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1.
Nat Immunol ; 22(5): 607-619, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33833438

RESUMO

FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Fatores de Transcrição Forkhead/deficiência , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças do Sistema Imunitário/congênito , Linfócitos T Reguladores/imunologia , Adolescente , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Conjuntos de Dados como Assunto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diarreia/sangue , Diarreia/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Mutação , RNA-Seq , Análise de Célula Única , Linfócitos T Reguladores/metabolismo , Adulto Jovem
2.
Cell ; 174(2): 285-299.e12, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29887374

RESUMO

Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.


Assuntos
Gordura Intra-Abdominal/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Reguladores/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Fatores de Transcrição Forkhead/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Gordura Intra-Abdominal/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , PPAR gama/genética , PPAR gama/metabolismo , Fenótipo , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina/metabolismo , Análise de Célula Única , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Transcriptoma
3.
Nat Immunol ; 19(3): 291-301, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29434354

RESUMO

CD4+ T regulatory cells (Treg) are central to immune homeostasis, their phenotypic heterogeneity reflecting the diverse environments and target cells that they regulate. To understand this heterogeneity, we combined single-cell RNA-seq, activation reporter and T cell receptor (TCR) analysis to profile thousands of Treg or conventional CD4+FoxP3- T cells (Tconv) from mouse lymphoid organs and human blood. Treg and Tconv pools showed areas of overlap, as resting 'furtive' Tregs with overall similarity to Tconvs or as a convergence of activated states. All Tregs expressed a small core of FoxP3-dependent transcripts, onto which additional programs were added less uniformly. Among suppressive functions, Il2ra and Ctla4 were quasiconstant, inhibitory cytokines being more sparsely distributed. TCR signal intensity did not affect resting/activated Treg proportions but molded activated Treg programs. The main lines of Treg heterogeneity in mice were strikingly conserved in human blood. These results reveal unexpected TCR-shaped states of activation, providing a framework to synthesize previous observations of Treg heterogeneity.


Assuntos
Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Ativação Linfocitária/imunologia , Camundongos , Fenótipo , Transcriptoma
4.
Nat Immunol ; 19(6): 645, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29725080

RESUMO

In the version of this article initially published, the Supplementary Note was missing. The Supplementary Note has now been provided online and is cited in the Methods section of the article. The error has been corrected in the HTML and PDF version of the article.

6.
Immunity ; 50(5): 1317-1334.e10, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30979687

RESUMO

Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients' blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Animais , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA
7.
Nat Immunol ; 16(9): 942-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26237550

RESUMO

The transcription factor Aire controls immunological tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire's specificity, we performed single-cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs). Each of Aire's target genes was induced in only a minority of mTECs, independently of DNA-methylation patterns, as small inter-chromosomal gene clusters activated in concert in a proportion of mTECs. These microclusters differed between individual mice. Thus, our results suggest an organization of the DNA or of the epigenome that results from stochastic determinism but is 'bookmarked' and stable through mTEC divisions, which ensures more effective presentation of self antigens and favors diversity of self-tolerance between individuals.


Assuntos
Metilação de DNA/genética , Células Epiteliais/imunologia , Regulação da Expressão Gênica/imunologia , RNA Mensageiro/metabolismo , Tolerância a Antígenos Próprios/imunologia , Timo/imunologia , Fatores de Transcrição/imunologia , Animais , Células Epiteliais/metabolismo , Camundongos , Tolerância a Antígenos Próprios/genética , Análise de Célula Única , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Proteína AIRE
8.
Mod Pathol ; 37(1): 100352, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37839675

RESUMO

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Humanos , Medula Óssea/patologia , Células Dendríticas/metabolismo , Mutação , Leucemia Mieloide Aguda/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Nucleares/genética
10.
Proc Natl Acad Sci U S A ; 117(10): 5402-5408, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32102913

RESUMO

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Músculo Esquelético/lesões , Músculo Esquelético/fisiologia , Nociceptores/fisiologia , Regeneração , Linfócitos T Reguladores/imunologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Comunicação Celular , Interleucina-33/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 114(17): E3472-E3480, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28396406

