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1.
Mol Psychiatry ; 25(11): 3053-3065, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-30279459

RESUMO

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Hipocampo/anatomia & histologia , Hipocampo/patologia , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
2.
FASEB J ; : fj201701408R, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29863913

RESUMO

Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

3.
Neuroimage ; 147: 243-252, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27916665

RESUMO

OBJECTIVE: An abundance of experimental studies have motivated a range of models concerning the cognitive underpinnings of severe mental disorders, yet the conception that cognitive and brain dysfunction is confined to specific cognitive domains and contexts has limited ecological validity. Schizophrenia and bipolar spectrum disorders have been conceptualized as disorders of brain connectivity; yet little is known about the pervasiveness across cognitive tasks. METHODS: To address this outstanding issue of context specificity, we estimated functional network connectivity from fMRI data obtained during five cognitive tasks (0-back, 2-back, go/no-go, recognition of positive faces, negative faces) in 90 patients with schizophrenia spectrum, 97 patients with bipolar spectrum disorder, and 136 healthy controls, including 1615 fMRI datasets in total. We tested for main effects of task and group, and their interactions, and used machine learning to classify task labels and predict cognitive domain scores from brain connectivity. RESULTS: Connectivity profiles were positively correlated across tasks, supporting the existence of a core functional connectivity backbone common to all tasks. However, 76.2% of all network links also showed significant task-related alterations, robust on the single subject level as evidenced by high machine-learning performance when classifying task labels. Independent of such task-specific modulations, 9.5% of all network links showed significant group effects, particularly including sensory (sensorimotor, visual, auditory) and cognitive (frontoparietal, default-mode, dorsal attention) networks. A lack of group by task interactions revealed that the pathophysiological sensitivity remained across tasks. Such pervasiveness across tasks was further supported by significant predictions of cognitive domain scores from the connectivity backbone obtained across tasks. CONCLUSIONS: The high accuracies obtained when classifying cognitive tasks support that brain connectivity indices provide sensitive and specific measures of cognitive states. Importantly, we provide evidence that brain network dysfunction in severe mental disorders is not confined to specific cognitive tasks and show that the connectivity backbone common to all tasks is predictive of cognitive domain traits. Such pervasiveness across tasks may support a generalization of pathophysiological models from different domains, thereby reducing their complexity and increasing their ecological validity. Future research incorporating a wider range of cognitive tasks, involving other sensory modalities (auditory, somatosensory, motor) and requirements (learning, perceptual inference, decision making, etc.), is needed to assess if under certain circumstances, context dependent aberrations may evolve. Our results provide further evidence from a large sample that fMRI based functional network connectivity can be used to reveal both, state and trait effects in the connectome.


Assuntos
Transtorno Bipolar/fisiopatologia , Encéfalo/fisiologia , Conectoma/métodos , Função Executiva/fisiologia , Reconhecimento Facial/fisiologia , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem
4.
Clin Sci (Lond) ; 128(2): 95-109, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25052203

RESUMO

In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.


Assuntos
Doenças Desmielinizantes/prevenção & controle , Encefalomielite Autoimune Experimental/tratamento farmacológico , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Receptor Tipo 2 de Angiotensina/agonistas , Linfócitos T/efeitos dos fármacos , Animais , Feminino , Interferon gama/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Óxido Nítrico/metabolismo , Ratos , Receptor Tipo 2 de Angiotensina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Linfócitos T/metabolismo
5.
J Immunol ; 191(11): 5594-602, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24146044

RESUMO

Although mechanisms leading to brain-specific inflammation and T cell activation have been widely investigated, regulatory mechanisms of local innate immune cells in the brain are only poorly understood. In this study, to our knowledge we show for the first time that MHC class II(+)CD40(dim)CD86(dim)IL-10(+) microglia are potent inducers of Ag-specific CD4(+)Foxp3(+) regulatory T cells (Tregs) in vitro. Microglia differentially regulated MHC class II expression, costimulatory molecules, and IL-10 depending on the amount of IFN-γ challenge and Ag dose, promoting either effector T cell or Treg induction. Microglia-induced Tregs were functionally active in vitro by inhibiting Ag-specific proliferation of effector T cells, and in vivo by attenuating experimental autoimmune encephalomyelitis disease course after adoptive transfer. These results indicate that MHC class II(+)CD40(dim)CD86(dim)IL-10(+) microglia have regulatory properties potentially influencing local immune responses in the CNS.


