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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809077

RESUMEN

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.


Asunto(s)
Vesículas Extracelulares/genética , Inmunidad/genética , Esclerosis Múltiple/genética , Proteoma/genética , Comunicación Celular/genética , Técnicas de Cocultivo , Citocinas/genética , Decidua/inmunología , Decidua/metabolismo , Vesículas Extracelulares/inmunología , Femenino , Humanos , Inmunomodulación/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Placenta/inmunología , Placenta/metabolismo , Embarazo , Linfocitos T Reguladores/inmunología , Trofoblastos/inmunología , Trofoblastos/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809384

RESUMEN

Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Ribonucleoproteína Nuclear Heterogénea A1/genética , Esclerosis Múltiple/genética , Degeneración Nerviosa/genética , Esclerosis Amiotrófica Lateral/patología , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Esclerosis Múltiple/patología , Mutación/genética
3.
Artículo en Inglés | MEDLINE | ID: mdl-33802599

RESUMEN

(1) Background: Complex genetic relationships, including gene-gene (G × G; epistasis), gene(n), and gene-environment (G × E) interactions, explain a substantial portion of the heritability in multiple sclerosis (MS). Machine learning and data mining methods are promising approaches for uncovering higher order genetic relationships, but their use in MS have been limited. (2) Methods: Association rule mining (ARM), a combinatorial rule-based machine learning algorithm, was applied to genetic data for non-Latinx MS cases (n = 207) and controls (n = 179). The objective was to identify patterns (rules) amongst the known MS risk variants, including HLA-DRB1*15:01 presence, HLA-A*02:01 absence, and 194 of the 200 common autosomal variants. Probabilistic measures (confidence and support) were used to mine rules. (3) Results: 114 rules met minimum requirements of 80% confidence and 5% support. The top ranking rule by confidence consisted of HLA-DRB1*15:01, SLC30A7-rs56678847 and AC093277.1-rs6880809; carriers of these variants had a significantly greater risk for MS (odds ratio = 20.2, 95% CI: 8.5, 37.5; p = 4 × 10-9). Several variants were shared across rules, the most common was INTS8-rs78727559, which was in 32.5% of rules. (4) Conclusions: In summary, we demonstrate evidence that specific combinations of MS risk variants disproportionately confer elevated risk by applying a robust analytical framework to a modestly sized study population.


Asunto(s)
Esclerosis Múltiple , Alelos , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Humanos , Esclerosis Múltiple/genética , Oportunidad Relativa , Polimorfismo de Nucleótido Simple
4.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805769

RESUMEN

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein-Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly.


Asunto(s)
Linfocitos B/virología , Sitios Genéticos , Interacciones Huésped-Patógeno/genética , MicroARNs/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Alelos , Linfocitos B/inmunología , Secuencia de Bases , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , MicroARNs/inmunología , Modelos Biológicos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/virología , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , ARN Mensajero/inmunología , Proteínas de Unión al ARN/inmunología , Transducción de Señal
5.
Biol Res ; 54(1): 12, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795012

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease with a high disability rate. Modern molecular biology techniques have identified a number of key genes and diagnostic markers to MS, but the etiology and pathogenesis of MS remain unknown. RESULTS: In this study, the integration of three peripheral blood mononuclear cell (PBMC) microarray datasets and one peripheral blood T cells microarray dataset allowed comprehensive network and pathway analyses of the biological functions of MS-related genes. Differential expression analysis identified 78 significantly aberrantly expressed genes in MS, and further functional enrichment analysis showed that these genes were associated with innate immune response-activating signal transduction (p = 0.0017), neutrophil mediated immunity (p = 0.002), positive regulation of innate immune response (p = 0.004), IL-17 signaling pathway (p < 0.035) and other immune-related signaling pathways. In addition, a network of MS-specific protein-protein interactions (PPI) was constructed based on differential genes. Subsequent analysis of network topology properties identified the up-regulated CXCR4, ITGAM, ACTB, RHOA, RPS27A, UBA52, and RPL8 genes as the hub genes of the network, and they were also potential biomarkers of MS through Rap1 signaling pathway or leukocyte transendothelial migration. RT-qPCR results demonstrated that CXCR4 was obviously up-regulated, while ACTB, RHOA, and ITGAM were down-regulated in MS patient PBMC in comparison with normal samples. Finally, support vector machine was employed to establish a diagnostic model of MS with a high prediction performance in internal and external datasets (mean AUC = 0.97) and in different chip platform datasets (AUC = (0.93). CONCLUSION: This study provides new understanding for the etiology/pathogenesis of MS, facilitating an early identification and prediction of MS.