RESUMO

A combination of transcription factors, enhancers, and epigenetic marks determines the expression of the key transcription factor FoxP3 in regulatory T cells (Tregs). Adding an additional layer of complexity, the long noncoding RNA (lncRNA) Flicr (Foxp3 long intergenic noncoding RNA) is a negative regulator that tunes Foxp3 expression, resulting in a subset of Tregs with twofold- to fivefold-lower levels of FoxP3 protein. The impact of Flicr is particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 represses Flicr expression. Flicr neighbors Foxp3 in mouse and human genomes, is specifically expressed in mature Tregs, and acts only in cis It does not affect DNA methylation, but modifies chromatin accessibility in the conserved noncoding sequence 3 (CNS3)/Accessible region 5 (AR5) region of Foxp3 Like many lncRNAs, Flicr's molecular effects are subtle, but by curtailing Treg activity, Flicr markedly promotes autoimmune diabetes and, conversely, restrains antiviral responses. This mechanism of FoxP3 control may allow escape from dominant Treg control during infection or cancer, at the cost of heightened autoimmunity.


Assuntos
Autoimunidade , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , RNA Longo não Codificante/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/genética , Genoma Humano , Humanos , Camundongos , Camundongos Knockout , RNA Longo não Codificante/genética
13.
Proc Natl Acad Sci U S A ; 110(8): 2946-51, 2013 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-23382184

RESUMO

Much of the knowledge about cell differentiation and function in the immune system has come from studies in mice, but the relevance to human immunology, diseases, and therapy has been challenged, perhaps more from anecdotal than comprehensive evidence. To this end, we compare two large compendia of transcriptional profiles of human and mouse immune cell types. Global transcription profiles are conserved between corresponding cell lineages. The expression patterns of most orthologous genes are conserved, particularly for lineage-specific genes. However, several hundred genes show clearly divergent expression across the examined cell lineages, and among them, 169 genes did so even with highly stringent criteria. Finally, regulatory mechanisms--reflected by regulators' differential expression or enriched cis-elements--are conserved between the species but to a lower degree, suggesting that distinct regulation may underlie some of the conserved transcriptional responses.


Assuntos
Perfilação da Expressão Gênica , Sistema Imunitário/metabolismo , Transcrição Gênica , Animais , Humanos , Ativação Linfocitária , Camundongos , Linfócitos T/imunologia
14.
bioRxiv ; 2023 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-37745414

RESUMO

The increasing utilization of anti-PD-1 immune checkpoint blockade (ICB) has led to the emergence of immune-related adverse events (irAEs), including sicca syndrome. Interestingly, we found that the submandibular gland (SMG) of PD-1 deficient mice harbors a large population of CD8 + T cells, reminiscing ICB induced sicca. This phenotype was also observed in the SMG of both NK cell-depleted C57BL/6 animals and NK cell-deficient animals. Mechanistically, using mice conditionally deficient for PD-L1 in the NK cell lineage, we discovered that NK cells regulate CD8 + T cell homeostasis via the PD-1/PD-L1 axis in this organ. Importantly, single-cell RNA sequencing of PD-1 deficient SMG CD8 + T cells reveals a unique transcriptional profile consistent with TCR activation. These cells have limited TCR diversity and phenotypically overlap with GzmK + CD8 + T autoimmune cells identified in primary Sjögren's syndrome patients. These insights into NK cell immunoregulation in the SMG, and the consequences of disrupted CD8 + T cell homeostasis, provide opportunities for preventing the development of irAEs. Highlights: Elevated CD8 + T cells in the submandibular gland (SMG) of PD-1 deficient mice parallel sicca-like irAEs seen in ICB patients. In addition to their previously described hyporesponsive phenotype, NK cells in the SMG regulate CD8 + T cell homeostasis through the PD-L1/PD-1 axis. PD-1 deficient SMG CD8 + T cells display unique transcriptional profiles associated with proinflammatory functions, TCR activation, interferon stimulation, and exhaustion. Oligoclonal expansion and similarities in TCR sequences indicate T cell activation and a preference for recognizing specific antigens.

15.
J Virol ; 85(5): 2458-62, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21159878

RESUMO

We sought to examine ADAR-1 editing of measles and influenza virus genomes derived from inactivated seasonal influenza and live attenuated measles virus vaccines grown on chicken cells as the culture substrate. Using highly sensitive 3DI-PCR (R. Suspène et al., Nucleic Acids Res. 36:e72, 2008), it was possible to show that ADAR-1 could hyperdeaminate adenosine residues in both measles virus and influenza virus A genomes. Detailed analysis of the dinucleotide editing context showed preferences for 5'ArA and 5'UrA, which is typical of editing in mammalian cells. The hyperedited mutant frequency, including genomes and antigenomes, was a log greater for influenza virus compared to measles virus, suggesting a greater sensitivity to restriction by ADAR-1.


