RESUMEN
Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.
Asunto(s)
Dimetilfumarato , Encefalomielitis Autoinmune Experimental , Ganglios Linfáticos , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ratones , Femenino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Mesenterio , Citocinas/metabolismo , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.
Asunto(s)
Interleucina-27 , Esclerosis Múltiple , Humanos , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas , Interleucina-27/metabolismo , Leucocitos Mononucleares/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Linfocitos T/metabolismoRESUMEN
Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-ß (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Antígenos CD19/uso terapéutico , Antígenos CD20 , Linfocitos B/metabolismo , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Humanos , Interferón beta/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Péptidos , Linfocitos TRESUMEN
BACKGROUND: Neurofilament Light (NfL) chain levels in both cerebrospinal fluid (CSF) and serum have been correlated with the reduction of axonal damage in multiple sclerosis (MS) patients treated with Natalizumab (NTZ). However, little is known about the function of plasmacytoid cells in NTZ-treated MS patients. OBJECTIVE: To evaluate CSF NfL, serum levels of soluble-HLA-G (sHLA-G), and eventual tolerogenic behavior of plasmacytoid dendritic cells (pDCs) in MS patients during NTZ treatment. METHODS: CSF NfL and serum sHLA-G levels were measured using an ELISA assay, while pDCs (BDCA-2+) were accessed through flow cytometry analyses. RESULTS: CSF levels of NfL were significantly reduced during NTZ treatment, while the serum levels of sHLA-G were increased. Moreover, NTZ treatment enhanced tolerogenic (HLA-G+, CD274+, and HLA-DR+) molecules and migratory (CCR7+) functions of pDCs in the peripheral blood. CONCLUSION: These findings suggest that NTZ stimulates the production of molecules with immunoregulatory function such as HLA-G and CD274 programmed death-ligand 1 (PD-L1) which may contribute to the reduction of axonal damage represented by the decrease of NfL levels in patients with MS.
RESUMEN
OBJECTIVE: Characterization of partial remission using the insulin dose-adjusted HbA1c (IDAA1c) ≤ 9 definition in a multiethnic Brazilian population of children and adolescents with type 1 diabetes (T1D), in addition with the determination of both Class II HLA genotype and autoantibodies. METHODS: We analyzed the prevalence of partial remission in 51 new-onset T1D patients with a median time follow-up of 13 months from diagnosis. For this study, anti-GAD65, anti-IA2 and HLA class II genotyping were considered. RESULTS: Partial remission occurred in 41.2% of T1D patients until 3 months after diagnosis, mainly in those aged 5-15 years. We have demonstrated a significant increase in the haplotypes of class II HLA DRB1*0301-DQB1*0201 in children and adolescents with a partial remission phase of the disease (42.9% vs 21.7% in non-remitters, P = .0291). This haplotype was also associated with the reduction of anti-IA2 antibodies production. Homozygote DRB1*03-DQB1*0201/DRB1*03-DQB1*0201 children had the lowest prevalence of IA-2A antibodies (P = .0402). However, this association does not correlate with the time of the remission phase. CONCLUSION: Although the number of patients studied was reduced, our data suggested that the association between genetics and decrease in antibody production to certain islet auto-antigen may contribute, at least in part, to the remission phase of T1D.
Asunto(s)
Autoanticuerpos/biosíntesis , Diabetes Mellitus Tipo 1 , Antígenos de Histocompatibilidad Clase II/genética , Adolescente , Adulto , Autoanticuerpos/genética , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Lactante , Masculino , Remisión Espontánea , Adulto JovenRESUMEN
Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.
Asunto(s)
Trastornos del Humor/diagnóstico , Esclerosis Múltiple/historia , Neurología/historia , Neuropsiquiatría/historia , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Malaria/historia , Malaria/terapia , Trastornos del Humor/etiología , Trastornos del Humor/historia , Esclerosis Múltiple/complicacionesRESUMEN
ABSTRACT Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.
RESUMO Os distúrbios neuropsiquiátricos na esclerose múltipla são conhecidos desde a descrição clínico-patológica original de Charcot no final do século XIX. Charcot nas últimas décadas de sua vida se envolveu no campo da neuropsiquiatria. Isso produziu uma batalha de escolas rivais na época que ainda ecoa até hoje. A intuição de Charcot, incluindo a linha de pensamento de Babinski, um de seus discípulos mais famosos, foi a teoria correta da conexão entre os transtornos do humor e muitas das doenças do sistema nervoso. A preocupação da Medicina em estabelecer uma relação entre transtornos do humor e doenças vem das idades antiga e média, com referências encontradas na doutrina hipocrática. No entanto, foi apenas na segunda metade do século XIX e início do século XX que, com as descobertas de Charcot essa discussão foi realizada de maneira estruturada, estabelecendo os fundamentos da neuropsiquiatria.
Asunto(s)
Humanos , Historia del Siglo XIX , Historia del Siglo XX , Trastornos del Humor/diagnóstico , Neuropsiquiatría/historia , Esclerosis Múltiple/historia , Neurología/historia , Trastornos del Humor/etiología , Trastornos del Humor/historia , Malaria/historia , Malaria/terapia , Esclerosis Múltiple/complicacionesRESUMEN
Malaria remains a world-threatening disease largely because of the lack of a long-lasting and fully effective vaccine. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of the Duffy binding-like erythrocyte binding protein and apical membrane antigen 1 (AMA1) antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, ectodomains M1 and M2, homologous to AMA1, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. Here, the Plasmodium yoelii MAEBL-M2 domain was expressed in a prokaryotic vector. C57BL/6J mice were immunized with doses of P. yoelii recombinant protein rPyM2-MAEBL. High levels of antibodies, with balanced IgG1 and IgG2c subclasses, were achieved. rPyM2-MAEBL antisera were capable of recognizing the native antigen. Anti-MAEBL antibodies recognized different MAEBL fragments expressed in CHO cells, showing stronger IgM and IgG responses to the M2 domain and repeat region, respectively. After a challenge with P. yoelii YM (lethal strain)-infected erythrocytes (IE), up to 90% of the immunized animals survived and a reduction of parasitemia was observed. Moreover, splenocytes harvested from immunized animals proliferated in a dose-dependent manner in the presence of rPyM2-MAEBL. Protection was highly dependent on CD4(+), but not CD8(+), T cells toward Th1. rPyM2-MAEBL antisera were also able to significantly inhibit parasite development, as observed in ex vivo P. yoelii erythrocyte invasion assays. Collectively, these findings support the use of MAEBL as a vaccine candidate and open perspectives to understand the mechanisms involved in protection.
Asunto(s)
Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Plasmodium yoelii/inmunología , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Animales , Anticuerpos Antiprotozoarios/inmunología , Eritrocitos/parasitología , Femenino , Humanos , Inmunización , Malaria/inmunología , Malaria/mortalidad , Malaria/parasitología , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/química , Vacunas contra la Malaria/genética , Masculino , Merozoítos/química , Merozoítos/crecimiento & desarrollo , Merozoítos/inmunología , Ratones , Ratones Endogámicos C57BL , Plasmodium yoelii/química , Plasmodium yoelii/genética , Plasmodium yoelii/crecimiento & desarrollo , Estructura Terciaria de Proteína , Proteínas Protozoarias/administración & dosificación , Proteínas Protozoarias/genética , Esporozoítos/química , Esporozoítos/crecimiento & desarrollo , Esporozoítos/inmunologíaRESUMEN
OBJECTIVE: To estimate the clinical and demographics aspects that may contribute to cognitive impairment and psychiatric symptoms in Parkinson's disease (PD). METHOD: All patients answered a structured standardized clinical questionnaire. Two movement disorders specialists performed the following scale: Unified Parkinson's disease rating score (UPDRS), the modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We built a generalized linear model to assess predictors for the SCOPA-COG and SCOPA-PC scores. RESULTS: Almost 37% of our patients were demented as per SCOPA-COG scores. Level of education and the UPDRS-Subscale III were predictors of cognitive impairment. Higher scores in domain 3 of NMSS and male gender were associated with psychiatric complications as assessed per the SCOPA-PC. CONCLUSION: Level of education and disease severity are predictors of dementia in PD. Psychiatric complications are more commonly observed in men.
Asunto(s)
Trastornos del Conocimiento/etiología , Trastornos Mentales/etiología , Enfermedad de Parkinson/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/uso terapéutico , Cognición/fisiología , Trastornos del Conocimiento/fisiopatología , Escolaridad , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Trastornos Mentales/fisiopatología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Escalas de Valoración Psiquiátrica , Psicometría , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
Multiple sclerosis affects more than 2.5 million people worldwide. Although multiple sclerosis was described almost 150 years ago, there are many knowledge gaps regarding its etiology, diagnosis, prognosis, and pathogenesis. Multiple sclerosis is an inflammatory, demyelinating, neurodegenerative disease of the CNS. During the last several decades, experimental models of multiple sclerosis have contributed to our understanding of the inflammatory disease mechanisms and have aided drug testing and development. However, little is known about the neurodegenerative mechanisms that operate during the evolution of the disease. Currently, all therapeutic approaches are primarily based on the inflammatory aspect of the disease. During the last decade, proteomics has emerged as a promising tool for revealing molecular pathways as well as identifying and quantifying differentially expressed proteins. Therefore, proteomics may be used for the discovery of biomarkers, potential drug targets, and new regulatory mechanisms. To date, a considerable number of proteomics studies have been conducted on samples from experimental models and patients with multiple sclerosis. These data form a solid base for further careful analysis and validation.