Assuntos
Encéfalo/patologia , Encefalomielite Autoimune Experimental/imunologia , Microglia/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Microambiente Celular , Técnicas de Cocultura , Fatores de Transcrição Forkhead/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Tolerância Imunológica , Interferon gama/imunologia , Interleucina-10/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
6.
Eur J Immunol ; 43(12): 3291-305, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23946112

RESUMO

The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long-term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti-CD4 antibody (aCD4). Here, we investigated whether adding TGF-ß and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg-cell generation and function. Murine CD4(+) T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF-ß+RA or aCD4+Rapa. Addition of TGF-ß+RA or Rapa resulted in an increase of CD25(+)Foxp3(+)-expressing T cells. Expression of CD40L and production of IFN-γ and IL-17 was abolished in aCD4+TGF-ß+RA aTreg cells. Additionally, aCD4+TGF-ß+RA aTreg cells showed the highest level of Helios and Neuropilin-1 co-expression. Although CD25(+)Foxp3(+) cells from all culture conditions displayed complete demethylation of the Treg-specific demethylated region, aCD4+TGF-ß+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF-ß+RA aTreg cells suppressed effector T-cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF-ß+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Anticorpos Monoclonais Murinos/farmacologia , Antígenos CD4/imunologia , Sirolimo/farmacologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/farmacologia , Tretinoína/farmacologia , Doença Aguda , Aloenxertos , Animais , Anticorpos Monoclonais Murinos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígenos CD4/genética , Ligante de CD40/genética , Ligante de CD40/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Transplante de Pele , Linfócitos T Reguladores/patologia
7.
Br J Psychiatry ; 204: 290-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24434074

RESUMO

BACKGROUND: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits. AIMS: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals. METHOD: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations. RESULTS: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder. CONCLUSIONS: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.


Assuntos
Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico , Feminino , Neuroimagem Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
8.
J Immunol ; 189(3): 1448-58, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22745379

RESUMO

Innate immune receptors represent an evolutionarily ancient system that allows organisms to detect and rapidly respond to pathogen- and host-derived factors. TLRs are predominantly expressed in immune cells and mediate such a response. Although this class of pattern recognition receptors is involved in CNS disorders, the knowledge of ligands leading to activation of TLRs and to subsequent CNS damage is limited. We report in this study that ssRNA causes neurodegeneration and neuroinflammation dependent on TLR7 in the CNS. TLR7 is not only expressed in microglia, the major immune cells of the brain, but also in neurons of the CNS. Extracellularly delivered ssRNA40, an oligoribonucleotide derived from HIV and an established ligand of TLR7, induces neuronal cell death dependent on TLR7 and the central adapter molecule MyD88 in vitro. Activation of caspase-3 is involved in neuronal damage mediated by TLR7. This cell-autonomous neuronal cell death induced by ssRNA40 is amplified in the presence of microglia that mount an inflammatory response to ssRNA40 through TLR7. Intrathecal administration of ssRNA40 causes widespread neurodegeneration in wild-type but not in TLR7(-/-) mice, confirming that neuronal cell death induced by ssRNA40 through TLR7 occurs in vivo. Our results point to a possible mechanism through which extracellularly delivered ssRNA contributes to CNS damage and determine an obligatory role for TLR7 in this pathway.


Assuntos
Líquido Extracelular/imunologia , Líquido Extracelular/virologia , Glicoproteínas de Membrana/fisiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/virologia , RNA Viral/administração & dosagem , Receptor 7 Toll-Like/fisiologia , Animais , Caspase 3/efeitos adversos , Caspase 3/fisiologia , Morte Celular/genética , Morte Celular/imunologia , Linhagem Celular Tumoral , Células HEK293 , HIV/genética , HIV/imunologia , Humanos , Injeções Espinhais , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/efeitos adversos , Fator 88 de Diferenciação Mieloide/fisiologia , Doenças Neurodegenerativas/patologia , Cultura Primária de Células , RNA Viral/efeitos adversos , RNA Viral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/deficiência , Receptor 7 Toll-Like/genética
9.
F1000Res ; 11: 12, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36636476

RESUMO

With the ongoing cost decrease of genotyping and sequencing technologies, accurate and fast phenotyping remains the bottleneck in the utilizing of plant genetic resources for breeding and breeding research. Although cost-efficient high-throughput phenotyping platforms are emerging for specific traits and/or species, manual phenotyping is still widely used and is a time- and money-consuming step. Approaches that improve data recording, processing or handling are pivotal steps towards the efficient use of genetic resources and are demanded by the research community. Therefore, we developed PhenoApp, an open-source Android app for tablets and smartphones to facilitate the digital recording of phenotypical data in the field and in greenhouses. It is a versatile tool that offers the possibility to fully customize the descriptors/scales for any possible scenario, also in accordance with international information standards such as MIAPPE (Minimum Information About a Plant Phenotyping Experiment) and FAIR (Findable, Accessible, Interoperable, and Reusable) data principles. Furthermore, PhenoApp enables the use of pre-integrated ready-to-use BBCH (Biologische Bundesanstalt für Land- und Forstwirtschaft, Bundessortenamt und CHemische Industrie) scales for apple, cereals, grapevine, maize, potato, rapeseed and rice. Additional BBCH scales can easily be added. The simple and adaptable structure of input and output files enables an easy data handling by either spreadsheet software or even the integration in the workflow of laboratory information management systems (LIMS). PhenoApp is therefore a decisive contribution to increase efficiency of digital data acquisition in genebank management but also contributes to breeding and breeding research by accelerating the labour intensive and time-consuming acquisition of phenotyping data.


Assuntos
Melhoramento Vegetal , Plantas , Software , Fenótipo
10.
Acta Neuropathol ; 121(4): 445-58, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21076838

RESUMO

Recent studies demonstrated that primary immune responses can be induced within the brain depending on vessel-associated cells expressing markers of dendritic cells (DC). Using mice transcribing the green fluorescent protein (GFP) under the promoter of the DC marker CD11c, we determined the distribution, phenotype, and source of CD11c+ cells in non-diseased brains. Predilection areas of multiple sclerosis (MS) lesions (periventricular area, adjacent fibre tracts, and optical nerve) were preferentially populated by CD11c+ cells. Most CD11c+ cells were located within the juxtavascular parenchyma rather than the perivascular spaces. Virtually all CD11c+ cells co-expressed ionized calcium-binding adaptor molecule 1 (IBA-1), CD11b, while detectable levels of major histocompatibility complex II (MHC-II) in non-diseased mice was restricted to CD11c+ cells of the choroid plexus. Cellular processes project into the glia limitans which may allow transport and/or presentation of intraparenchymal antigens to extravasated T cells in perivascular spaces. In chimeric mice bearing CD11c-GFP bone marrow, fluorescent cells appeared in the CNS between 8 and 12 weeks after transplantation. In organotypic slice cultures from CD11c-GFP mice, the number of fluorescent cells strongly increased within 72 h. Strikingly, using anti-CD209, an established marker for human DC, a similar population was detected in human brains. Thus, we show for the first time that CD11c+ cells can not only be recruited from the blood into the parenchyma, but also develop from an intraneural precursor in situ. Dysbalance in their recruitment/development may be an initial step in the pathogenesis of chronic (autoimmune) neuroinflammatory diseases such as MS.


Assuntos
Antígeno CD11c/metabolismo , Sistema Nervoso/citologia , Neuroglia/citologia , Neurópilo/metabolismo , Linfócitos T/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Células da Medula Óssea/metabolismo , Antígeno CD11b/metabolismo , Antígeno CD11c/genética , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Córtex Cerebral/lesões , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Imageamento Tridimensional , Lectinas Tipo C/metabolismo , Antígeno de Macrófago 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos , Microscopia Eletrônica de Transmissão , Sistema Nervoso/metabolismo , Neuroglia/metabolismo , Neurópilo/ultraestrutura , Técnicas de Cultura de Órgãos , Receptores de Superfície Celular/metabolismo , Linfócitos T/ultraestrutura , Fatores de Tempo , Irradiação Corporal Total
11.
J Immunol ; 183(6): 4077-87, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19684086

