Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 176
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nature ; 572(7770): 481-487, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391585

RESUMO

Experimental autoimmune encephalomyelitis is a model for multiple sclerosis. Here we show that induction generates successive waves of clonally expanded CD4+, CD8+ and γδ+ T cells in the blood and central nervous system, similar to gluten-challenge studies of patients with coeliac disease. We also find major expansions of CD8+ T cells in patients with multiple sclerosis. In autoimmune encephalomyelitis, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35-55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Adulto , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Celíaca , Células Clonais/citologia , Células Clonais/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Antígenos H-2/imunologia , Humanos , Imunização , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
2.
Ann Neurol ; 94(2): 384-397, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37127916

RESUMO

OBJECTIVE: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS. METHODS: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization. RESULTS: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10-3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10-5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10-3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10-7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10-3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10-11 ), and vitamin D level (OR 0.75, p = 9.4 × 10-3 ). INTERPRETATION: By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.


Assuntos
Esclerose Múltipla , Psoríase , Humanos , Diabetes Mellitus Tipo 2/complicações , Estudo de Associação Genômica Ampla , Interleucina-17/genética , Análise da Randomização Mendeliana , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Esclerose Múltipla/complicações , Polimorfismo de Nucleotídeo Único/genética , Psoríase/epidemiologia , Psoríase/genética , Fatores de Risco , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo
3.
Brain ; 146(2): 645-656, 2023 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-35253861

RESUMO

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.


Assuntos
Estudo de Associação Genômica Ampla , Esclerose Múltipla , Humanos , Herança Multifatorial/genética , Esclerose Múltipla/genética , Epigênese Genética , População Europeia , Fatores de Risco , Predisposição Genética para Doença/genética , Fenótipo
4.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34911760

RESUMO

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.


Assuntos
Linfócitos B/metabolismo , Ativação Linfocitária , Esclerose Múltipla/metabolismo , Linfócitos B/patologia , Diferenciação Celular , Metilação de DNA , Epigênese Genética , Epigenômica , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Ativação Transcricional
5.
Ann Neurol ; 91(2): 268-281, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34878197

RESUMO

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.


Assuntos
Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Medula Espinal/patologia , Adulto , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Progressão da Doença , Feminino , Forame Magno/diagnóstico por imagem , Forame Magno/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medula Espinal/diagnóstico por imagem
6.
Proc Natl Acad Sci U S A ; 117(38): 23742-23750, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32878998

RESUMO

Ataxin-1 (ATXN1) is a ubiquitous polyglutamine protein expressed primarily in the nucleus where it binds chromatin and functions as a transcriptional repressor. Mutant forms of ataxin-1 containing expanded glutamine stretches cause the movement disorder spinocerebellar ataxia type 1 (SCA1) through a toxic gain-of-function mechanism in the cerebellum. Conversely, ATXN1 loss-of-function is implicated in cancer development and Alzheimer's disease (AD) pathogenesis. ATXN1 was recently nominated as a susceptibility locus for multiple sclerosis (MS). Here, we show that Atxn1-null mice develop a more severe experimental autoimmune encephalomyelitis (EAE) course compared to wildtype mice. The aggravated phenotype is mediated by increased T helper type 1 (Th1) cell polarization, which in turn results from the dysregulation of B cell activity. Ataxin-1 ablation in B cells leads to aberrant expression of key costimulatory molecules involved in proinflammatory T cell differentiation, including cluster of differentiation (CD)44 and CD80. In addition, comprehensive phosphoflow cytometry and transcriptional profiling link the exaggerated proliferation of ataxin-1 deficient B cells to the activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) pathways. Lastly, selective deletion of the physiological binding partner capicua (CIC) demonstrates the importance of ATXN1 native interactions for correct B cell functioning. Altogether, we report a immunomodulatory role for ataxin-1 and provide a functional description of the ATXN1 locus genetic association with MS risk.


Assuntos
Ataxina-1/metabolismo , Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Animais , Apresentação de Antígeno , Proliferação de Células , Encefalomielite Autoimune Experimental/fisiopatologia , Camundongos , Camundongos Knockout , Esclerose Múltipla , Transdução de Sinais
7.
Artigo em Inglês | MEDLINE | ID: mdl-35710320

RESUMO

BACKGROUND: Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored. METHODS: Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period. RESULTS: NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power. CONCLUSIONS: In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination. TRIAL REGISTRATION NUMBER: NCT02040298.

