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1.
PLoS One ; 15(8): e0238070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853219

RESUMO

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.


Assuntos
Antígenos de Diferenciação/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Regulação da Expressão Gênica , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Adulto , Alelos , Animais , Autoimunidade , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Linfócitos T/imunologia , Adulto Jovem
2.
Nat Commun ; 11(1): 3871, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747712

RESUMO

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.


Assuntos
Encefalomielite Autoimune Experimental/terapia , Imunoterapia/métodos , Monitorização Fisiológica/métodos , Esclerose Múltipla/terapia , Animais , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Recidiva , Resultado do Tratamento
3.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792491

RESUMO

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.


Assuntos
Glutationa Transferase/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Caspase 8/genética , Caspase 8/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glutationa Transferase/genética , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Fagocitose/genética , Fagocitose/fisiologia , Processamento de Proteína Pós-Traducional , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Remielinização/genética , Remielinização/fisiologia
4.
Mol Immunol ; 125: 32-42, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32629323

RESUMO

Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.


Assuntos
Quimiocina CCL7/biossíntese , Encefalomielite Autoimune Experimental/genética , Regulação da Expressão Gênica/imunologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Células Th17/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Quimiocina CCL7/genética , Quimiocina CCL7/imunologia , Encefalomielite Autoimune Experimental/imunologia , Camundongos , MicroRNAs/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , RNA Longo não Codificante/imunologia , Regulação para Cima
5.
Gene ; 758: 144959, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32683075

RESUMO

Multiple sclerosis (MS) is a clinically heterogeneous multifactorial disorder which is one of the most prevalent neurological disorders of females and young people. Both genetic and environmental factors are playing an important role in the pathophysiology of MS. The main objective of this study is to identify the relationship between numbers of genetic variants within different candidate genes (IL7R, LAG3, and CD40) and the risk of developing MS in the Jordanian Arab population. This case-control study consists of 218 MS patients chosen from neurology clinics at different hospitals in Jordan and ethnically matched 227 healthy controls. Genomic DNA was extracted from blood samples. Genotyping of the candidate gene polymorphisms was conducted using the Sequenom MassARRAY system. Statistical analysis was performed to identify the genetic association of the studied SNPs with MS. Twenty-one variants were studied, three of them were found to be associated with MS (rs6897932 (P-value = 0.01) and rs13188960 (P-value = 0.005) within IL7R gene and LAG3 rs2365095, (P-value = 0.03) within LAG3 gene). Moreover, no significant association was found between MS and the genetic polymorphisms of the CD40 gene. After correction for multiple comparisons, only rs13188960 SNP remained significantly with MS. This is the first study of the genetic association with MS in the Jordanian Arab population to provided evidence of the genetic association of IL7R (rs6897932, rs13188960) and LAG3 (rs2365095) gene polymorphisms with MS. These findings may contribute to our understanding of MS and optimize the therapy protocol for individuals.


Assuntos
Antígenos CD/genética , Predisposição Genética para Doença/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Esclerose Múltipla/genética , Adulto , Árabes/genética , Antígenos CD40/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Jordânia/epidemiologia , Masculino , Esclerose Múltipla/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
6.
Gene ; 758: 144962, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687946

RESUMO

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by the autoimmune inflammation, demyelination, and neurodegeneration. This complex disease develops in genetically predisposed individuals under adverse environmental factors. To date, a large number of MS-associated polymorphic loci of the nuclear genome have been identified; however, their total variability can explain only about 48% of the observed inheritance of MS. Polymorphic variants of the mitochondrial genome and interactions of mitochondrial and nuclear genes (mitonuclear interactions) may be the possible sources of the "missing heritability". We analyzed the association with MS of 10 mitochondrial DNA polymorphisms (m.1719, m.4216, m.4580, m.4917, m.7028, m.9055, m.10398, m.12308, m.13368, m.13708) in DNA of 540 MS patients and 406 healthy individuals. The allele m.9055*G was the only mitochondrial variant associated with MS (Pf = 0.027). To evaluate interactions of mitochondrial and nuclear genomes, we searched for biallelic combinations containing one of 10 mitochondrial variants and one of 35 variants of immune-related nuclear genes. Carriership of mitochondrial variants m.4216, m.4580, or m.13708 in biallelic combinations with variants of nuclear genes IL7R, CLEC16A, CD6, CD86 or PVT1 was associated with MS (Pf = 0.0036-0.00030). We identified epistatic interaction between components of a combination (m.13708*A + PVT1 rs4410871*T). The existence of epistatic biallelic combination can reflect the genuine mitonuclear epistasis.


