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1.
Nat Commun ; 12(1): 5074, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417463

RESUMO

ß cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human ß cells with inflammation but its expression is reduced in surviving ß cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate ß cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO ß cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between ß cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in ß cells may reduce activating pathologic immune cells and killing of ß cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/patologia , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sequência de Bases , Citotoxicidade Imunológica , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Humanos , Imunidade , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Transcrição Genética
2.
Front Cell Neurosci ; 15: 726479, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456686

RESUMO

The emergence of single cell technologies provides the opportunity to characterize complex immune/central nervous system cell assemblies in multiple sclerosis (MS) and to study their cell population structures, network activation and dynamics at unprecedented depths. In this review, we summarize the current knowledge of astrocyte subpopulations in MS tissue and discuss the challenges associated with resolving astrocyte heterogeneity with single-nucleus RNA-sequencing (snRNA-seq). We further discuss multiplexed imaging techniques as tools for defining population clusters within a spatial context. Finally, we will provide an outlook on how these technologies may aid in answering unresolved questions in MS, such as the glial phenotypes that drive MS progression and/or neuropathological differences between different clinical MS subtypes.

3.
NMR Biomed ; 34(11): e4590, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34318959

RESUMO

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease-modifying therapies. Proton MRS (1 H-MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ-aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H-MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N-acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing-remitting (N = 26) or progressive (N = 21) multiple sclerosis or healthy control adults (N = 25) in a cross-sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate (F2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine (F2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA (F2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione (F2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p < 0.1). As a group, multiple sclerosis patients demonstrated significant negative correlations between disease duration and glutamate or GABA (ρ = -0.4, p = 0.02) but not glutamine or glutathione. Alone, only relapsing-remitting multiple sclerosis patients exhibited a significant negative correlation between disease duration and GABA (ρ = -0.5, p = 0.03). Taken together, these results indicate that frontal cortex metabolism is differentially disturbed in progressive and relapsing-remitting multiple sclerosis.

4.
Ann Clin Transl Neurol ; 8(4): 877-886, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33704933

RESUMO

BACKGROUND: Inflammation in chronic active lesions occurs behind a closed blood-brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. OBJECTIVE: To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. METHODS: MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal-appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human-induced pluripotent stem cell (iPSC)-derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro-inflammatory cytokines. RESULTS: QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron- myeloid cells. In vitro, iron accumulation was highest in M1-polarized human iPSC-derived microglia, but it did not enhance ROS or cytokine production. CONCLUSION: A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

5.
J Environ Manage ; 275: 111075, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32861905

RESUMO

We investigate a new framework for estimating the frequency and severity of losses associated with catastrophic risks such as bushfires, storms and floods. We explore generalized additive models for location, scale and shape (GAMLSS) for the quantification of regional risk factors - geographical, weather and climate variables - with the aim of better quantifying the frequency and severity of catastrophic losses from natural perils. Due to the flexibility of the GAMLSS approach, we find a superior fit to empirical loss data for the applied models in comparison to generalized linear regression models typically applied in the literature. In particular the generalized beta distribution of the second kind (GB2) provides a good fit to the severity of losses. Including covariates in the calibration of the scale parameter, we obtain vastly differently shaped distributions for the predicted individual losses at different levels of the covariates. Testing the GAMLSS approach in an out-of-sample validation exercise, we also find support for a correct specification of the estimated models. More accurate models for the losses from natural hazards will help state and local government policy development, in particular for risk management and scenario planning for emergency services with respect to these perils.


Assuntos
Clima , Tempo (Meteorologia) , Inundações , Modelos Lineares , Fatores de Risco
6.
Artigo em Inglês | MEDLINE | ID: mdl-32269065

RESUMO

OBJECTIVE: To identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy. METHODS: We collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry. RESULTS: We found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction. CONCLUSIONS: The opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.