RESUMO

Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137(+) cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Antígenos CD/genética , Doenças Autoimunes/diagnóstico , Regulação da Expressão Gênica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Mitocondriais/genética , Valor Preditivo dos Testes , Alefacept , Animais , Apoptose , Doenças Autoimunes/terapia , Antígeno B7-H1 , Proliferação de Células , Fármacos Dermatológicos , Proteínas da Matriz Extracelular , Humanos , Receptores de Hialuronatos , Imunoterapia , Leucócitos/efeitos dos fármacos , Camundongos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico
13.
JAMA Psychiatry ; 76(7): 739-748, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969333

RESUMO

Importance: Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. Objectives: To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and Participants: This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and Measures: Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. Results: A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion. Conclusions and Relevance: This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.


Assuntos
Encéfalo/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Substância Branca/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Herança Multifatorial , Tamanho do Órgão/fisiologia , Adulto Jovem
14.
Nat Neurosci ; 22(10): 1617-1623, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551603

RESUMO

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Encéfalo/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/genética , Esquizofrenia/patologia , Caracteres Sexuais , Adulto Jovem
15.
FASEB J ; 21(2): 415-26, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17167072

RESUMO

The let-7 miRNA regulates developmental timing in C. elegans and is an important paradigm for investigations of miRNA functions in mammalian development. We have examined the role of miRNA precursor processing in the temporal control and lineage specificity of the let-7 miRNA. In situ hybridization (ISH) in E9.5 mouse embryos revealed early induction of let-7 in the developing central nervous system. The expression pattern of three let-7 family members closely resembled that of the brain-enriched miRNAs mir-124, mir-125 and mir-128. Comparison of primary, precursor, and mature let-7 RNA levels during both embryonic brain development and neural differentiation of embryonic stem cells and embryocarcinoma (EC) cells suggest post-transcriptional regulation of let-7 accumulation. Reflecting these results, let-7 sensor constructs were strongly down-regulated during neural differentiation of EC cells and displayed lineage specificity in primary cells. Neural differentiation of EC cells was accompanied by an increase in let-7 precursor processing activity in vitro. Furthermore, undifferentiated and differentiated cells contained distinct precursor RNA binding complexes. A neuron-enhanced binding complex was shown by antibody challenge to contain the miRNA pathway proteins Argonaute1 and FMRP. Developmental regulation of the processing pathway correlates with differential localization of the proteins Argonaute, FMRP, MOV10, and TNRC6B in self-renewing stem cells and neurons.


Assuntos
Encéfalo/metabolismo , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Animais , Northern Blotting , Encéfalo/citologia , Encéfalo/embriologia , Diferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Imunoprecipitação da Cromatina , Células-Tronco Embrionárias/citologia , Humanos , Hibridização In Situ , Camundongos , Transcrição Gênica
16.
Brain Imaging Behav ; 12(3): 640-652, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28444556

RESUMO

The thalamus is a highly connected subcortical structure that relays and integrates sensory and cortical information, which is critical for coherent and accurate perceptual awareness and cognition. Thalamic dysfunction is a classical finding in schizophrenia (SZ), and resting-state functional MRI has implicated somatomotor and frontal lobe thalamic dysconnectivity. However, it remains unclear whether these findings generalize to different psychotic disorders, are confined to specific thalamic sub-regions, and how they relate to structural thalamic alterations. Within-thalamic and thalamo-cortical functional connectivity was assessed using resting-state functional MRI data obtained from patients with SZ (n = 96), bipolar disorder (BD, n = 57), and healthy controls (HC, n = 280). Further, we used thalamic sub-regions as seeds to investigate specific cortical connectivity patterns, and performed structural analyses of thalamic volume and shape. Results showed reduced within-thalamic connectivity and thalamo-frontoparietal coupling in SZ and increased thalamo-somatomotor connectivity in BD. One thalamic sub-region showed increased sensory connectivity in SZ and eight sub-regions showed reductions with frontal and posterior areas. Reduced gray matter and shape abnormalities were found in frontal-projecting regions in both SZ and BD, but did not seem to explain reduced functional connectivity. Aberrant thalamo-cortical connectivity patterns in SZ and BD supports the notion of the thalamus as a key structure in the functional connectome across the psychosis spectrum, and the frontal and somatomotor anatomical distribution is in line with the characteristic cognitive and perceptual symptoms in psychotic disorders.


