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1.
Artigo em Inglês | MEDLINE | ID: mdl-32033981

RESUMO

OBJECTIVE: To perform a comprehensive multicompartment analysis of microRNA (miRNA) expression in multiple sclerosis (MS) linked to disease activity and compared with other neuroinflammatory diseases through a retrospective cross-sectional study. METHODS: One hundred twenty-seven miRNAs were measured by PCR arrays on pooled CSF, serum, and peripheral blood mononuclear cell (PBMC) samples of 10 patients with relapsing MS and 10 controls. Sixty-four miRNAs were then measured by quantitative PCR on individual CSF samples of patients with relapsing or remitting MS and controls (n = 68). Fifty-seven miRNAs were analyzed in the CSF from a second cohort (n = 75), including patients with MS, neuroinfectious, or neuroinflammatory diseases and controls. MiRNAs significantly dysregulated in the CSF were analyzed on individual serum/PBMC samples (n = 59/48) of patients with relapsing or remitting MS and controls. Post hoc analysis consisted of principal component analysis (PCA), gene set, and pathway enrichment analysis. RESULTS: Twenty-one miRNAs were differentially expressed, mainly upregulated in the CSF during MS relapses. Relapsing MS and neuroinfectious/inflammatory diseases exhibited a partially overlapping CSF miRNA expression profile. Besides confirming the association of miR-146a-5p/150-5p/155-5p with MS, 7 miRNAs uncharacterized for MS emerged (miR-15a-3p/124-5p/149-3p/29c-3p/33a-3p/34c-5p/297). PCA showed that distinct miRNA sets segregated MS from controls and relapse from remission. In silico analysis predicted the involvement of these miRNAs in cell cycle, immunoregulation, and neurogenesis, but also revealed that the signaling pathway pattern of remitting MS is more akin to controls rather than patients with relapsing MS. CONCLUSIONS: This study highlights the CSF-predominant dysregulation of miRNAs in MS by identifying a signature of disease activity and intrathecal inflammation among neuroinflammatory disorders.


Assuntos
MicroRNAs/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue
2.
PLoS One ; 12(3): e0173780, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28301515

RESUMO

Multiple sclerosis (MS) is thought to be a Th17-mediated dysimmune disease of the central nervous system. However, recent publications have questioned the pathogenicity of IL-17 per se and rather suggest the implication of other Th17-related inflammatory mediators. Therefore, we studied the expression of GM-CSF, IL-22, IL-24, IL-26 and CD39 in peripheral blood mononuclear cells (PBMCs) from MS patients during relapses, remission and following corticosteroid treatment. We performed qPCR to measure mRNA levels from ex vivo or in vitro-stimulated PBMCs. Cytokine levels were determined by ELISA. We used flow cytometry to assess GM-CSF+, IL-22+ and CD39+ cells in relationship to IL-17+ CD4+ T cells. Our results showed that IL-22 mRNA and IL-22+CD4+ lymphocytes are increased in circulating cells of relapsing MS patients compared to remitting patients while GM-CSF was unchanged. We have further shown that 12.9, 39 and 12.4% of Th17 cells from MS patients during relapses expressed IL-22, GM-CSF and CD39 respectively. No changes in these proportions were found in stable MS patients. However, the majority of GM-CSF+ or IL-22+ T cells did not co-express IL-17. GM-CSF mRNA, but not IL-22 mRNA, was dramatically decreased ex vivo by ivMP. Our results contribute to a better characterisation of Th17, Th22 and ThGM-CSF cells in the setting of MS and according to disease activity.


Assuntos
Corticosteroides/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Interleucina-17/sangue , Interleucinas/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , RNA Mensageiro/sangue , Adulto Jovem , Interleucina 22
3.
Mult Scler ; 21(12): 1533-45, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25662347

