod is considered a disease-modifying therapy (DMT), possessing immunomodulatory effects on the immune system, especially autoreactive T cells being licensed in lymph nodes. Although the fidelity of the drug is undeniable in the management of disease course, various adverse effects have been reported in some patients taking this medication. In this study, 420 MS patients, consisted of 210 patients receiving interferon-beta (IFN-beta) and 210 patients receiving fingolimod therapies. As a control group, 210 age- and sex-matched healthy individuals were recruited in our study. The levels of anti-VZV IgG and IgM were determined using enzyme-linked immunosorbent assay (ELISA). The presence of VZV DNA in peripheral blood mononuclear cells (PBMCs) was also investigated using the PCR method. The percentage of seropositivity for anti-VZV IgG and anti-VZV IgM in MS patients was 94.8% and 0%, respectively in those taking fingolimod therapy. In patients receiving IFN-beta, the rate of seropositivity for anti-VZV IgG and anti-VZV IgM was 93.8% and 0%, respectively. In healthy individuals, the rate of seropositivity for anti-VZV IgG and anti-VZV IgM was 84.3% and 0%, respectively. The PCR results showed that 7.6% of patients receiving fingolimod were positive for VZV DNA, while none of the healthy subjects nor MS patients taking IFN-beta were positive for DNA of VZV. The statistical analysis indicated that the frequency of VZV DNA in patients receiving fingolimod was significantly (p = .00) higher than MS patients taking IFN-beta and healthy subjects. It seems that the use of fingolimod should be carefully prescribed as the occurrence of VZV infection/reactivation is increased in comparison to other MS patients who receive different therapy.


Assuntos
Herpes Zoster/imunologia , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Estudos de Casos e Controles , Feminino , Cloridrato de Fingolimode/efeitos adversos , Herpes Zoster/epidemiologia , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Estudos Soroepidemiológicos
18.
Ann Clin Transl Neurol ; 6(1): 33-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30656182

RESUMO

Objective: Identify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects. Methods: We enrolled 18 MS patients and obtained blood prior to DMF and 6 months postinitiation. We also enrolled 18 healthy controls for comparison. We performed global metabolomics on plasma and used weighted correlation network analysis (WGCNA) to identify modules of correlated metabolites. We identified modules that changed with treatment, followed by targeted metabolomics to corroborate changes identified in global analyses. We correlated changes in metabolite modules and individual metabolites with changes in immunological parameters. Results: We identified alterations in lipid metabolism after DMF treatment - increases in two modules (phospholipids, lysophospholipids and plasmalogens) and reduction in one module (saturated and poly-unsaturated fatty acids) eigen-metabolite values (all P < 0.05). Change in the fatty acid module was greater in participants who developed lymphopenia and was strongly associated with both reduction in absolute lymphocyte counts (r = 0.65; P = 0.005) and change in CD8+ T cell subsets. We also noted significant correlation of change in lymphocyte counts with multiple fatty acid levels (measured by targeted or untargeted methods). Interpretation: This study demonstrates that DMF treatment alters lipid metabolism and that changes in fatty acid levels are related to DMF-induced immunological changes.


Assuntos
Fumarato de Dimetilo/administração & dosagem , Metabolismo dos Lipídeos/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Adulto , Ácidos Graxos/metabolismo , Feminino , Humanos , Contagem de Linfócitos , Masculino , Metabolômica , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Subpopulações de Linfócitos T/metabolismo
19.
J Neuroimmunol ; 327: 15-21, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30683426

RESUMO

BACKGROUND: Multiple sclerosis is a chronic incapacitating disease of the central nervous system, it has been reported that the disturbance in the development and function of Treg subpopulations is associated with the disability status in the RRMS. Accordingly, in the current study, the objective was to specify nanocurcumin effects on Treg cells frequency, and function in patients with RRMS. METHODS AND MATERIALS: 50 patients with RRMS were enrolled in this study in which 25 were treated for at least six months with nanocurcumin capsules while the other half received placebo capsules as the control group. The blood sample was collected prior to the administration of nanocurcumin and placebo capsules and following six months. At baseline and after a six-month treatment, the frequency of Treg lymphocytes, the expression of transcription factor related to these cells and the secretion levels of cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. RESULTS: A significant reduction was observed in the proportion of peripheral Treg cell frequency, and the levels of TGF-ß, IL-10 and FoxP3 expression in patients with RRMS. Our data revealed that the frequency of Treg cells (p = .0027), the expression of FoxP3 (p = .0005), TGF-ß (p = .0005), and IL-10 (p = .0002) and the secretion levels of the TGF-ß (p = .033), and IL-10 (p = .029) in cultured PBMCs are increased in nanocurcumin-treated group compared to placebo group. CONCLUSION: The results of the current work indicated that nanocurcumin is capable of restoring the frequency and function of Treg cells in MS patients.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Nanopartículas , Linfócitos T Reguladores/imunologia
20.
J Neuroimmunol ; 326: 49-54, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30476705

RESUMO

Our aim was to quantify circulating B cell subsets; immature/transitional, naïve, CD27- and CD27+ memory cells and plasmablasts, in relapsing-remitting multiple sclerosis patients treated with IFN-ß. The most relevant findings were a significant increase of plasmablasts and a decrease of immature/transitional B cells, resulting in a decreased ratio between those cells in relapse RRMS, together with an increase of CD27- and CD27+IgM+ memory B cell subsets in both phases of the disease. These alterations point to an active B cell response, particularly in relapse, and the above referred ratio could constitute a good biomarker of relapse in patients that underwent IFN-ß treatment.


Assuntos
Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/imunologia
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