Asunto(s)
Biomarcadores , Perfilación de la Expresión Génica , Leucocitos Mononucleares , Esclerosis Múltiple , Biología Computacional , Redes Reguladoras de Genes , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/genética , Análisis de Secuencia por Matrices de Oligonucleótidos
6.
Nat Commun ; 12(1): 1923, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772011

RESUMEN

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.


Asunto(s)
Diferenciación Celular/genética , Microambiente Celular/genética , Enfermedades Desmielinizantes/genética , Perfilación de la Expresión Génica/métodos , Células Precursoras de Oligodendrocitos/metabolismo , Remielinización/genética , Animales , Axones/metabolismo , Células Cultivadas , Enfermedades Desmielinizantes/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Células Precursoras de Oligodendrocitos/citología , Sulfatasas/genética , Sulfatasas/metabolismo , Sulfotransferasas/genética , Sulfotransferasas/metabolismo
7.
BMC Bioinformatics ; 22(1): 132, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33736614

RESUMEN

BACKGROUND: Historical and updated information provided by time-course data collected during an entire treatment period proves to be more useful than information provided by single-point data. Accurate predictions made using time-course data on multiple biomarkers that indicate a patient's response to therapy contribute positively to the decision-making process associated with designing effective treatment programs for various diseases. Therefore, the development of prediction methods incorporating time-course data on multiple markers is necessary. RESULTS: We proposed new methods that may be used for prediction and gene selection via time-course gene expression profiles. Our prediction method consolidated multiple probabilities calculated using gene expression profiles collected over a series of time points to predict therapy response. Using two data sets collected from patients with hepatitis C virus (HCV) infection and multiple sclerosis (MS), we performed numerical experiments that predicted response to therapy and evaluated their accuracies. Our methods were more accurate than conventional methods and successfully selected genes, the functions of which were associated with the pathology of HCV infection and MS. CONCLUSIONS: The proposed method accurately predicted response to therapy using data at multiple time points. It showed higher accuracies at early time points compared to those of conventional methods. Furthermore, this method successfully selected genes that were directly associated with diseases.


Asunto(s)
Hepatitis C , Esclerosis Múltiple , Teorema de Bayes , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/genética , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Transcriptoma
8.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670164

RESUMEN

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Asunto(s)
Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Neurodegenerativas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Transducción de Señal/genética
9.
Gene ; 781: 145488, 2021 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-33588040

RESUMEN

Oxidative stress (OS) plays an essential role in demyelination and tissue injury related to pathogenesis of multiple sclerosis (MS). On the other hand, vitamin D (VD) as an antioxidant reduces oxidative stress and has been used as adjuvant therapy in autoimmune diseases. Although VD supplementation is suggested as a protective and immunomodulation factor for MS patients, the molecular mechanisms remain unclear. Given that VD may modulate the immune system of MS patients through the DNA repair pathway, we aimed to evaluate the effects of VD supplementation in DNA repair genes expression including OGG1, MYH, MTH1, and ITPA. Transcript levels were measured using the RT-qPCR method in peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) patients before and after two months of VD supplementation. Furthermore, in silico analysis and correlation gene expression analysis was performed to find the biological binding sites and the effect of NRF2 on the regulation of DNA repair genes. Our data revealed that in MS patients, 2-month VD treatment significantly altered the expression of MYH, OGG1, MTH1, and NRF2 genes. A significant correlation was observed between DNA repair genes and NRF2 expression, which was confirmed by the presence of antioxidant response element (ARE) binding sites in the promoter of OGG1, MYH, and MTH1 genes. This study demonstrated that the impact of VD on MS patients may be mediated through the improvement of DNA repair system efficiency. This finding brought some new evidence for the involvement of DNA repair genes in the physiopathology of MS patients.