Assuntos
Adenosina Desaminase/metabolismo , Genoma Viral , Vírus da Influenza A/genética , Influenza Humana/enzimologia , Vírus do Sarampo/genética , Sarampo/enzimologia , Mutação , Adenosina Desaminase/genética , Animais , Sequência de Bases , Linhagem Celular , Chlorocebus aethiops , Humanos , Vacinas contra Influenza/genética , Influenza Humana/virologia , Sarampo/virologia , Vacina contra Sarampo/genética , Dados de Sequência Molecular , Proteínas de Ligação a RNA , Estações do Ano , Vacinas Atenuadas/genética , Células Vero
16.
Genes (Basel) ; 12(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200671

RESUMO

Technology to generate single cell RNA-sequencing (scRNA-seq) datasets and tools to annotate them have advanced rapidly in the past several years. Such tools generally rely on existing transcriptomic datasets or curated databases of cell type defining genes, while the application of scalable natural language processing (NLP) methods to enhance analysis workflows has not been adequately explored. Here we deployed an NLP framework to objectively quantify associations between a comprehensive set of over 20,000 human protein-coding genes and over 500 cell type terms across over 26 million biomedical documents. The resultant gene-cell type associations (GCAs) are significantly stronger between a curated set of matched cell type-marker pairs than the complementary set of mismatched pairs (Mann Whitney p = 6.15 × 10-76, r = 0.24; cohen's D = 2.6). Building on this, we developed an augmented annotation algorithm (single cell Annotation via Literature Encoding, or scALE) that leverages GCAs to categorize cell clusters identified in scRNA-seq datasets, and we tested its ability to predict the cellular identity of 133 clusters from nine datasets of human breast, colon, heart, joint, ovary, prostate, skin, and small intestine tissues. With the optimized settings, the true cellular identity matched the top prediction in 59% of tested clusters and was present among the top five predictions for 91% of clusters. scALE slightly outperformed an existing method for reference data driven automated cluster annotation, and we demonstrate that integration of scALE can meaningfully improve the annotations derived from such methods. Further, contextualization of differential expression analyses with these GCAs highlights poorly characterized markers of well-studied cell types, such as CLIC6 and DNASE1L3 in retinal pigment epithelial cells and endothelial cells, respectively. Taken together, this study illustrates for the first time how the systematic application of a literature-derived knowledge graph can expedite and enhance the annotation and interpretation of scRNA-seq data.


Assuntos
Bases de Dados Genéticas/normas , Processamento de Linguagem Natural , RNA-Seq/métodos , Análise de Célula Única/métodos , Humanos , Anotação de Sequência Molecular/métodos , Especificidade de Órgãos
17.
NPJ Digit Med ; 4(1): 117, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315980

RESUMO

Understanding the relationships between pre-existing conditions and complications of COVID-19 infection is critical to identifying which patients will develop severe disease. Here, we leverage ~1.1 million clinical notes from 1803 hospitalized COVID-19 patients and deep neural network models to characterize associations between 21 pre-existing conditions and the development of 20 complications (e.g. respiratory, cardiovascular, renal, and hematologic) of COVID-19 infection throughout the course of infection (i.e. 0-30 days, 31-60 days, and 61-90 days). Pleural effusion was the most frequent complication of early COVID-19 infection (89/1803 patients, 4.9%) followed by cardiac arrhythmia (45/1803 patients, 2.5%). Notably, hypertension was the most significant risk factor associated with 10 different complications including acute respiratory distress syndrome, cardiac arrhythmia, and anemia. The onset of new complications after 30 days is rare and most commonly involves pleural effusion (31-60 days: 11 patients, 61-90 days: 9 patients). Lastly, comparing the rates of complications with a propensity-matched COVID-negative hospitalized population confirmed the importance of hypertension as a risk factor for early-onset complications. Overall, the associations between pre-COVID conditions and COVID-associated complications presented here may form the basis for the development of risk assessment scores to guide clinical care pathways.