8.
Arch Biochem Biophys ; 719: 109156, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35218721

RESUMO

The human leukocyte antigen (HLA) locus encodes a large group of proteins governing adaptive and innate immune responses. Among them, HLA class II proteins form α/ß heterodimers on the membrane of professional antigen-presenting cells (APCs), where they display both, self and pathogen-derived exogenous antigens to CD4+ T lymphocytes. We have previously shown that a shorter HLA-DRA isoform (sHLA-DRA) lacking 25 amino acids can be presented onto the cell membrane via binding to canonical HLA-DR2 heterodimers. Here, we employed atomistic molecular dynamics simulations to decipher the binding position of sHLA-DRA and its structural impact on functional regions of the HLA-DR2 molecule. We show that a loop region exposed only in the short isoform (residues R69 to G83) is responsible for binding to the outer domain of the HLA-DR2 peptide-binding site, and experimentally validated the critical role of F76 in mediating such interaction. Additionally, sHLA-DRA allosterically modifies the peptide-binding pocket conformation. In summary, this study unravels key molecular mechanisms underlying sHLA-DRA function, providing important insights into the role of full-length proteins in structural modulation of HLA class II receptors.


Assuntos
Antígeno HLA-DR2 , Peptídeos , Sítios de Ligação , Cadeias alfa de HLA-DR , Antígeno HLA-DR2/química , Antígeno HLA-DR2/metabolismo , Humanos , Isoformas de Proteínas/metabolismo
9.
J Immunol ; 205(5): 1323-1330, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32709660

RESUMO

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.


Assuntos
Doença de Parkinson/genética , Polimorfismo Genético/genética , Receptores KIR3DL1/genética , Alelos , Feminino , Genótipo , Antígenos HLA-B/genética , Humanos , Células Matadoras Naturais/metabolismo , Ligantes , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
10.
Proc Natl Acad Sci U S A ; 116(15): 7419-7424, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910980

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.


Assuntos
Genótipo , Cadeias HLA-DRB1/química , Cadeias HLA-DRB1/genética , Modelos Moleculares , Doença de Parkinson/genética , Fumar/genética , Motivos de Aminoácidos , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Fatores de Risco
11.
Immunology ; 162(2): 194-207, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32986852

RESUMO

Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen-derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/ß-heterodimers on the surface of professional antigen-presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA-DRA gene mediates the transcription of an alternative version of the α-chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA-DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding ß-chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide-binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA-DRA functions as a novel intact antigen for class II HLA molecules.


Assuntos
Cadeias alfa de HLA-DR/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Isoformas de Proteínas/imunologia , Adulto , Idoso , Aminoácidos/imunologia , Células Apresentadoras de Antígenos/imunologia , Sítios de Ligação/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/imunologia , Retículo Endoplasmático/imunologia , Feminino , Células HEK293 , Células HeLa , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeos/imunologia , T-Linfocitopenia Idiopática CD4-Positiva/imunologia
12.
Trends Genet ; 33(12): 960-970, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28987266

RESUMO

Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Esclerose Múltipla/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo
13.
J Neuroinflammation ; 17(1): 297, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046105

RESUMO

BACKGROUND: MicroRNAs (miRNAs) belong to a class of evolutionary conserved, non-coding small RNAs with regulatory functions on gene expression. They negatively affect the expression of target genes by promoting either RNA degradation or translational inhibition. In recent years, converging studies have identified miRNAs as key regulators of oligodendrocyte (OL) functions. OLs are the cells responsible for the formation and maintenance of myelin in the central nervous system (CNS) and represent a principal target of the autoimmune injury in multiple sclerosis (MS). METHODS: MiRAP is a novel cell-specific miRNA affinity-purification technique which relies on genetically tagging Argonaut 2 (AGO2), an enzyme involved in miRNA processing. Here, we exploited miRAP potentiality to characterize OL-specific miRNA dynamics in the MS model experimental autoimmune encephalomyelitis (EAE). RESULTS: We show that 20 miRNAs are differentially regulated in OLs upon transition from pre-symptomatic EAE stages to disease peak. Subsequent in vitro differentiation experiments demonstrated that a sub-group of them affects the OL maturation process, mediating either protective or detrimental signals. Lastly, transcriptome profiling highlighted the endocytosis, ferroptosis, and FoxO cascades as the pathways associated with miRNAs mediating or inhibiting OL maturation. CONCLUSIONS: Altogether, our work supports a dual role for miRNAs in autoimmune demyelination. In particular, the enrichment in miRNAs mediating pro-myelinating signals suggests an active involvement of these non-coding RNAs in the homeostatic response toward neuroinflammatory injury.


Assuntos
Proteínas Argonautas/biossíntese , Encefalomielite Autoimune Experimental/metabolismo , Perfilação da Expressão Gênica/métodos , MicroRNAs/biossíntese , Oligodendroglia/metabolismo , Animais , Proteínas Argonautas/genética , Células Cultivadas , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética
14.
Ann Neurol ; 86(5): 671-682, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31486104

RESUMO

OBJECTIVE: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). METHODS: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. RESULTS: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). INTERPRETATION: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.


Assuntos
Esclerose Múltipla , Telômero/metabolismo , Adulto , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Estudos de Coortes , Estudos Transversais , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Telômero/patologia , Homeostase do Telômero/fisiologia
15.
Ann Neurol ; 85(5): 653-666, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851128

RESUMO

OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates. RESULTS: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.