Asunto(s)
Reparación del ADN/genética , Expresión Génica/efectos de los fármacos , Esclerosis Múltiple/genética , Vitamina D/farmacología , Vitaminas/farmacología , Adulto , Simulación por Computador , ADN Glicosilasas/genética , Reparación del ADN/efectos de los fármacos , Enzimas Reparadoras del ADN/genética , Femenino , Humanos , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/genética , Monoéster Fosfórico Hidrolasas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
10.
Gene ; 774: 145422, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33450350

RESUMEN

BACKGROUND: Leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1A) are involved in the pathogenesis of multiple sclerosis (MS) by affecting the inflammatory response and reactive oxygen species production. LEP rs7799039 and LEPR rs1137101 genetic variants modify the serum LEP levels and PGC1A rs8192678 alters the PGC1A activity. The study objective was to explore the associations of these variants with susceptibility to MS, disease course/clinical parameters and also with peripheral blood mononuclear cell expression of the target genes and plasma LEP concentrations, in the study subjects. METHODS: The study groups included 528 patients with MS and 429 controls. TaqMan® assays were used for genotyping and gene expression quantification. The Chi-square, parametric and nonparametric tests and simple/multiple logistic regression were performed for the statistical analysis of data. RESULTS: A multiple logistic regression model including all three investigated variants, applied to patients (RRMS + SPMS) and controls, showed that PGC1A rs8192678 minor allele had an increased risk for the occurrence of disease, with OR (95%CI) = 1,32 (1,01-1,73), P = 0,04. Between-effect of gender and LEPR variant on the multiple sclerosis severity score (MSSS) was identified (P = 0,005). In male patients (relapsing-remitting and secondary progressive), LEPR minor allele carriers had increased MSSS (GG + AG vs AA, median (minimum-maximum) = 5,38 (0,64-9,88) vs 4,27 (0,78-9,63); P = 0,01, Padj = 0,03). In relapsing-remitting patients LEP rs7799039 affected the LEP gene expression (P = 0,006; Padj = 0,04). CONCLUSION: The current findings implicate an impact of investigated genetic variants on the pathogenesis of MS.


Asunto(s)
Leptina/genética , Esclerosis Múltiple/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Polimorfismo de Nucleótido Simple , Receptores de Leptina/genética , Adulto , Estudios de Casos y Controles , Femenino , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Leptina/sangre , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Reacción en Cadena en Tiempo Real de la Polimerasa
11.
J Clin Neurosci ; 84: 75-81, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33485603

RESUMEN

PURPOSE: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Vitamin D has a major role in preventing inflammatory disorders. Therefore, any alteration in vitamin D receptor (VDR) might be a genetic risk factor for MS development. This study aimed to evaluate the effect of serum levels and VDR FokI, BsmI, and TaqI gene polymorphisms on the severity of MS. METHODS: This case-control study recruited 160 MS patients (71.9% females, mean age of 34.3 ± 8.3 years) and 162 (66.7% females, mean age 35.4 ± 7.9 year) age, sex, and ethnicity matched healthy controls. FokI (rs2228570), BsmI (rs1544410), and TaqI (rs731236) polymorphisms were carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Demographic, clinical parameters, and the levels of vitamin D were compared between groups. RESULTS: We found that the frequency of FokI and TaqI polymorphisms significantly differed between the patients and the controls (p = 0.0127 and p = 0.0236, respectively). The MS patients had low levels of vitamin D compared to the controls (p = 0.011). In addition, TaqI T/C polymorphism significantly decreased the levels of vitamin D in the MS patients (p = 0.002). However, there was no significant association between FokI or BsmI SNPs and the levels of vitamin D in MS patients (p > 0.5). CONCLUSION: Our results suggest that FokI and TaqI polymorphisms of VDR are associated with MS risk and TaqI polymorphism is associated with Vitamin D levels in MS patients. Meanwhile, no difference was observed between VDR gene polymorphisms and any types of MS.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Receptores de Calcitriol/genética , Vitamina D/sangre , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Polimorfismo de Nucleótido Simple
12.
Mol Genet Genomics ; 296(2): 423-435, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33507382