Asunto(s)
Esclerosis Múltiple/metabolismo , Proteómica/métodos , Animales , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Humanos , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
Objective To estimate the clinical and demographics aspects that may contribute to cognitive impairment and psychiatric symptoms in Parkinson’s disease (PD). Method All patients answered a structured standardized clinical questionnaire. Two movement disorders specialists performed the following scale: Unified Parkinson’s disease rating score (UPDRS), the modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We built a generalized linear model to assess predictors for the SCOPA-COG and SCOPA-PC scores. Results Almost 37% of our patients were demented as per SCOPA-COG scores. Level of education and the UPDRS-Subscale III were predictors of cognitive impairment. Higher scores in domain 3 of NMSS and male gender were associated with psychiatric complications as assessed per the SCOPA-PC. Conclusion Level of education and disease severity are predictors of dementia in PD. Psychiatric complications are more commonly observed in men. .
Objetivo Estimar aspectos clínicos e demográficos que podem contribuir para o comprometimento cognitivo e sintomas psiquiátricos na doença de Parkinson (DP). Método Todos pacientes responderam questionário clínico padrão. Duas especialistas em distúrbios do movimento aplicaram as seguintes escalas: Unified Parkinson’s disease rating score (UPDRS), Hoehn and Yahr estágios, Schwab and England Scale, SCOPA cognição (SCOPA-COG), SCOPA-Complicações psiquiátricas (SCOPA-CP) e Escala de sintomas não motores (NMSS). Utilizamos análise multivariada, para avaliar os preditores relacionados ao SCOPA-COG e SCOPA CP. Resultados Aproximadamente 37% dos nossos pacientes foram classificados como dementes utilizando-se os valores obtidos no SCOPA-COG. Nível educacional e a parte III do UPDRS foram preditores de comprometimento cognitivo. Escores elevados no domínio 3 do NMSS e sexo masculino associaram-se com complicações psiquiátricas quando acessadas pelo SCOPA-CP. Conclusão Nível educacional e gravidade de doença são preditores de demência na DP. Complicações psiquiátricas são mais comumente observadas em homens. .
Asunto(s)
Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Conocimiento/etiología , Trastornos Mentales/etiología , Enfermedad de Parkinson/complicaciones , Antiparkinsonianos/uso terapéutico , Trastornos del Conocimiento/fisiopatología , Cognición/fisiología , Escolaridad , Métodos Epidemiológicos , Trastornos Mentales/fisiopatología , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Psicometría , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
BACKGROUND: Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. AIMS: The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. METHODS AND RESULTS: The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. CONCLUSIONS: Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Neuroglía/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Sinapsis/efectos de los fármacos , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Proteínas de Unión al Calcio/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/fisiopatología , Inmunohistoquímica , Proteínas de Microfilamentos/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Neuronas Motoras/fisiología , Neuroglía/patología , Neuroglía/fisiología , Plasticidad Neuronal/fisiología , Pregabalina , Ratas Endogámicas Lew , Reacción en Cadena en Tiempo Real de la Polimerasa , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Médula Espinal/fisiopatología , Sinapsis/patología , Sinapsis/fisiología , Sinaptofisina/metabolismo , Ácido gamma-Aminobutírico/farmacologíaAsunto(s)
Linfocitos B/fisiología , Células Dendríticas/fisiología , Fosfatos de Dinucleósidos/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Receptor Toll-Like 9/agonistas , Traslado Adoptivo/métodos , Animales , Linfocitos B/efectos de los fármacos , Complejo CD3/metabolismo , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidad , Fragmentos de Péptidos/toxicidadRESUMEN
Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.