Assuntos
Progressão da Doença , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/terapia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
Proc Natl Acad Sci U S A ; 114(40): E8421-E8429, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28923927

RESUMO

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a -794CATT5-8 microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.


Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/fisiologia , Esclerose Múltipla/patologia , Índice de Gravidade de Doença , Adulto , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Polimorfismo Genético
17.
Genes Immun ; 20(4): 308-326, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29307888

RESUMO

We investigated association between HLA class I and class II alleles and haplotypes, and KIR loci and their HLA class I ligands, with multiple sclerosis (MS) in 412 European American MS patients and 419 ethnically matched controls, using next-generation sequencing. The DRB1*15:01~DQB1*06:02 haplotype was highly predisposing (odds ratio (OR) = 3.98; 95% confidence interval (CI) = 3-5.31; p-value (p) = 2.22E-16), as was DRB1*03:01~DQB1*02:01 (OR = 1.63; CI = 1.19-2.24; p = 1.41E-03). Hardy-Weinberg (HW) analysis in MS patients revealed a significant DRB1*03:01~DQB1*02:01 homozyote excess (15 observed; 8.6 expected; p = 0.016). The OR for this genotype (5.27; CI = 1.47-28.52; p = 0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C*03:04~B*40:01 haplotype (OR = 0.27; CI = 0.14-0.51; p = 6.76E-06) was highly protective for MS, especially in haplotypes with A*02:01 (OR = 0.15; CI = 0.04-0.45; p = 6.51E-05). By itself, A*02:01 is moderately protective, (OR = 0.69; CI = 0.54-0.87; p = 1.46E-03), and haplotypes of A*02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (OR = 0.53; CI = 0.35-0.78; p = 7.55E-04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB1*15:01, but the Bw4T variant was protective (OR = 0.64; CI = 0.49-0.82; p = 3.37-04) independent of LD with DRB1*15:01. The Bw4I variant was not associated with MS. Overall, we find specific class I HLA polymorphisms to be protective for MS, independent of the strong predisposition conferred by DRB1*15:01.


Assuntos
Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Motivos de Aminoácidos , Haplótipos , Humanos , Desequilíbrio de Ligação
18.
Genes Immun ; 20(4): 340, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29915315

RESUMO

Since the publication of this article, the authors have found that the numbers of patients and controls were reversed. This study included 412 MS patients and 419 controls. This correction applies to the Abstract, the final paragraph of the Introduction, and the first paragraph of the Materials and Methods. This was entirely a reporting error and does not impact the Results or Conclusions.

19.
Am J Hum Genet ; 99(2): 375-91, 2016 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-27486779

RESUMO

The physiological functions of natural killer (NK) cells in human immunity and reproduction depend upon diverse interactions between killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands: HLA-A, HLA-B, and HLA-C. The genomic regions containing the KIR and HLA class I genes are unlinked, structurally complex, and highly polymorphic. They are also strongly associated with a wide spectrum of diseases, including infections, autoimmune disorders, cancers, and pregnancy disorders, as well as the efficacy of transplantation and other immunotherapies. To facilitate study of these extraordinary genes, we developed a method that captures, sequences, and analyzes the 13 KIR genes and HLA-A, HLA-B, and HLA-C from genomic DNA. We also devised a bioinformatics pipeline that attributes sequencing reads to specific KIR genes, determines copy number by read depth, and calls high-resolution genotypes for each KIR gene. We validated this method by using DNA from well-characterized cell lines, comparing it to established methods of HLA and KIR genotyping, and determining KIR genotypes from 1000 Genomes sequence data. This identified 116 previously uncharacterized KIR alleles, which were all demonstrated to be authentic by sequencing from source DNA via standard methods. Analysis of just two KIR genes showed that 22% of the 1000 Genomes individuals have a previously uncharacterized allele or a structural variant. The method we describe is suited to the large-scale analyses that are needed for characterizing human populations and defining the precise HLA and KIR factors associated with disease. The methods are applicable to other highly polymorphic genes.


Assuntos
Genes MHC Classe I/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Receptores KIR/genética , Alelos , Dosagem de Genes , Genoma Humano/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Polimorfismo Genético
20.
J Autoimmun ; 101: 56-69, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010726

RESUMO

The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases.


Assuntos
Regulação da Expressão Gênica , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Neurônios/metabolismo , Sinapses/genética , Sinapses/metabolismo , Proteínas tau/metabolismo , Animais , Autoimunidade , Linhagem Celular , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Feminino , Redes Reguladoras de Genes , Masculino , Metilação , Camundongos , Camundongos Knockout , Modelos Moleculares , Esclerose Múltipla/patologia , Transdução de Sinais , Relação Estrutura-Atividade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Gênica , Proteínas tau/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA