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1.
Hum Mol Genet ; 32(10): 1634-1646, 2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-36621967

RESUMO

Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.


Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Criança , Humanos , Animais , Feminino , Transtorno do Espectro Autista/etiologia , Cromatina/genética , Processamento Alternativo/genética , Ácido Valproico/efeitos adversos , RNA Mensageiro/metabolismo , Modelos Animais de Doenças
2.
Mult Scler ; 30(4-5): 585-593, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38357863

RESUMO

BACKGROUND: Despite advancements in treatments of multiple sclerosis (MS), there is a lack of awareness of early MS symptoms, especially in students and the public, contributing to delays in diagnosis and treatment. This review aims to identify gaps in tools to increase awareness and to provide a bilingual framework to facilitate recognition of early MS symptoms. METHODS: We performed a literature review to determine the use of English and Spanish mnemonics in MS education for medical students and patients. RESULTS: There is no educational tool to help remember the early signs of MS at present. Here we present a framework for early awareness encompassed in the bilingual mnemonics VISIBLY (English) and VISIBLE (Spanish). VISIBLY stands for (1) Vision changes: Painful vision loss, loss of color vision or double vision; (2) Belly or Back numbness and Balance issues; (3) Limb weakness or Numbness; (4), Young people. Spanish version is included in the manuscript. CONCLUSION: We posit that VISIBL-MS provides a framework for MS awareness that addresses the interconnection between language, culture, health literacy, and health outcomes and can be a useful educational tool to tackle the effects of health literacy on diverse communities.


Assuntos
Hipestesia , Esclerose Múltipla , Humanos , Escolaridade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/terapia
3.
J Neurooncol ; 161(1): 67-76, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36595192

RESUMO

PURPOSE: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults with a median overall survival of only 14.6 months despite aggressive treatment. While immunotherapy has been successful in other cancers, its benefit has been proven elusive in GBM, mainly due to a markedly immunosuppressive tumor microenvironment. SARS-CoV-2 has been associated with the development of a pronounced central nervous system (CNS) inflammatory response when infecting different cells including astrocytes, endothelial cells, and microglia. While SARS-CoV2 entry factors have been described in different tissues, their presence and implication on GBM aggressiveness or microenvironment has not been studied on appropriate preclinical models. METHODS: We evaluated the presence of crucial SARS-CoV-2 entry factors: ACE2, TMPRSS2, and NRP1 in matched surgically-derived GBM tissue, cells lines, and organoids; as well as in human brain derived specimens using immunohistochemistry, confocal pixel line intensity quantification, and transcriptome analysis. RESULTS: We show that patient derived-GBM tissue and cell cultures express SARS-CoV2 entry factors, being NRP1 the most crucial facilitator of SARS-CoV-2 infection in GBM. Moreover, we demonstrate that, receptor expression remains present in our GBM organoids, making them an adequate model to study the effect of this virus in GBM for the potential development of viral therapies in the future. CONCLUSION: Our findings suggest that the SARS-CoV-2 virus entry factors are expressed in primary tissues and organoid models and could be potentially utilized to study the susceptibility of GBM to this virus to target or modulate the tumor microenviroment.


Assuntos
COVID-19 , Glioblastoma , Adulto , Humanos , Glioblastoma/patologia , SARS-CoV-2 , RNA Viral/metabolismo , RNA Viral/uso terapêutico , Células Endoteliais/metabolismo , Organoides/metabolismo , Organoides/patologia , Microambiente Tumoral
4.
Semin Cell Dev Biol ; 95: 84-92, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31310810

RESUMO

Human central nervous system (CNS) regeneration is considered the holy grail of neuroscience research, and is one of the most pressing and difficult questions in biology and science. Despite more than 20 years of work in the field of neural stem cells (NSCs), the area remains in its infancy as our understanding of the fundamental mechanisms that can be leveraged to improve CNS regeneration in neurological diseases is still growing. Here, we focus on the recent lessons from lower organism CNS regeneration genetics and how such findings are starting to illuminate our understanding of NSC signaling pathways in humans. These findings will allow us to improve upon our knowledge of endogenous NSC function, the utility of exogenous NSCs, and the limitations of NSCs as therapeutic vehicles for providing relief from devastating human neurological diseases. We also discuss the limitations of activating NSC signaling for CNS repair in humans, especially the potential for tumor formation. Finally, we will review the recent advances in new culture techniques, including patient-derived cells and cerebral organoids to model the genetic regulation of signaling pathways controlling the function of NSCs during injury and disease states.


Assuntos
Sistema Nervoso Central/fisiologia , Modelos Biológicos , Regeneração Nervosa/genética , Células-Tronco Neurais/metabolismo , Transdução de Sinais/genética , Animais , Humanos , Células-Tronco Neurais/citologia , Pesquisa Translacional Biomédica
5.
Ann Neurol ; 88(4): 661-668, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32632977

RESUMO

"Stem cell tourism," the practice of offering unproven cellular preparations to patients as approved therapy, is rising in neurology. Currently, the experiences of patients and reported complications from these procedures are unknown in the United States. We evaluate academic neurologists' experiences with stem cell tourism and assess perceived competency on discussing this topic with patients. We found a lack of neurologist preparedness to discuss stem cell therapies with patients and an alarming list of unreported complications from these unregulated procedures. We also identified an urgent need for neurologist education and the creation of a national registry for reporting patient complications resulting from experimental stem cell interventions. ANN NEUROL 2020;88:661-668.


Assuntos
Turismo Médico , Neurologia , Transplante de Células-Tronco/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurologistas , Inquéritos e Questionários
6.
Immunity ; 37(2): 249-63, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22884314

RESUMO

Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Galectina 1/imunologia , Antígenos Comuns de Leucócito/metabolismo , Microglia/imunologia , Animais , Astrócitos/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Quimiocina CCL2/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/terapia , Feminino , Galectina 1/metabolismo , Galectina 1/uso terapêutico , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Polissacarídeos/metabolismo , Ligação Proteica , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Semin Neurol ; 38(2): 176-181, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29791943

RESUMO

"Stem cell tourism" is defined as the unethical practice of offering unproven cellular preparations to patients suffering from various medical conditions. This phenomenon is rising in the field of neurology as patients are requesting information and opportunities for treatment with stem cells for incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, despite their clinical research and experimental designation. Here, we review the recent trends in "stem cell tourism" in both the United States and abroad, and discuss the recent reports of neurological complications from these activities. Finally, we frame critical questions for the field of neurology regarding training in the ethical, legal, and societal issues of the global "stem cell tourism," as well as suggest strategies to alleviate this problem. Although there are ongoing legitimate clinical trials with stem cells for neurological diseases, procedures offered by "stem cell clinics" cannot be defined as clinical research. They lack the experimental and state-of-the-art framework defined by peers and the FDA that focus on human research that safeguard the protection of human subjects against economical exploitation, unwanted side effects, and futility of unproven procedures. "Stem cell tourism" ultimately exploits therapeutic hope of patients and families with incurable neurological diseases and can put in danger the legitimacy of stem cell research as a whole. We posit that an improvement in education, regulation, legislation, and involvement of authorities in global health in neurology and neurosurgery is required.


Assuntos
Saúde Global , Doenças do Sistema Nervoso/cirurgia , Transplante de Células-Tronco/métodos , Células-Tronco/fisiologia , Humanos , Doenças do Sistema Nervoso/epidemiologia
9.
J Immunol ; 194(11): 5085-93, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25917097

RESUMO

Multiple sclerosis (MS) is an autoimmune disease of the CNS. Studies in animal models of MS have shown that GM-CSF produced by T cells is necessary for the development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients and to determine the effect of IFN-ß therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-ß were characterized in samples of untreated and IFN-ß-treated MS patients versus healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF(+)CD4(+) and CD8(+) T cells in PB compared with healthy controls and IFN-ß-treated MS patients. IFN-ß significantly suppressed GM-CSF production by T cells in vitro. A number of CD4(+) and CD8(+) T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-ß therapy, namely suppression of GM-CSF production.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/patologia , Feminino , Humanos , Inflamação/imunologia , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia
11.
J Neurovirol ; 22(5): 683-687, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27273076