7.
Front Neurol ; 10: 1173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803127

RESUMO

Proton magnetic resonance spectroscopy (1H-MRS) offers a growing variety of methods for querying potential diagnostic biomarkers of multiple sclerosis in living central nervous system tissue. For the past three decades, 1H-MRS has enabled the acquisition of a rich dataset suggestive of numerous metabolic alterations in lesions, normal-appearing white matter, gray matter, and spinal cord of individuals with multiple sclerosis, but this body of information is not free of seeming internal contradiction. The use of 1H-MRS signals as diagnostic biomarkers depends on reproducible and generalizable sensitivity and specificity to disease state that can be confounded by a multitude of influences, including experiment group classification and demographics; acquisition sequence; spectral quality and quantifiability; the contribution of macromolecules and lipids to the spectroscopic baseline; spectral quantification pipeline; voxel tissue and lesion composition; T 1 and T 2 relaxation; B1 field characteristics; and other features of study design, spectral acquisition and processing, and metabolite quantification about which the experimenter may possess imperfect or incomplete information. The direct comparison of 1H-MRS data from individuals with and without multiple sclerosis poses a special challenge in this regard, as several lines of evidence suggest that experimental cohorts may differ significantly in some of these parameters. We review the existing findings of in vivo 1H-MRS on central nervous system metabolic abnormalities in multiple sclerosis and its subtypes within the context of study design, spectral acquisition and processing, and metabolite quantification and offer an outlook on technical considerations, including the growing use of machine learning, by future investigations into diagnostic biomarkers of multiple sclerosis measurable by 1H-MRS.

8.
Elife ; 82019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31368890

RESUMO

Multiple sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord that are highly variable in terms of cellular content. Here, we used imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within staged MS lesions. To test the potential for IMC to discriminate between different types of lesions, we selected a case with severe rebound MS disease activity after natalizumab cessation. With post-acquisition analysis pipelines we were able to: (1) Discriminate demyelinating macrophages from the resident microglial pool; (2) Determine which types of lymphocytes reside closest to blood vessels; (3) Identify multiple subsets of T and B cells, and (4) Ascertain dynamics of T cell phenotypes vis-à-vis lesion type and location. We propose that IMC will enable a comprehensive analysis of single-cell phenotypes, their functional states and cell-cell interactions in relation to lesion morphometry and demyelinating activity in MS patients.


Assuntos
Citometria por Imagem/métodos , Leucócitos/classificação , Leucócitos/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Adulto , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Proteínas/análise
9.
Acta Neuropathol Commun ; 7(1): 130, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405387

RESUMO

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled two active MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In the acutely demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In the post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.


Assuntos
Astrócitos/patologia , Comunicação Celular/fisiologia , Esclerose Múltipla Recidivante-Remitente/patologia , Células Mieloides/patologia , Fenótipo , Adulto , Astrócitos/metabolismo , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/metabolismo , Células Mieloides/metabolismo
10.
Brain ; 142(1): 133-145, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561514

RESUMO

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.


Assuntos
Inflamação/diagnóstico por imagem , Inflamação/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Doença Crônica , Estudos Transversais , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Ferro/metabolismo , Isoquinolinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Masculino , Microglia/imunologia , Microglia/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/metabolismo , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Adulto Jovem
12.
Nat Commun ; 9(1): 5337, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559390

RESUMO

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.


Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/citologia , Esclerose Múltipla/genética , Subunidade p50 de NF-kappa B/genética , Células Cultivadas , Sistema Nervoso Central/patologia , Predisposição Genética para Doença/genética , Humanos , Esclerose Múltipla/patologia , Subunidade p50 de NF-kappa B/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
13.
Front Immunol ; 9: 217, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515568

RESUMO

The role traditionally assigned to astrocytes in the pathogenesis of multiple sclerosis (MS) lesions has been the formation of the glial scar once inflammation has subsided. Astrocytes are now recognized to be early and highly active players during lesion formation and key for providing peripheral immune cells access to the central nervous system. Here, we review the role of astrocytes in the formation and evolution of MS lesions, including the recently described functional polarization of astrocytes, discuss prototypical pathways for astrocyte activation, and summarize mechanisms by which MS treatments affect astrocyte function.


Assuntos
Astrócitos/imunologia , Barreira Hematoencefálica/imunologia , Sistema Nervoso Central/imunologia , Imunossupressores/uso terapêutico , Esclerose Múltipla/imunologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/efeitos dos fármacos , Sistema Nervoso Central/citologia , Sistema Nervoso Central/patologia , Humanos , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Transdução de Sinais/imunologia
14.
Front Immunol ; 9: 255, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515576

RESUMO

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.


Assuntos
Inflamação/imunologia , Microglia/fisiologia , Esclerose Múltipla/imunologia , Substância Branca/patologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Humanos , Inflamação/diagnóstico , Ferro/metabolismo , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Bainha de Mielina/metabolismo , Fagocitose
15.
J Magn Reson Imaging ; 48(5): 1281-1287, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29517817

RESUMO

BACKGROUND: The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. PURPOSE: To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. STUDY TYPE: Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. POPULATION/SPECIMENS: Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. FIELD STRENGTH/SEQUENCE: 3D T 2 * -weighted spoiled multiecho gradient echo scans performed at 3T. ASSESSMENT: Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. STATISTICAL TESTS: Not applicable. RESULTS: MBP degradation by trypsin increased the QSM measurement by an average of 112 ± 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 ± 3.7 days, their susceptibility increased by an average of 7.5 ± 6.3 ppb. DATA CONCLUSION: Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287.