RESUMEN

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, and the pathogenesis is influenced by genetic susceptibility. Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play essential roles in complex diseases, including acting as competing endogenous RNAs (ceRNAs). However, the functional roles and regulatory mechanisms of lncRNAs acting as ceRNAs in MS are still unclear. In this study, we identified hub lncRNA ceRNAs in MS based on ceRNA mechanisms and annotated their functions. The lncRNA-associated ceRNA network (LACN) was constructed by integrating the expression profiles of lncRNA/mRNA and miRNA in MS and normal samples, and the experimentally validated interactions of lncRNA-miRNA and mRNA-miRNA. We found three hub lncRNA ceRNAs (XIST, OIP5-AS1, and CTB-89H12.4) using the network analysis and obtained 96 lncRNA-mediated competing triplets (LCTs, lncRNA-miRNA-mRNA) with the hub lncRNA ceRNAs, which constituted 3 hub ceRNA modules. The functional analysis identified 12 pathways enriched by the 3 hub lncRNA ceRNAs, of which 6 were confirmed to be related to MS. For example, XIST was enriched in the 'spliceosome' and 'RNA transport' related to the typing of MS, and CTB-89H12.4 was enriched in the 'mTOR signaling pathway,' a potential therapeutic target for MS. We dissected the expression patterns of the 96 LCTs in MS individually. LCT XIST-miR-326-HNRNPA1, for which the expression pattern in MS revealed that XIST and HNRNPA1 were up-regulated and miR-326 was down-regulated, consisted of risk RNAs for MS that were validated by other research. Therefore, XIST-miR-326-HNRNPA1 might play a central role in the pathogenesis of MS. These results will contribute to the discovery of novel biomarkers and the development of new therapeutic methods for MS.


Asunto(s)
Ribonucleoproteína Nuclear Heterogénea A1/genética , MicroARNs/genética , Esclerosis Múltiple/genética , ARN Largo no Codificante/genética , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Anotación de Secuencia Molecular , ARN Mensajero/genética
13.
Sci Rep ; 10(1): 22383, 2020 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-33361796

RESUMEN

Disruption of blood-brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , Barrera Hematoencefálica/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Linfocinas/antagonistas & inhibidores , Esclerosis Múltiple/inmunología , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Barrera Hematoencefálica/patología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-1alfa/genética , Interleucina-1alfa/inmunología , Linfocinas/genética , Linfocinas/inmunología , Ratones , Ratones Transgénicos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
14.
Sci Rep ; 10(1): 22217, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33335118

RESUMEN

The pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4+ T cells of relapsing-remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39. This study aimed to investigate the DNA methylation profiles of the CD4+ T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A, SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block; however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.


Asunto(s)
Epigénesis Genética , Regulación de la Expresión Génica , Sitios Genéticos , Esclerosis Múltiple/genética , Receptor de Serotonina 5-HT2A/genética , Anciano , Alelos , Biología Computacional/métodos , Metilación de ADN , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple , Transcriptoma
15.
BMC Bioinformatics ; 21(1): 443, 2020 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-33028195

