RESUMO
Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.
Assuntos
Biomarcadores , Progressão da Doença , Esclerose Múltipla , Humanos , Biomarcadores/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , RecidivaRESUMO
Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.
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Biomarcadores , Proteína Glial Fibrilar Ácida , Proteínas de Neurofilamentos , Humanos , Adulto , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Feminino , Masculino , Proteína Glial Fibrilar Ácida/sangue , Idoso , Adolescente , Biomarcadores/sangue , Adulto Jovem , Estudos Transversais , Voluntários Saudáveis , Fatores Etários , Valores de ReferênciaRESUMO
Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.
Assuntos
Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/líquido cefalorraquidiano , Cadeias kappa de Imunoglobulina/líquido cefalorraquidiano , Imunoglobulina G/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Sensibilidade e Especificidade , Bandas Oligoclonais/líquido cefalorraquidianoRESUMO
BACKGROUND: The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. METHODS: Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients' peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. RESULTS: Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. CONCLUSION: Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Células Supressoras Mieloides , Humanos , Animais , Camundongos , Cloridrato de Fingolimode/uso terapêutico , Células Supressoras Mieloides/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Leucócitos Mononucleares , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , BiomarcadoresRESUMO
BACKGROUND AND PURPOSE: Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum. METHODS: We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry. RESULTS: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio = 165, 95% confidence interval = 10.2-239.4, p < 0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women. CONCLUSIONS: Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period.
Assuntos
Esclerose Múltipla , Ácidos Graxos Voláteis , Feminino , Humanos , Razão de Chances , Gravidez , Estudos Prospectivos , RecidivaRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a highly variable condition. Validated tools to assist in the early detection of patients at high risk of mortality can help guide medical decisions. OBJECTIVE: We sought to validate externally, as well as in patients from the second pandemic wave in Europe, our previously developed mortality prediction model for hospitalized COVID-19 patients. METHODS: Three validation cohorts were generated: 2 external with 185 and 730 patients from the first wave and 1 internal with 119 patients from the second wave. The probability of death was calculated for all subjects using our prediction model, which includes peripheral blood oxygen saturation/fraction of inspired oxygen ratio, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, IL-6, and age. Discrimination and calibration were evaluated in the validation cohorts. The prediction model was updated by reestimating individual risk factor effects in the overall cohort (N = 1477). RESULTS: The mortality prediction model showed good performance in the external validation cohorts 1 and 2, and in the second wave validation cohort 3 (area under the receiver-operating characteristic curve, 0.94, 0.86, and 0.86, respectively), with excellent calibration (calibration slope, 0.86, 0.94, and 0.79; intercept, 0.05, 0.03, and 0.10, respectively). The updated model accurately predicted mortality in the overall cohort (area under the receiver-operating characteristic curve, 0.91), which included patients from both the first and second COVID-19 waves. The updated model was also useful to predict fatal outcome in patients without respiratory distress at the time of evaluation. CONCLUSIONS: This is the first COVID-19 mortality prediction model validated in patients from the first and second pandemic waves. The COR+12 online calculator is freely available to facilitate its implementation (https://utrero-rico.shinyapps.io/COR12_Score/).
Assuntos
COVID-19 , Interleucina-6/imunologia , Modelos Imunológicos , SARS-CoV-2/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/mortalidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
Immunosuppression (IS) and autoimmune disease (AD) are prevalent in patients with severe coronavirus disease 2019 (COVID-19), but their impact on its clinical course is unknown. We investigated relationships between IS, AD, and outcomes in patients hospitalized with COVID-19. Data on consecutive admissions for COVID-19 were extracted retrospectively from medical records. Patients were assigned to one of four cohorts, according to whether or not they had an AD (AD and NAD) or were immunosuppressed (IS and NIS). The primary endpoint was development of severe acute respiratory distress syndrome (ARDS); secondary endpoints included death, and a composite of mechanical ventilation (MV) or death. A total of 789 patients were included: 569 (72.1%) male, 76 (9.6%) with an AD, and 63 (8.0%) with IS. Relative to the NIS-NAD cohort, patients in the IS-AD cohort had a significantly reduced risk of severe ARDS (adjusted hazard ratio [aHR] 0.42; 95% confidence interval [CI] 0.23-0.80; p = 0.008). No significant relationships between IS or AD status and either death or the composite of MV and death were identified, although a trend towards higher mortality was identified in the IS-NAD cohort (aHR vs NIS-NAD 1.71; 95% CI 0.94-3.12; p = 0.081). Patients in this cohort also had higher median serum levels of interleukin-6 compared with IS-AD patients (98.2 vs 21.6 pg/mL; p = 0.0328) and NIS-NAD patients (29.1 pg/mL; p = 0.0057). In conclusion, among patients hospitalized with COVID-19, those receiving immunosuppressive treatment for an AD may have a reduced risk of developing severe ARDS.