Assuntos
Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Bainha de Mielina/química , Algoritmos , Animais , Autopsia , Biomarcadores/química , Bovinos , Humanos , Proteína Básica da Mielina/química , Imagens de Fantasmas , Tripsina/química , Substância Branca/diagnóstico por imagem
16.
Ann Neurol ; 83(1): 131-141, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29283442

RESUMO

OBJECTIVE: Myeloid cells, including macrophages and dendritic cells, are a prominent component of central nervous system (CNS) infiltrates during multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Although myeloid cells are generally thought to be proinflammatory, alternatively polarized subsets can serve noninflammatory and/or reparative functions. Here we investigate the heterogeneity and biological properties of myeloid cells during central nervous system autoimmunity. METHODS: Myeloid cell phenotypes in chronic active MS lesions were analyzed by immunohistochemistry. In addition, immune cells were isolated from the CNS during exacerbations and remissions of EAE and characterized by flow cytometric, genetic, and functional assays. RESULTS: Myeloid cells expressing inducible nitric oxide synthase (iNOS), indicative of a proinflammatory phenotype, were detected in the actively demyelinating rim of chronic active MS lesions, whereas macrophages expressing mannose receptor (CD206), a marker of alternatively polarized human myeloid cells, were enriched in the quiescent lesion core. During EAE, CNS-infiltrating myeloid cells, as well as microglia, shifted from expression of proinflammatory markers to expression of noninflammatory markers immediately prior to clinical remissions. Murine CNS myeloid cells expressing the alternative lineage marker arginase-1 (Arg1) were partially derived from iNOS+ precursors and were deficient in activating encephalitogenic T cells compared with their Arg1- counterparts. INTERPRETATION: These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141.


Assuntos
Doenças Autoimunes do Sistema Nervoso/patologia , Plasticidade Celular , Células Mieloides/patologia , Animais , Arginase/genética , Células da Medula Óssea/patologia , Quimera , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Humanos , Imuno-Histoquímica , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/biossíntese , Lectinas de Ligação a Manose/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Fenótipo , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética
17.
JCI Insight ; 2(17)2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28878118

RESUMO

Recent data indicate that there are different subpopulations of Th17 cells that can express a regulatory as opposed to an inflammatory gene signature. The transmembrane glycoprotein PDPN is critical in the development of multiple organs including the lymphatic system and has been described on T cells in mouse models of autoimmune Th17 inflammation. Here, we demonstrate that unlike in mice, PDPN+ T cells induced under classic Th17-polarizing conditions express transcription factors associated with Th17 cells but do not produce IL-17. Moreover, these cells express a transcriptional profile enriched for immunosuppressive and regulatory pathways and express a distinct cytokine profile compared with potentially pathogenic PDPN- Th17 cells. Ligation of PDPN by its ligand CLEC-2 ameliorates the Th17 inflammatory response. IL-17 secretion is restored with shRNA gene silencing of PDPN. Furthermore, PDPN expression is reduced via an Sgk1-mediated pathway under proinflammatory, high sodium chloride conditions. Finally, CD3+PDPN+ T cells are devoid of IL-17 in skin biopsies from patients with candidiasis, a prototypical Th17-driven skin disease. Thus, our data support the hypothesis that PDPN may serve as a marker of a nonpathogenic Th17 cell subset and may also functionally regulate pathogenic Th17 inflammation.


Assuntos
Inflamação/patologia , Glicoproteínas de Membrana/fisiologia , Células Th17/patologia , Células Cultivadas , Citocinas/metabolismo , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Proteínas Imediatamente Precoces/metabolismo , Interleucina-17/biossíntese , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , Células Th17/metabolismo , Transcrição Genética
18.
J Magn Reson Imaging ; 46(4): 951-971, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28295954

RESUMO

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.


Assuntos
Artefatos , Meios de Contraste , Aumento da Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Metais , Humanos
19.
Brain ; 140(2): 399-413, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28007993

RESUMO

Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-κB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-κB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions.


Assuntos
Astrócitos/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fagocitose/fisiologia , Adulto , Idoso , Animais , Animais Recém-Nascidos , Astrócitos/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Pré-Escolar , Cultura , Citocinas/metabolismo , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , Feminino , Humanos , Hidrazonas/farmacologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Fatores de Tempo , Fator de Crescimento Transformador beta/farmacologia
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