RESUMEN

BACKGROUND: Gene-set analysis tools, which make use of curated sets of molecules grouped based on their shared functions, aim to identify which gene-sets are over-represented in the set of features that have been associated with a given trait of interest. Such tools are frequently used in gene-centric approaches derived from RNA-sequencing or microarrays such as Ingenuity or GSEA, but they have also been adapted for interval-based analysis derived from DNA methylation or ChIP/ATAC-sequencing. Gene-set analysis tools return, as a result, a list of significant gene-sets. However, while these results are useful for the researcher in the identification of major biological insights, they may be complex to interpret because many gene-sets have largely overlapping gene contents. Additionally, in many cases the result of gene-set analysis consists of a large number of gene-sets making it complicated to identify the major biological insights. RESULTS: We present GeneSetCluster, a novel approach which allows clustering of identified gene-sets, from one or multiple experiments and/or tools, based on shared genes. GeneSetCluster calculates a distance score based on overlapping gene content, which is then used to cluster them together and as a result, GeneSetCluster identifies groups of gene-sets with similar gene-set definitions (i.e. gene content). These groups of gene-sets can aid the researcher to focus on such groups for biological interpretations. CONCLUSIONS: GeneSetCluster is a novel approach for grouping together post gene-set analysis results based on overlapping gene content. GeneSetCluster is implemented as a package in R. The package and the vignette can be downloaded at https://github.com/TranslationalBioinformaticsUnit.


Asunto(s)
Interfaz Usuario-Computador , Línea Celular , Análisis por Conglomerados , Metilación de ADN/efectos de los fármacos , Minería de Datos , Dimetilfumarato/farmacología , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Especies Reactivas de Oxígeno/metabolismo
16.
J Pharmacol Sci ; 144(3): 119-122, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32921392

RESUMEN

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by apoptotic death of mature oligodendrocytes, neuroinflammation, and motor dysfunction. A pentacyclic triterpenoid compound, ursolic acid (UA), has various pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-apoptotic effects. In the present study, we investigated the effects of UA on cuprizone-induced demyelination, which is a model of MS. Oral administration of UA effectively suppressed cuprizone-induced demyelination and motor dysfunction via the enhancement of IGF-1 levels in the demyelinating lesions. Our results suggest that UA might be therapeutically useful for demyelination in MS.


Asunto(s)
Cuprizona/efectos adversos , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/genética , Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Triterpenos/administración & dosificación , Triterpenos/farmacología , Regulación hacia Arriba/efectos de los fármacos , Administración Oral , Animales , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/fisiopatología , Modelos Animales de Enfermedad , Ratones , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/fisiopatología
18.
Proc Natl Acad Sci U S A ; 117(35): 21546-21556, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32817525

RESUMEN

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.


Asunto(s)
Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Adulto , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Metilación de ADN , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Síntomas Prodrómicos , Gemelos Monocigóticos/genética
19.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32792491

RESUMEN

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.


Asunto(s)
Glutatión Transferasa/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Caspasa 8/genética , Caspasa 8/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Glutatión Transferasa/genética , Homeostasis/genética , Homeostasis/fisiología , Inmunohistoquímica , Masculino , Microglía/citología , Microglía/metabolismo , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Fagocitosis/genética , Fagocitosis/fisiología , Procesamiento Proteico-Postraduccional , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Remielinización/genética , Remielinización/fisiología
20.
Nat Commun ; 11(1): 3871, 2020 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-32747712

RESUMEN

Relapses in multiple sclerosis can result in irreversible nervous system tissue injury. If these events could be detected early, targeted immunotherapy could potentially slow disease progression. We describe the use of engineered biomaterial-based immunological niches amenable to biopsy to provide insights into the phenotype of innate immune cells that control disease activity in a mouse model of multiple sclerosis. Differential gene expression in cells from these niches allow monitoring of disease dynamics and gauging the effectiveness of treatment. A proactive treatment regimen, given in response to signal within the niche but before symptoms appeared, substantially reduced disease. This technology offers a new approach to monitor organ-specific autoimmunity, and represents a platform to analyze immune dysfunction within otherwise inaccessible target tissues.


Asunto(s)
Encefalomielitis Autoinmune Experimental/terapia , Inmunoterapia/métodos , Monitoreo Fisiológico/métodos , Esclerosis Múltiple/terapia , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Expresión Génica/genética , Expresión Génica/inmunología , Perfilación de la Expresión Génica/métodos , Humanos , Ratones Endogámicos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Recurrencia , Resultado del Tratamiento
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