Assuntos
Doenças Autoimunes/complicações , Doenças Autoimunes/epidemiologia , COVID-19/complicações , COVID-19/epidemiologia , Avaliação do Impacto na Saúde , Terapia de Imunossupressão/efeitos adversos , SARS-CoV-2 , Idoso , Doenças Autoimunes/metabolismo , Doenças Autoimunes/terapia , Biomarcadores , COVID-19/diagnóstico , COVID-19/metabolismo , Terapia Combinada , Comorbidade , Citocinas/metabolismo , Feminino , Hospitalização , Humanos , Terapia de Imunossupressão/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índices de Gravidade do Trauma , Resultado do TratamentoRESUMO
Syncytin-1 is the envelope protein of the human endogenous retrovirus W (HERV-W). It has been related to multiple sclerosis (MS) but its role in cellular immunity and its pathogenic mechanism in the autoimmune context are not fully understood. We analyzed syncytin-1 levels in peripheral blood mononuclear cells (PBMC) subsets from healthy donors, MS patients in relapse or remission, and patients with acute infections by flow cytometry. PBMC cultures were also prepared to analyze protein expression kinetics. MS patients had higher levels of syncytin-1 levels than controls. We found that syncytin-1 is elevated in monocytes during MS relapses and infections. Cells expressing syncytin-1, including monocytes, T and B lymphocytes, and NKs presented mainly an activated phenotype and, upon stimulation with LPS, its levels increased rapidly on antigen-presenting cells. Syncytin-1 ligation promoted the activation of monocytes, as demonstrated by the upregulation of CD80 and the nonclassical subset CD14low CD16+ . Our results suggest an important role for syncytin-1 in the activation of leukocytes. Given that the expression of syncytin-1 is upregulated in MS patients, this protein might be contributing to the autoimmune cascade in the disease.
Assuntos
Retrovirus Endógenos/imunologia , Produtos do Gene env/genética , Monócitos/virologia , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Proteínas da Gravidez/genética , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/virologia , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Estudos de Casos e Controles , Retrovirus Endógenos/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica , Produtos do Gene env/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Proteínas da Gravidez/imunologia , Cultura Primária de Células , Receptores de IgG/genética , Receptores de IgG/imunologia , Recidiva , Indução de Remissão , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologiaRESUMO
Despite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients. We evaluated the mortality, the risk of need for mechanical ventilation (MV), or death and the risk of developing a severe acute respiratory distress syndrome (ARDS) between high (HD) and standard doses (SD) among patients with a severe COVID-19. All consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an ARDS. Patients were allocated to the HD (≥ 250 mg/day of methylprednisolone) of corticosteroids or the SD (≤ 1.5 mg/kg/day of methylprednisolone) at discretion of treating physician. Five hundred seventy-three patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54-73) years. In the HD group, a worse baseline respiratory situation was observed and male gender, older age, and comorbidities were significantly more common. After adjusting by baseline characteristics, HDs were associated with a higher mortality than SD (adjusted OR 2.46, 95% CI 1.59-3.81, p < 0.001) and with an increased risk of needing MV or death (adjusted OR 2.35, p = 0.001). Conversely, the risk of developing a severe ARDS was similar between groups. Interaction analysis showed that HD increased mortality exclusively in elderly patients. Our real-world experience advises against exceeding 1-1.5 mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.