Assuntos
Transtorno Bipolar/fisiopatologia , Córtex Cerebral/fisiopatologia , Esquizofrenia/fisiopatologia , Tálamo/fisiopatologia , Adulto , Transtorno Bipolar/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Conectoma , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia , Descanso , Esquizofrenia/diagnóstico por imagem , Tálamo/diagnóstico por imagem
17.
Neurosci Lett ; 425(3): 156-61, 2007 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-17825988

RESUMO

Fibre tract injury evokes recruitment of antigen-presenting- and T cells, but does not cause autoimmune demyelination. This implies that immune tolerance to myelin is actively maintained or readily re-established. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus of adult mice, we studied the induction of B7-H1 (PD-L1) in zones of axonal degeneration. This member of the B7-family has been shown to be expressed on parenchymal cells of various organs, where it strongly down-modulates the activity of T cells. Real-time reverse transcriptase (RT)-PCR revealed low mRNA levels in brain compared to lung and spleen under normal conditions. After ECL, a twofold increase could be observed. Immunocytochemistry revealed astrocytes as source of B7-H1, while immune positive microglia were not detected. Thus, axonal degeneration induces astrocytes to express B7-H1, a potent inhibitor of effector T cells.


Assuntos
Antígeno B7-1/imunologia , Lesões Encefálicas/complicações , Lesões Encefálicas/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Encefalite/imunologia , Tolerância Imunológica/imunologia , Glicoproteínas de Membrana/imunologia , Peptídeos/imunologia , Degeneração Walleriana/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Astrócitos/imunologia , Autoimunidade/imunologia , Axônios/imunologia , Antígeno B7-1/genética , Antígeno B7-H1 , Lesões Encefálicas/fisiopatologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Encefalite/fisiopatologia , Córtex Entorrinal/imunologia , Córtex Entorrinal/fisiopatologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/imunologia , Gliose/fisiopatologia , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/genética , Linfócitos T/imunologia , Degeneração Walleriana/fisiopatologia
18.
J Leukoc Biol ; 80(4): 797-801, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16885505

RESUMO

Although drainage pathways of soluble antigens from brain to cervical lymph nodes have been well established, there is no direct evidence for similar routes of leukocytes leaving the central nervous system. We developed a protocol allowing the cross-sectioning of an entire head-neck preparation while preserving the signal of the GFP. We monitored how GFP-expressing CD4 T lymphocytes injected into the entorhinal cortex after lesion or the lateral ventricle of unlesioned C57/bl6 mice reach cervical lymph nodes. Irrespective of the injection site, we demonstrate their passage through the cribroid plate, appearance in the nasal mucosa, and specific accumulation in one of the cervical lymph nodes.


Assuntos
Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/imunologia , Osso Etmoide/imunologia , Linfonodos/imunologia , Mucosa Nasal/imunologia , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/administração & dosagem , Proteínas de Fluorescência Verde/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pescoço
19.
Nat Neurosci ; 20(4): 513-515, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28218917

RESUMO

The brain functional connectome constitutes a unique fingerprint allowing identification of individuals among a pool of people. Here we establish that the connectome develops into a more stable, individual wiring pattern during adolescence and demonstrate that a delay in this network tuning process is associated with reduced mental health in the formative years of late neurodevelopment.


Assuntos
Envelhecimento/fisiologia , Conectoma/psicologia , Transtornos Mentais/fisiopatologia , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Neuroimagem Funcional , Humanos , Individualidade , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/fisiologia , Transtornos Mentais/diagnóstico , Reconhecimento Psicológico/fisiologia , Adulto Jovem
20.
Neuroimage Clin ; 15: 719-731, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28702349

RESUMO

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders.


Assuntos
Transtorno Bipolar/patologia , Encéfalo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Esquizofrenia/patologia , Adulto , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/genética , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Masculino , Herança Multifatorial , Análise Multivariada , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética
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