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Axones/metabolismo , Esclerosis Múltiple/metabolismo , Proteómica , Axones/patología , Biomarcadores/metabolismo , Encefalomielitis Autoinmune Experimental/diagnóstico , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/patologíaRESUMEN
Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis. However, the underlying cellular and molecular mechanisms resulting in the increased prevalence of autoimmunity remain elusive. To clarify these mechanisms, we studied various markers of immune activation in individuals occupationally exposed to silica dust, i.e., serum levels of soluble IL-2 receptor (sIL-2R), levels of IL-2, other pro- and anti-inflammatory cytokines and lymphoproliferation. Our results demonstrate that silica-exposed individuals present important alterations in their immune response when compared to controls, as shown by increased serum sIL-2R levels, decreased production of IL-2 and increased levels of the pro-inflammatory (IFN-γ, IL-1α, TNF-α, IL-6) as well as anti-inflammatory (IL-10 and TGF-ß) cytokines. Furthermore, silica-exposed individuals presented enhanced lymphoproliferative responses. Our findings provide evidence that the maintenance of immune homeostasis may be disturbed in silica-exposed individuals, possibly resulting in autoimmune disorders.
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Contaminantes Ambientales/toxicidad , Activación de Linfocitos , Exposición Profesional , Dióxido de Silicio/toxicidad , Anciano , Brasil , Proliferación Celular , Femenino , Humanos , Interleucina-2/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Receptores de Interleucina-2/sangreRESUMEN
BACKGROUND: Both Th1 and Th17 cells specific for neuroantigen are described as encephalitogenic in the experimental autoimmune encephalomyelitis (EAE) model. AIM: The proposal of this study was to investigate how carbon nanotubes internalized by antigen-presenting cells (APCs) affect the development of encephalitogenic CD4(+) T cells. METHODS: Therefore, we stimulated encephalitogenic T cells in the presence or not of multiwalled carbon nanotube (MWCNT). After the incubation, we analyzed the expression profile of the encephalitogenic T cells and their capacity to induce EAE. RESULTS: Encephalitogenic CD4(+) T cells cultured with APCs that were previously incubated with MWCNTs do not express IL-17. The adoptive transfer of these cells causes less severe EAE than the transfer of both Th1 and Th17 cells that are not incubated with MWCNTs. These results suggest that the increased IL-27 level produced by the APCs incubated with the carbon nanotubes inhibits the development of Th17 cells. This observation is confirmed by the concomitant reduction in the level of RORγt, which is a transcription factor essential for the development of Th17 cells. Moreover, the incubation of encephalitogenic T cells devoid of Th17 cells with neutralizing anti-IL-27 antibodies restored the production of IL-17. CONCLUSION: This finding confirms the suppressive effect of IL-27 on encephalitogenic Th17 cells. The results presented suggest that the stimulation of APCs with carbon nanoparticles prior to neuroantigen presentation affects the development of the Th17 subset of encephalitogenic CD4(+) T lymphocytes and results in less severe EAE.
Asunto(s)
Encefalomielitis Autoinmune Experimental/etiología , Interleucina-27/fisiología , Nanotubos de Carbono , Células Th17/inmunología , Traslado Adoptivo , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Ratas , Ratas Endogámicas LewRESUMEN
BACKGROUND: A growing body of evidence supports the hypothesis that vitamin D is an important environmental factor in the etiology of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS). AIM: The purpose of this study was exploring the mechanisms underlying the beneficial effect of vitamin D3 in encephalomyelitis (EAE). METHODS: We treated monophasic experimental autoimmune EAE, induced in Lewis rat, with vitamin D3 and adoptively transfer tolerogenic bone marrow-derived DCs generated in the presence of vitamin D3. RESULTS: This study provides evidence that the in vivo administration of vitamin D3, as well as the adoptive transfer of vitamin D3 -induced IDO(+) immature/tolerogenic dendritic cells, leads to a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the lymph nodes in a rat model of MS, experimental autoimmune EAE. Concomitant with the increase in this cell population, there is a significant decrease in the number of autoreactive T cells in the central nervous system. Bone marrow-derived DCs cultivated in the presence of vitamin D3 present a tolerogenic profile with high IL-10, TNFα, and IDO expression and decreased MHC-II and CD80 expression. The adoptive transfer of IDO (+) DCs induces a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) T cells in the lymph nodes, comparable with vitamin D3 treatment. CONCLUSION: These mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system.
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Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Células Dendríticas/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/efectos de los fármacos , Animales , Células Dendríticas/inmunología , Células Dendríticas/patología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratas , Ratas Endogámicas Lew , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS. METHODS: Thirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients. RESULTS: Electroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure. CONCLUSION: This paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly. TRIAL REGISTRATION: RBR-58yq52.
Asunto(s)
Electroacupuntura , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/terapia , Adulto , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases. OBJECTIVE: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD. PATIENTS AND METHODS: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting. RESULTS: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups. CONCLUSIONS: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.