18.
JAMA Netw Open ; 4(11): e2132540, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34726743

RESUMO

Importance: Continuous assessment of the effectiveness and safety of the US Food and Drug Administration-authorized SARS-CoV-2 vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes. Objective: To evaluate the effectiveness of the Johnson & Johnson Ad26.COV2.S vaccine for preventing SARS-CoV-2 infection. Design, Setting, and Participants: This comparative effectiveness research study used large-scale longitudinal curation of electronic health records from the multistate Mayo Clinic Health System (Minnesota, Arizona, Florida, Wisconsin, and Iowa) to identify vaccinated and unvaccinated adults between February 27 and July 22, 2021. The unvaccinated cohort was matched on a propensity score derived from age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 polymerase chain reaction tests. The final study cohort consisted of 8889 patients in the vaccinated group and 88 898 unvaccinated matched patients. Exposure: Single dose of the Ad26.COV2.S vaccine. Main Outcomes and Measures: The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts, measured by SARS-CoV-2 polymerase chain reaction testing. Results: The study was composed of 8889 vaccinated patients (4491 men [50.5%]; mean [SD] age, 52.4 [16.9] years) and 88 898 unvaccinated patients (44 748 men [50.3%]; mean [SD] age, 51.7 [16.7] years). The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts was 0.26 (95% CI, 0.20-0.34) (60 of 8889 vaccinated patients vs 2236 of 88 898 unvaccinated individuals), which corresponds to an effectiveness of 73.6% (95% CI, 65.9%-79.9%) and a 3.73-fold reduction in SARS-CoV-2 infections. Conclusions and Relevance: This study's findings are consistent with the clinical trial-reported efficacy of Ad26.COV2.S and the first retrospective analysis, suggesting that the vaccine is effective at reducing SARS-CoV-2 infection, even with the spread of variants such as Alpha or Delta that were not present in the original studies, and reaffirm the urgent need to continue mass vaccination efforts globally.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Ad26COVS1 , Adolescente , Adulto , Idoso , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Teste de Ácido Nucleico para COVID-19 , Vacinas contra COVID-19/administração & dosagem , Avaliação de Medicamentos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias , Pontuação de Propensão , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores de Tempo , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricos , Adulto Jovem
19.
JCI Insight ; 6(18)2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34403365

RESUMO

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1ß pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.


Assuntos
Autofagia , Mitofagia , Síndrome de Linfonodos Mucocutâneos/patologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/sangue , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Butanos/farmacologia , Extratos Celulares , Parede Celular , Vasos Coronários/patologia , DNA Glicosilases/genética , Modelos Animais de Doenças , Hipoglicemiantes/farmacologia , Lacticaseibacillus casei , Masculino , Metformina/farmacologia , Camundongos , Mitofagia/genética , Síndrome de Linfonodos Mucocutâneos/induzido quimicamente , Síndrome de Linfonodos Mucocutâneos/genética , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organofosforados/farmacologia , Compostos de Piridínio/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquitina-Proteína Ligases/genética
20.
Nucleic Acids Res ; 36(12): e72, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18515351

RESUMO

DNA complementarity is expressed by way of three hydrogen bonds for a G:C base pair and two for A:T. As a result, careful control of the denaturation temperature of PCR allows selective amplification of AT-rich alleles. Yet for the same reason, the converse is not possible, selective amplification of GC-rich alleles. Inosine (I) hydrogen bonds to cytosine by two hydrogen bonds while diaminopurine (D) forms three hydrogen bonds with thymine. By substituting dATP by dDTP and dGTP by dITP in a PCR reaction, DNA is obtained in which the natural hydrogen bonding rule is inversed. When PCR is performed at limiting denaturation temperatures, it is possible to recover GC-rich viral genomes and inverted Alu elements embedded in cellular mRNAs resulting from editing by dsRNA dependent host cell adenosine deaminases. The editing of Alu elements in cellular mRNAs was strongly enhanced by type I interferon induction indicating a novel link mRNA metabolism and innate immunity.


Assuntos
Adenosina Desaminase/metabolismo , DNA/química , Sequência Rica em GC , Reação em Cadeia da Polimerase/métodos , Edição de RNA , 2-Aminopurina/análogos & derivados , 2-Aminopurina/química , Sequência Rica em At , Elementos Alu , Animais , Sequência de Bases , Linhagem Celular , Chlorocebus aethiops , Rearranjo Gênico do Linfócito B , Ligação de Hidrogênio , Região Variável de Imunoglobulina/genética , Inosina Trifosfato/química , Vírus do Sarampo/genética , Dados de Sequência Molecular , Desnaturação de Ácido Nucleico , RNA Mensageiro/química , Proteínas de Ligação a RNA , Células Vero
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