RESUMO

BACKGROUND: Accumulating data highlight proinflammatory processes leading to MS relapses. Whether anti-inflammatory mechanisms are concomitantly activated is unclear. The ectonucleotidase CD39 has been described as a novel T regulatory cell (Treg) marker. The purpose of this study was to explore whether regulatory mechanisms are activated during MS relapses and reinforced by intravenous methylprednisolone (ivMP). METHODS: Blood samples were collected from stable and relapsing MS patients and healthy controls. We used FOXP3 methylation-specific qPCR and CD4(+)CD25(high)FOXP3(+) analysis to quantify Tregs. Cytokine mRNA expression levels were measured in peripheral blood mononuclear cells (PBMCs) and in CD4(+) T cells. CD39 expression was determined by flow cytometry in monocytes, NK, T and B cells. CD39 enzymatic activity was assessed by ATP luminometry. RESULTS: The proportion of Tregs was similar in relapsing MS patients and healthy controls. CD39 mRNA level was higher in PBMCs of relapsing MS patients than in controls. The proportion of CD39-expressing Tregs was higher in MS patients. IvMP decreased the overall proportion of Tregs while it increased CD39 mRNA levels, the proportions of CD39-expressing Tregs and monocytes as well as CD39 ectonucleotidase activity. CONCLUSIONS: Our data suggest that immunoregulatory mechanisms are ongoing in MS patients, particularly during relapses, and strengthened by ivMP.


Assuntos
Antígenos CD/metabolismo , Apirase/metabolismo , Glucocorticoides/farmacologia , Metilprednisolona/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfócitos T Reguladores/metabolismo , Administração Intravenosa , Adulto , Antígenos CD/efeitos dos fármacos , Apirase/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Humanos , Metilprednisolona/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/sangue , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento
4.
PLoS One ; 9(11): e113025, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25411844

RESUMO

BACKGROUND: Multiple sclerosis (MS) likely results from an imbalance between regulatory and inflammatory immune processes. CD39 is an ectoenzyme that cleaves ATP to AMP and has been suggested as a novel regulatory T cells (Treg) marker. As ATP has numerous proinflammatory effects, its degradation by CD39 has anti-inflammatory influence. The purpose of this study was to explore regulatory and inflammatory mechanisms activated in fingolimod treated MS patients. METHODS AND FINDINGS: Peripheral blood mononuclear cells (PBMCs) were isolated from relapsing-remitting MS patients before starting fingolimod and three months after therapy start. mRNA expression was assessed in ex vivo PBMCs. The proportions of CD8, B cells, CD4 and CD39-expressing cells were analysed by flow cytometry. Treg proportion was quantified by flow cytometry and methylation-specific qPCR. Fingolimod treatment increased mRNA levels of CD39, AHR and CYP1B1 but decreased mRNA expression of IL-17, IL-22 and FOXP3 mRNA in PBMCs. B cells, CD4+ cells and Treg proportions were significantly reduced by this treatment, but remaining CD4+ T cells were enriched in FOXP3+ cells and in CD39-expressing Tregs. CONCLUSIONS: In addition to the decrease in circulating CD4+ T cells and CD19+ B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.


Assuntos
Antígenos CD/genética , Apirase/genética , Cloridrato de Fingolimode/administração & dosagem , Imunossupressores/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Reguladores/metabolismo , Antígenos CD/metabolismo , Antígenos CD19/metabolismo , Apirase/metabolismo , Linfócitos B/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linfócitos T CD4-Positivos/metabolismo , Citocromo P-450 CYP1B1/genética , Citocinas/metabolismo , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunossupressores/farmacologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Receptores de Hidrocarboneto Arílico/genética
5.
J Neuroimmunol ; 243(1-2): 73-80, 2012 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-22245284

RESUMO

The concomitant production of IL-17A and IL-9, both Th17 cytokines, has not been compared in MS patients. We show that IL-17A but not IL-9 expression by CD3(+) cells was increased during a MS relapse. Co-expression of IL-17A and IL-9 was marginal. In addition to Th1 and Th2 cytokines, IL-17A, IL-6 and IL-23p19 were down-regulated by ivMP, but Foxp3 was not, while an increase in IL-10, TGF-ß1 and IL-27p28 mRNA was observed. This change in the Th17, Treg and IL-10 balance could be an additional mechanism by which corticosteroids shorten the duration of a MS relapse and promote recovery.


Assuntos
Corticosteroides/farmacologia , Células Sanguíneas/efeitos dos fármacos , Doenças Desmielinizantes/patologia , Interleucina-17/metabolismo , Interleucina-9/metabolismo , Esclerose Múltipla/patologia , Regulação para Cima/efeitos dos fármacos , Análise de Variância , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Interleucina-17/genética , Interleucina-9/genética
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