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a viral demyelinating disease due to the reactivation of the JC virus (JCV), which usually occurs in the context of immunosuppression in HIV infection, malignancy, or in patients on disease modifying therapy for autoimmune diseases, such as multiple sclerosis (MS) and Crohn's disease. Notably, there is growing recognition that PML can occur in patients with transient immune dysfunction. Here, we present a case of a 55-year-old man without history of immunosuppression or evidence of ICL who was diagnosed with PML on brain biopsy. We will discuss the potential etiologies of mild and transient immunosuppression that can lead to PML with non-apparent immunosuppression.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/patologia , Diplopia/patologia , Leucoencefalopatia Multifocal Progressiva/patologia , Incontinência Urinária/patologia , Vertigem/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Encéfalo/virologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/virologia , Diplopia/diagnóstico por imagem , Diplopia/imunologia , Diplopia/virologia , Progressão da Doença , Evolução Fatal , Humanos , Imunocompetência , Vírus JC/imunologia , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Incontinência Urinária/diagnóstico por imagem , Incontinência Urinária/imunologia , Incontinência Urinária/virologia , Vertigem/diagnóstico por imagem , Vertigem/imunologia , Vertigem/virologia
12.
Am J Med Genet A ; 170(9): 2282-91, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27282419

RESUMO

Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Adaptação Psicológica , Adolescente , Atenção , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Cognição , Feminino , Deleção de Genes , Humanos , Masculino , Testes Neuropsicológicos , Fenótipo
14.
Glycobiology ; 25(12): 1392-409, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26153105

RESUMO

Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs ("GPS-NSCs") with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule ("NCAM-E"). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.


Assuntos
Movimento Celular , Encefalomielite Autoimune Experimental/terapia , Células-Tronco Neurais/metabolismo , Polissacarídeos/metabolismo , Animais , Terapia Genética , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/transplante , Selectinas/metabolismo
15.
Am J Med Genet A ; 167A(11): 2808-16, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26238961

RESUMO

2q37 microdeletion syndrome is a rare syndrome characterized by neurodevelopmental delay, bone, cardiovascular, and neurological alterations. This syndrome is typically associated with loss of genetic material of approximately 100 genes in the 2q37 band. However, the genes associated with neurodevelopmental phenotype in this syndrome are still unknown. We identified a deleted region of 496 kb by whole genome array CGH in a patient who fulfilled criteria for 2q37 microdeletion syndrome with developmental delay, microcephaly, hypoplasia of the corpus callosum, hand wringing, toe walking, and seizures. The deleted segment contains genes that are highly expressed in the developing human cortical plate and the subventricular zone (SVZ) in vivo and human neural progenitors in vitro, including SEPT2, THAP4, ATG4B, PPP1R7, and STK25. Network analysis revealed that STK25 was the most interacting gene associated with neural development in this deletion. Our report narrows the likely causative genomic region for microcephaly and neurodevelopmental delay in 2q37 microdeletion syndrome to a small genomic region enriched with neural progenitor genes that may represent an important locus for the development of the human cortex and corpus callosum.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microcefalia/genética , Células-Tronco Neurais/metabolismo , Proteínas Serina-Treonina Quinases/genética , Cefalometria , Pré-Escolar , Deleção Cromossômica , Cromossomos Artificiais Bacterianos/genética , Cromossomos Humanos Par 2/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/complicações , Epilepsia/complicações , Feminino , Regulação da Expressão Gênica , Humanos , Microcefalia/complicações , Fenótipo
16.
Oxf Open Neurosci ; 3: kvae003, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665176

RESUMO

Autism spectrum disorder (ASD) affects 1 in 36 people and is more often diagnosed in males than in females. Core features of ASD are impaired social interactions, repetitive behaviors and deficits in verbal communication. ASD is a highly heterogeneous and heritable disorder, yet its underlying genetic causes account only for up to 80% of the cases. Hence, a subset of ASD cases could be influenced by environmental risk factors. Maternal immune activation (MIA) is a response to inflammation during pregnancy, which can lead to increased inflammatory signals to the fetus. Inflammatory signals can cross the placenta and blood brain barriers affecting fetal brain development. Epidemiological and animal studies suggest that MIA could contribute to ASD etiology. However, human mechanistic studies have been hindered by a lack of experimental systems that could replicate the impact of MIA during fetal development. Therefore, mechanisms altered by inflammation during human pre-natal brain development, and that could underlie ASD pathogenesis have been largely understudied. The advent of human cellular models with induced pluripotent stem cell (iPSC) and organoid technology is closing this gap in knowledge by providing both access to molecular manipulations and culturing capability of tissue that would be otherwise inaccessible. We present an overview of multiple levels of evidence from clinical, epidemiological, and cellular studies that provide a potential link between higher ASD risk and inflammation. More importantly, we discuss how stem cell-derived models may constitute an ideal experimental system to mechanistically interrogate the effect of inflammation during the early stages of brain development.