Assuntos
Tratamento Farmacológico da COVID-19 , Glucocorticoides/administração & dosagem , Metilprednisolona/administração & dosagem , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/mortalidade , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-ß compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.
Assuntos
Predisposição Genética para Doença , Esclerose Múltipla/genética , Linfócitos B , Estudos de Casos e Controles , Análise Mutacional de DNA , Humanos , Leucócitos Mononucleares , Proteínas de Membrana/genética , Proteínas RGS/genética , Espanha , Fator 3 Associado a Receptor de TNF/genética , Vitamina D3 24-Hidroxilase/genéticaRESUMO
BACKGROUND: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-ß (IFNß) treatment in MS patients. OBJECTIVES: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNß therapy in MS patients and to better investigate its functional role. METHODS: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNß and TTFR. RESULTS: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10-4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10-6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNß treatment and related to TTFR. CONCLUSIONS: Rs7298096 could influence MS disease activity during IFNß treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.
Assuntos
Moléculas de Adesão Celular Neuronais , Interferon beta , Esclerose Múltipla , Moléculas de Adesão Celular Neuronais/metabolismo , Células Endoteliais , Humanos , Interferon beta/uso terapêutico , Interferons , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Testes FarmacogenômicosRESUMO
BACKGROUND: MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS). In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available. OBJECTIVE: The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity. METHODS: Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd- patients) was performed by TaqMan assays and qPCR. Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis. Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares). RESULTS: Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples. Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients. This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways. CONCLUSION: Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.
Assuntos
MicroRNAs/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Adulto JovemRESUMO
Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7. By exon splicing assay, we have demonstrated that the rs28445040 variant was the causal factor for skipping of exon 7. Western blots of peripheral blood mononuclear cells from MS patients showed a significant allele-dependent reduction of the SP140 protein expression. To confirm the association of this functional variant with MS and to compare it with the best-associated variant previously reported by GWAS (rs10201872), a case-control study including 4384 MS patients and 3197 controls was performed. Both variants, in strong LD (r(2) = 0.93), were found similarly associated with MS [P-values, odds ratios: 1.9E-9, OR = 1.35 (1.22-1.49) and 4.9E-10, OR = 1.37 (1.24-1.51), respectively]. In conclusion, our data uncover the causal variant for the SP140 locus and the molecular mechanism associated with MS risk. In addition, this study and others previously reported strongly suggest that this functional variant may be shared with other immune-mediated diseases as CD and CLL.
Assuntos
Antígenos Nucleares/sangue , Antígenos Nucleares/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/sangue , Fatores de Transcrição/genética , Estudos de Casos e Controles , Éxons , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Esclerose Múltipla/sangue , Locos de Características Quantitativas , Análise de Sequência de RNARESUMO
Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.
Assuntos
Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL11 , Quimiocina CCL2 , Quimiocina CCL4 , Quimiocina CCL5 , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/sangue , Quimiocina CXCL9/líquido cefalorraquidiano , Árvores de Decisões , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/líquido cefalorraquidiano , Diagnóstico Precoce , Fator de Crescimento Epidérmico , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/líquido cefalorraquidiano , Fator de Crescimento de Hepatócito , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-7/sangue , Interleucina-7/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Análise Multivariada , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Prognóstico , Medição de RiscoRESUMO
Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fator de Transcrição MafB/metabolismo , Mieloma Múltiplo/metabolismo , Animais , Antígenos CD34/biossíntese , Antígenos Ly/metabolismo , Linfócitos B/metabolismo , Metilação de DNA , DNA Complementar/metabolismo , Epigênese Genética , Perfilação da Expressão Gênica , Biblioteca Gênica , Células-Tronco Hematopoéticas/citologia , Humanos , Hibridização in Situ Fluorescente , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mieloma Múltiplo/genética , Translocação GenéticaRESUMO
BACKGROUND: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS). OBJECTIVES: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters. METHODS: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients. RESULTS: We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06). CONCLUSIONS: Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.