Assuntos
Núcleo Celular/genética , DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Genoma Mitocondrial/genética , Esclerose Múltipla/genética , Adulto , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Antígeno B7-2/genética , Feminino , Estudos de Associação Genética , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Lectinas Tipo C/genética , Masculino , Mitocôndrias/genética , Proteínas de Transporte de Monossacarídeos/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética
7.
Nucleic Acids Res ; 48(W1): W244-W251, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32484539

RESUMO

miRNet is an easy-to-use, web-based platform designed to help elucidate microRNA (miRNA) functions by integrating users' data with existing knowledge via network-based visual analytics. Since its first release in 2016, miRNet has been accessed by >20 000 researchers worldwide, with ∼100 users on a daily basis. While version 1.0 was focused primarily on miRNA-target gene interactions, it has become clear that in order to obtain a global view of miRNA functions, it is necessary to bring other important players into the context during analysis. Driven by this concept, in miRNet version 2.0, we have (i) added support for transcription factors (TFs) and single nucleotide polymorphisms (SNPs) that affect miRNAs, miRNA-binding sites or target genes, whilst also greatly increased (>5-fold) the underlying knowledgebases of miRNAs, ncRNAs and disease associations; (ii) implemented new functions to allow creation and visual exploration of multipartite networks, with enhanced support for in situ functional analysis and (iii) revamped the web interface, optimized the workflow, and introduced microservices and web application programming interface (API) to sustain high-performance, real-time data analysis. The underlying R package is also released in tandem with version 2.0 to allow more flexible data analysis for R programmers. The miRNet 2.0 website is freely available at https://www.mirnet.ca.


Assuntos
Redes Reguladoras de Genes , MicroRNAs/metabolismo , Software , Gráficos por Computador , Regulação da Expressão Gênica , Humanos , Bases de Conhecimento , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Polimorfismo de Nucleotídeo Único , Biologia de Sistemas , Fatores de Transcrição/metabolismo
8.
Adv Exp Med Biol ; 1253: 309-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445101

RESUMO

Multiple sclerosis (MS) is an aggravating autoimmune disease that cripples young patients slowly with physical, sensory and cognitive deficits. The break of self-tolerance to neuronal antigens is the key to the pathogenesis of MS, with autoreactive T cells causing demyelination that subsequently leads to inflammation-mediated neurodegenerative events in the central nervous system. The exact etiology of MS remains elusive; however, the interplay of genetic and environmental factors contributes to disease development and progression. Given that genetic variation only accounts for a fraction of risk for MS, extrinsic risk factors including smoking, infection and lack of vitamin D or sunshine, which cause changes in gene expression, contribute to disease development through epigenetic regulation. To date, there is a growing body of scientific evidence to support the important roles of epigenetic processes in MS. In this chapter, the three main layers of epigenetic regulatory mechanisms, namely DNA methylation, histone modification and microRNA-mediated gene regulation, will be discussed, with a particular focus on the role of epigenetics on dysregulated immune responses and neurodegenerative events in MS. Also, the potential for epigenetic modifiers as biomarkers and therapeutics for MS will be reviewed.


Assuntos
Epigênese Genética , Esclerose Múltipla/genética , Metilação de DNA , Humanos , Fatores de Risco
9.
BMC Neurol ; 20(1): 218, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471473

RESUMO

BACKGROUND: Several studies have reported the association between polymorphisms in Matrix metalloproteinases (MMPs) gene family and risk of Multiple sclerosis (MS). However, the results have been inconsistent and inconclusive. To resolve this issue, here we performed a systematic review and meta-analysis of the MMP-91562 C/T (rs3918242), MMP-3 (- 1612 5A/6A), and MMP-2 (- 1306 C/T) polymorphisms and susceptibility to MS. METHODS: We conducted a comprehensive systematic search in the major electronic database, including Scopus and PubMed to look up for relevant studies published before December 2019 that surveyed the association between the MMP-91562 C/T (rs3918242), MMP-3 (- 1612 5A/6A), and MMP-2 (- 1306 C/T) polymorphisms and susceptibility to MS. The level of association between the polymorphisms and susceptibility to MS in the polled analysis was determined by calculating the odds ratio (OR) and the corresponding 95% confidence interval (CI). RESULTS: We found 15 studies containing 2430 MS subjects and 2304 controls. A statistically significant association was observed in the all five comparisons of the MMP-91562 C/T polymorphism and MS risk as follows: dominant model (OR = 1.62, 95% CI = 1.03-2.53, P = 0.03), recessive model (OR = 2.69, 95% CI = 1.68-4.29, P < 0.001), allelic model (OR = 1.51, 95% CI = 1-2.28, P = 0.04), TT vs. CC model (OR = 3.20, 95% CI = 1.87-5.46, P < 0.001), and CT vs. CC model (OR = 1.53, 95% CI = 1.02-2.28, P = 0.04). CONCLUSIONS: Our meta-analysis revealed significant association of MMP-9 (- 1562 C/T) Single-nucleotide polymorphism (SNP) with MS susceptibility that increased the disease risk.


Assuntos
Predisposição Genética para Doença , Metaloproteinase 9 da Matriz/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Humanos , Masculino , Metaloproteinases da Matriz/genética , Razão de Chances
10.
Nat Immunol ; 21(5): 513-524, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284594

RESUMO

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.


Assuntos
Encefalomielite Autoimune Experimental/genética , Perfilação da Expressão Gênica/métodos , Microglia/fisiologia , Esclerose Múltipla/genética , Inflamação Neurogênica/genética , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Redes Reguladoras de Genes , Ensaios de Triagem em Larga Escala , Humanos , Imunidade Inata , Isoxazóis/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Esclerose Múltipla/tratamento farmacológico , Inflamação Neurogênica/tratamento farmacológico , Estresse Oxidativo , Análise de Sequência de RNA , Análise de Célula Única
11.
Medicine (Baltimore) ; 99(15): e19530, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282702

RESUMO

BACKGROUND: The aim of this study was to explore the association between CD24 Ala/Val polymorphism and susceptibility of multiple sclerosis (MS). METHODS: A comprehensive literature search for relevant studies was performed on google scholar, PubMed, Web of science, Embase, the Chinese National Knowledge Infrastructure and the Chinese Biology Medicine. This meta-analysis was conducted using the STATA 11.0 software and the pooled odds ratio with 95% confidence interval was calculated. RESULTS: Seven case-control studies were included in this meta-analysis. The results showed significant association between CD24 Ala/Val polymorphism and susceptibility to MS. Stratified analysis by areas also showed significant association in Asians. However, no association was found in Europeans. CONCLUSION: This study suggested that the CD24 Val allele was associated with an increased risk of MS and larger-scale studies of populations are needed to explore the role of CD24 Ala/Val polymorphism during the pathogenesis of MS.


Assuntos
Antígeno CD24/genética , Esclerose Múltipla/genética , Substituição de Aminoácidos , Predisposição Genética para Doença , Humanos
12.
PLoS One ; 15(4): e0226050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240164

RESUMO

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.


Assuntos
Encefalomielite Autoimune Experimental/genética , Lisofosfolipídeos/genética , Esclerose Múltipla/genética , Diester Fosfórico Hidrolases/genética , Animais , Antígeno CD11b/genética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/fisiopatologia , Deleção de Genes , Expressão Gênica/genética , Humanos , Lisofosfolipídeos/biossíntese , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
13.
Ann Neurol ; 87(5): 774-787, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32162725

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS. METHODS: We included 8- to 12-year-old genotyped participants from the Generation R Study in whom T1-weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA), and global mean diffusivity using linear regression. RESULTS: No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (ß = 0.098, standard error [SE] = 0.030, p = 1.08 × 10-3 ). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; ß = 0.189, SE = 0.072, p = 9.40 × 10-3 ). INTERPRETATION: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020;87:774-787.


Assuntos
Encéfalo/patologia , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Criança , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Herança Multifatorial , Neuroimagem
14.
PLoS One ; 15(2): e0228883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084151

RESUMO

IgG oligoclonal bands (OCBs) are present in the cerebrospinal fluid (CSF) of more than 95% of patients with multiple sclerosis (MS), and are considered to be the immunological hallmark of disease. However, the target specificities of the IgG in MS OCBs have remained undiscovered. Nevertheless, evidence that OCBs are associated with increased levels of disease activity and disability support their probable pathological role in MS. We investigated the antigen specificity of individual MS CSF IgG from 20 OCB-positive patients and identified 40 unique peptides by panning phage-displayed random peptide libraries. Utilizing our unique techniques of phage-mediated real-time Immuno-PCR and phage-probed isoelectric focusing immunoblots, we demonstrated that these peptides were targeted by intrathecal oligoclonal IgG antibodies of IgG1 and IgG3 subclasses. In addition, we showed that these peptides represent epitopes sharing sequence homologies with proteins of viral origin, and proteins involved in cell stress, apoptosis, and inflammatory processes. Although homologous peptides were found within individual patients, no shared peptide sequences were found among any of the 42 MS and 13 inflammatory CSF control specimens. The distinct sets of oligoclonal IgG-reactive peptides identified by individual MS CSF suggest that the elevated intrathecal antibodies may target patient-specific antigens.


Assuntos
Autoanticorpos/líquido cefalorraquidiano , Imunoglobulina G/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Bandas Oligoclonais/líquido cefalorraquidiano , Sequência de Aminoácidos , Especificidade de Anticorpos , Autoanticorpos/sangue , Autoanticorpos/classificação , Autoantígenos/genética , Autoantígenos/imunologia , Estudos de Casos e Controles , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Masculino , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/genética , Bandas Oligoclonais/sangue , Bandas Oligoclonais/classificação , Biblioteca de Peptídeos , Peptídeos/genética , Peptídeos/imunologia
15.
J Pathol ; 250(5): 496-509, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32073139

RESUMO

Multiple sclerosis (MS) is a chronic disease of the CNS, hallmarked by inflammation and demyelination. Early stages of the disease frequently show active lesions containing numerous foamy macrophages and inflammatory cells. Disease progression is highlighted by increasing numbers of mixed active/inactive or inactive lesions showing sparse inflammation and pronounced astrogliosis. Furthermore, gray matter lesions increase in number and extent during disease progression. MicroRNAs (miRNAs) comprise a group of several thousand (in humans more than 2000), small non-coding RNA molecules with a fundamental influence on about one-third of all protein-coding genes. Furthermore, miRNAs have been detected in body fluids, including spinal fluid, and they are assumed to participate in intercellular communications. Several studies have determined miRNA profiles from dissected white and gray matter lesions of autoptic MS patients. In this review, we summarize in detail the current knowledge of individual miRNAs in gray and white matter lesions of MS patients and present the concepts of MS tissue lesion development based on the altered miRNA profiles. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Sistema Nervoso Central/patologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Substância Branca/patologia , Progressão da Doença , Humanos , MicroRNAs/genética , Esclerose Múltipla/genética , Reino Unido
16.
J Neuroimmunol ; 341: 577187, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32050150

RESUMO

Relative telomere length (TL) is regarded as a biomarker of biological age. Accelerated immune aging, as represented by TL reduction, has been demonstrated in autoimmune diseases, including multiple sclerosis (MS). However, it is still unresolved whether telomere shortening is the cause or the consequence of the pathogenic events underlying autoimmunity. Assessing TL in whole blood DNA samples in 138 MS patients and 120 healthy controls showed reduced TL in patients as compared with controls There seems to be a prelude of accelerated telomere shortening, which may increase the risk for development of MS.


Assuntos
Leucócitos/ultraestrutura , Esclerose Múltipla/genética , Encurtamento do Telômero , Adulto , Idoso , Envelhecimento/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Caracteres Sexuais
17.
J Neuroimmunol ; 341: 577166, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32062178

RESUMO

BACKGROUND: Multiple sclerosis (MS) is recognized as the most prevalent chronic inflammatory neurological disorder diagnosed in young adults. Recent evidence suggests that the T244I polymorphism of the IL7Rα gene (rs6897932) May influence MS susceptibility; however, individual studies have provided conflicting and controversial results. Therefore, this meta-analysis was conducted to assess the association between the IL7R T244I polymorphism and the risk of MS. METHOD: An extensive search for published literature up to May 2019 was accomplished in the electronic databases, and 28 studies consisting of 16,260 MS patients and 18,335 controls were included. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to investigate the strength of association. RESULTS: The results of the present meta-analysis represented significant association between the IL7R T244I polymorphism and MS susceptibility. (recessive model: OR = 1.126, 95% CI 1.026-1.236, P = .012; dominant model: OR = 1.172, 95% CI 1.024-1.341, P = .021; homozygous model: OR = 1.213, 95% CI 1.038-1.417, P = .015; and allelic model: OR = 1.109, 95% CI 1.025-1.200, P = .010, respectively). In the subgroup analysis according to region, our findings showed significant association in Europe. However, no association was found in Middle East. CONCLUSION: The current meta-analysis demonstrated that the C allele of IL7R T244I polymorphism might be a risk factor for the MS susceptibility in Europe but not in Middle East.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Alelos , Substituição de Aminoácidos , Intervalos de Confiança , Grupos de Populações Continentais/genética , Grupos Étnicos/genética , Europa (Continente)/etnologia , Predisposição Genética para Doença , Humanos , Subunidade alfa de Receptor de Interleucina-7/fisiologia , Oriente Médio/etnologia , Modelos Genéticos , Esclerose Múltipla/etnologia , Razão de Chances , Fatores de Risco
18.
Proc Natl Acad Sci U S A ; 117(7): 3848-3857, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32024760

RESUMO

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.


Assuntos
Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Regulação Alostérica , Sítio Alostérico , Animais , Biocatálise , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos Knockout , Esclerose Múltipla/enzimologia , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Serotonina/análogos & derivados , Serotonina/química , Serotonina/metabolismo , Triptofano/metabolismo
19.
Proc Natl Acad Sci U S A ; 117(10): 5430-5441, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094172

RESUMO

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. Dysregulation of STAT3, a transcription factor pivotal to various cellular processes including Th17 cell differentiation, has been implicated in MS. Here, we report that STAT3 is activated in infiltrating monocytic cells near active MS lesions and that activation of STAT3 in myeloid cells is essential for leukocyte infiltration, neuroinflammation, and demyelination in experimental autoimmune encephalomyelitis (EAE). Genetic disruption of Stat3 in peripheral myeloid lineage cells abrogated EAE, which was associated with decreased antigen-specific T helper cell responses. Myeloid cells from immunized Stat3 mutant mice exhibited impaired antigen-presenting functions and were ineffective in driving encephalitogenic T cell differentiation. Single-cell transcriptome analyses of myeloid lineage cells from preclinical wild-type and mutant mice revealed that loss of myeloid STAT3 signaling disrupted antigen-dependent cross-activation of myeloid cells and T helper cells. This study identifies a previously unrecognized requisite for myeloid cell STAT3 in the activation of myelin-reactive T cells and suggests myeloid STAT3 as a potential therapeutic target for autoimmune demyelinating disease.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Linfocitária , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Células Mieloides/imunologia , Fator de Transcrição STAT3/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Antígeno CD11b/análise , Diferenciação Celular , Encefalomielite Autoimune Experimental/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Esclerose Múltipla/genética , Fator de Transcrição STAT3/genética , Análise de Célula Única , Transcriptoma
20.
Oxid Med Cell Longev ; 2020: 8171020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089782

RESUMO

This work is the first to demonstrate that class G immunoglobulins (IgGs) in patients with multiple sclerosis and healthy individuals have the ability to catalyze the dismutation reaction of the superoxide anion radical. Thus, superoxide dismutase (SOD) activity is an intrinsic property of antibodies, which is confirmed by a number of stringent criteria. SOD activity of IgGs in patients with multiple sclerosis statistically significantly exceeds such activity in healthy individuals by 2-4 times. Moreover, the maximum activity has been registered in patients with relapsing remitting multiple sclerosis. The kinetic characteristics of the SOD reaction of IgGs are several orders of magnitude lower than those for the SOD enzyme but do not differ between patients with multiple sclerosis and healthy individuals. Consequently, abzymes with SOD activity have a lower catalysis rate than that of the enzymes and form a stronger complex with the substrates. Inhibitory analysis showed that this activity is inhibited by classical metal-dependent SOD inhibitors. The activity of IgGs was inhibited by classical metal-dependent inhibitors EDTA and TETA (triethylenetetramine). Also, high catalase activity of IgGs was detected in these patients. We suggest that these abzymes help protect the body from oxidative stress.


Assuntos
Imunoglobulina G/metabolismo , Esclerose Múltipla/genética , Superóxido Dismutase/metabolismo , Adulto , Idoso , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo
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