17.
PNAS Nexus ; 3(2): pgae051, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38384384

RESUMO

Glioblastoma multiforme (GBM) is a highly lethal human cancer thought to originate from a self-renewing and therapeutically-resistant population of glioblastoma stem cells (GSCs). The intrinsic mechanisms enacted by GSCs during 3D tumor formation, however, remain unclear, especially in the stages prior to angiogenic/immunological infiltration. In this study, we performed a deep characterization of the genetic, immune, and metabolic profiles of GBM organoids from several patient-derived GSCs (GBMO). Despite being devoid of immune cells, transcriptomic analysis across GBMO revealed a surprising immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We find two important cell populations thought to drive GBM progression, Special AT-rich sequence-binding protein 2 (SATB2+) and homeodomain-only protein homeobox (HOPX+) progenitors, contribute to this immune landscape in GBMO and GBM in vivo. These progenitors, but not other cell types in GBMO, are resistant to conventional GBM therapies, temozolomide and irradiation. Our work defines a novel intrinsic immune-like landscape in GBMO driven, in part, by SATB2+ and HOPX+ progenitors and deepens our understanding of the intrinsic mechanisms utilized by GSCs in early GBM formation.

18.
J Exp Med ; 204(7): 1691-702, 2007 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-17606630

RESUMO

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti-Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-gamma and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti-Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-gamma and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti-Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged.


Assuntos
Proteínas de Membrana/imunologia , Linfócitos T/imunologia , Animais , Anticorpos/farmacologia , Autoimunidade , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Encefalomielite/imunologia , Receptor Celular 1 do Vírus da Hepatite A , Tolerância Imunológica , Interferon gama/imunologia , Interleucina-17/imunologia , Ativação Linfocitária , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Proteínas Recombinantes/imunologia , Células Th2/imunologia , Transfecção
19.
Nat Genet ; 36(1): 69-76, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14647276

RESUMO

Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.


Assuntos
Fatores de Ribosilação do ADP/genética , Córtex Cerebral/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Proteínas de Saccharomyces cerevisiae , Adolescente , Sequência de Aminoácidos , Animais , Divisão Celular , Movimento Celular , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Mutação , Neurônios/fisiologia
20.
J Neuroimaging ; 33(4): 521-526, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36978252

RESUMO

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) plays a key role in diagnosing and monitoring multiple sclerosis (MS). Double inversion recovery (DIR) is a pulse sequence that has proven highly effective at detecting cortical lesions but is understudied in the spinal cord. We hypothesize that DIR images obtained during brain MRI can be of value in assessing the upper spinal cord of MS patients. METHODS: We retrospectively examined brain MRI exams of 64 patients with established MS, who had also undergone cervical spine MRI. Two blinded MS expert readers, who assessed the scans for lesion numbers and rated lesion visibility and overall image quality, reviewed brain 3-dimensional DIR sagittal and coronal images. Standardized mean contrast-to-noise ratios (C/N) and standard deviation (SD) were calculated in representative lesions for each patient and compared to those of 3-dimensional FLAIR images. RESULTS: For the analysis of lesions categorized as "definite lesions," the sensitivity was 87%, specificity was 61%, and negative predictive value was 80%. On the other hand, for "definite" plus "probable" lesions, the sensitivity was 91%, the specificity was 54%, and negative predictive value was 86%. DIR demonstrated lesions with an average C/N of 7.56 with an SD of 1.77. FLAIR sequence demonstrated lesions with an average C/N of 0.67 and SD of 1.27. CONCLUSIONS: Sagittally acquired brain DIR can provide useful information on upper spinal cord lesions, with high C/N. In theory, this should facilitate the attainment of McDonald's or the Magnetic Resonance Imaging in MS (MAGNIMS) criteria in some cases, without a dedicated cervical spine MRI exam.


Assuntos
Medula Cervical , Esclerose Múltipla , Humanos , Esclerose Múltipla/patologia , Medula Cervical/diagnóstico por imagem , Medula Cervical/patologia , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia
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