Assuntos
Genes de Cadeia Pesada de Imunoglobulina/genética , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Adulto , Feminino , Loci Gênicos , Genótipo , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina M/líquido cefalorraquidiano , Focalização Isoelétrica , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Bandas Oligoclonais/líquido cefalorraquidiano , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-ß-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques. METHODS: In a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders. Semaphorin 7A and ala-ß-his-dipeptidase levels were determined by selected reaction monitoring (SRM) in CSF of 36 patients (18 MS converters, 18 non-converters) and 20 controls. In a second replication study, apolipoprotein AI levels were measured by ELISA in CSF of 74 CIS patients (47 MS converters, 27 non-converters) and 50 individual controls, and levels of semaphorin 7A and ala-beta-his-dipeptidase were determined by SRM in 49 patients (24 MS converters, 25 non-converters) and 22 controls. RESULTS: CSF levels of apolipoprotein AI were increased (P = 0.043) and levels of semaphorin 7A and ala-ß-his-dipeptidase decreased (P = 4.4 × 10(-10) and P = 0.033 respectively) in MS converters compared to non-converters. No significant differences were found in serum levels for apolipoproteins AI and AIV, vitronectin, and plasminogen. Findings with semaphorin 7A and ala-ß-his-dipeptidase were also validated in the second replication study, and CSF levels for these two proteins were again decreased in MS converters versus non-converters (P = 1.2 × 10(-4) for semaphorin 7A; P = 3.7 × 10(-8) for ala-ß-his-dipeptidase). Conversely, apolipoprotein AI findings were not replicated and CSF levels for this protein did not significantly differ between groups. Furthermore, CSF semaphorin 7A levels were negatively associated with the number of T2 lesions at baseline and one-year follow-up. CONCLUSIONS: These results validate previous findings for semaphorin 7A and ala-ß-his-dipeptidase, and suggest that these proteins play a role as CSF biomarkers associated with the conversion to CDMS in CIS patients.
Assuntos
Antígenos CD/líquido cefalorraquidiano , Doenças Desmielinizantes/líquido cefalorraquidiano , Dipeptidases/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Semaforinas/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas Ligadas por GPI/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Background: Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders. Objective: The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up. Methods: A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed. Results: A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0). Conclusion: MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.
Assuntos
Progressão da Doença , Antígenos Nucleares do Vírus Epstein-Barr , Cloridrato de Fingolimode , Imunoglobulina G , Humanos , Cloridrato de Fingolimode/uso terapêutico , Feminino , Masculino , Adulto , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Estudos Retrospectivos , Imunoglobulina G/sangue , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/sangue , Resultado do Tratamento , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Esclerose Múltipla/sangueRESUMO
Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology. Materials and methods: A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence. Conclusion: Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.
Assuntos
Biomarcadores , Técnicas de Apoio para a Decisão , Esclerose Múltipla , Proteínas de Neurofilamentos , Humanos , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Espanha , Adulto , Feminino , Pessoa de Meia-Idade , MasculinoRESUMO
INTRODUCTION: Continuously acquired smartphone keyboard interactions may be useful to monitor progression in multiple sclerosis (MS). We aimed to study the correlation between tapping speed (TS), measured as keys/s, and baseline disability scales in patients with MS. METHODS: Single-center prospective study in patients with MS. We passively assessed TS during first week, measured by an "in house" smartphone application. Reliability was assessed by intraclass correlation coefficient (ICC). Correlations between median and maximum keys/s of first week of assessment and baseline disability measures were explored. RESULTS: One-hundred three patients were included: 62.1 % women, with a median (IQR) age of 47 (40.4-54.8) years-old and an EDSS score of 3.0 (2.0-4.0). Distribution by MS subtypes was: 77.7 % relapsing-remitting MS (RRMS), 17.5 % secondary-progressive MS (SPMS) and 4.9 % primary-progressive MS (PPMS). ICC during first week was 0.714 (p < 0.00001). Both median and maximum keys/s showed a negative correlation with Expanded Disability Status Score, 9-hole peg test and timed 25-foot walk and a positive correlation with Processing Speed Test CogEval® raw and Z-score. Median and maximum keys/s were lower in patients diagnosed with SPMS than in RRMS. Both measures of tapping speed were associated with MS phenotype independently of age. CONCLUSION: TS measured through our application is reliable and correlates with baseline disability scales.