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1.
J Biomed Semantics ; 12(1): 18, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454610

RESUMO

BACKGROUND: With COVID-19 still in its pandemic stage, extensive research has generated increasing amounts of data and knowledge. As many studies are published within a short span of time, we often lose an integrative and comprehensive picture of host-coronavirus interaction (HCI) mechanisms. As of early April 2021, the ImmPort database has stored 7 studies (with 6 having details) that cover topics including molecular immune signatures, epitopes, and sex differences in terms of mortality in COVID-19 patients. The Coronavirus Infectious Disease Ontology (CIDO) represents basic HCI information. We hypothesize that the CIDO can be used as the platform to represent newly recorded information from ImmPort leading the reinforcement of CIDO. METHODS: The CIDO was used as the semantic platform for logically modeling and representing newly identified knowledge reported in the 6 ImmPort studies. A recursive eXtensible Ontology Development (XOD) strategy was established to support the CIDO representation and enhancement. Secondary data analysis was also performed to analyze different aspects of the HCI from these ImmPort studies and other related literature reports. RESULTS: The topics covered by the 6 ImmPort papers were identified to overlap with existing CIDO representation. SARS-CoV-2 viral S protein related HCI knowledge was emphasized for CIDO modeling, including its binding with ACE2, mutations causing different variants, and epitope homology by comparison with other coronavirus S proteins. Different types of cytokine signatures were also identified and added to CIDO. Our secondary analysis of two cohort COVID-19 studies with cytokine panel detection found that a total of 11 cytokines were up-regulated in female patients after infection and 8 cytokines in male patients. These sex-specific gene responses were newly modeled and represented in CIDO. A new DL query was generated to demonstrate the benefits of such integrative ontology representation. Furthermore, IL-10 signaling pathway was found to be statistically significant for both male patients and female patients. CONCLUSION: Using the recursive XOD strategy, six new ImmPort COVID-19 studies were systematically reviewed, the results were modeled and represented in CIDO, leading to the enhancement of CIDO. The enhanced ontology and further seconary analysis supported more comprehensive understanding of the molecular mechanism of host responses to COVID-19 infection.


Assuntos
Ontologias Biológicas , COVID-19 , Interações entre Hospedeiro e Microrganismos , Humanos , Semântica , Glicoproteína da Espícula de Coronavírus/metabolismo
2.
Front Immunol ; 12: 639491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777032

RESUMO

Vaccines stimulate various immune factors critical to protective immune responses. However, a comprehensive picture of vaccine-induced immune factors and pathways have not been systematically collected and analyzed. To address this issue, we developed VaximmutorDB, a web-based database system of vaccine immune factors (abbreviated as "vaximmutors") manually curated from peer-reviewed articles. VaximmutorDB currently stores 1,740 vaccine immune factors from 13 host species (e.g., human, mouse, and pig). These vaximmutors were induced by 154 vaccines for 46 pathogens. Top 10 vaximmutors include three antibodies (IgG, IgG2a and IgG1), Th1 immune factors (IFN-γ and IL-2), Th2 immune factors (IL-4 and IL-6), TNF-α, CASP-1, and TLR8. Many enriched host processes (e.g., stimulatory C-type lectin receptor signaling pathway, SRP-dependent cotranslational protein targeting to membrane) and cellular components (e.g., extracellular exosome, nucleoplasm) by all the vaximmutors were identified. Using influenza as a model, live attenuated and killed inactivated influenza vaccines stimulate many shared pathways such as signaling of many interleukins (including IL-1, IL-4, IL-6, IL-13, IL-20, and IL-27), interferon signaling, MARK1 activation, and neutrophil degranulation. However, they also present their unique response patterns. While live attenuated influenza vaccine FluMist induced significant signal transduction responses, killed inactivated influenza vaccine Fluarix induced significant metabolism of protein responses. Two different Yellow Fever vaccine (YF-Vax) studies resulted in overlapping gene lists; however, they shared more portions of pathways than gene lists. Interestingly, live attenuated YF-Vax simulates significant metabolism of protein responses, which was similar to the pattern induced by killed inactivated Fluarix. A user-friendly web interface was generated to access, browse and search the VaximmutorDB database information. As the first web-based database of vaccine immune factors, VaximmutorDB provides systematical collection, standardization, storage, and analysis of experimentally verified vaccine immune factors, supporting better understanding of protective vaccine immunity.


Assuntos
Anticorpos Antivirais/imunologia , Imunidade/imunologia , Fatores Imunológicos/imunologia , Vacinas/imunologia , Animais , Bases de Dados Factuais , Humanos , Internet , Transdução de Sinais/imunologia , Vacinação/métodos
3.
BMC Bioinformatics ; 22(1): 82, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622235

RESUMO

BACKGROUND: Immunofluorescent confocal microscopy uses labeled antibodies as probes against specific macromolecules to discriminate between multiple cell types. For images of the developmental mouse lung, these cells are themselves organized into densely packed higher-level anatomical structures. These types of images can be challenging to segment automatically for several reasons, including the relevance of biomedical context, dependence on the specific set of probes used, prohibitive cost of generating labeled training data, as well as the complexity and dense packing of anatomical structures in the image. The use of an application ontology helps surmount these challenges by combining image data with its metadata to provide a meaningful biological context, modeled after how a human expert would make use of contextual information to identify histological structures, that constrains and simplifies the process of segmentation and object identification. RESULTS: We propose an innovative approach for the semi-supervised analysis of complex and densely packed anatomical structures from immunofluorescent images that utilizes an application ontology to provide a simplified context for image segmentation and object identification. We describe how the logical organization of biological facts in the form of an ontology can provide useful constraints that facilitate automatic processing of complex images. We demonstrate the results of ontology-guided segmentation and object identification in mouse developmental lung images from the Bioinformatics REsource ATlas for the Healthy lung database of the Molecular Atlas of Lung Development (LungMAP1) program CONCLUSION: We describe a novel ontology-guided approach to segmentation and classification of complex immunofluorescence images of the developing mouse lung. The ontology is used to automatically generate constraints for each image based on its biomedical context, which facilitates image segmentation and classification.


Assuntos
Algoritmos , Processamento de Imagem Assistida por Computador , Pulmão , Microscopia Confocal , Animais , Imunofluorescência , Pulmão/diagnóstico por imagem , Camundongos
4.
Nat Commun ; 10(1): 2450, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164648

RESUMO

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/imunologia , Carcinoma/imunologia , Neoplasias Mamárias Animais/imunologia , Células Mieloides/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células , Quimiocinas/imunologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral/genética
5.
J Biomed Semantics ; 10(1): 25, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888755

RESUMO

BACKGROUND: Host-microbiome interactions (HMIs) are critical for the modulation of biological processes and are associated with several diseases. Extensive HMI studies have generated large amounts of data. We propose that the logical representation of the knowledge derived from these data and the standardized representation of experimental variables and processes can foster integration of data and reproducibility of experiments and thereby further HMI knowledge discovery. METHODS: Through a multi-institutional collaboration, a community-based Ontology of Host-Microbiome Interactions (OHMI) was developed following the Open Biological/Biomedical Ontologies (OBO) Foundry principles. As an OBO library ontology, OHMI leverages established ontologies to create logically structured representations of (1) microbiomes, microbial taxonomy, host species, host anatomical entities, and HMIs under different conditions and (2) associated study protocols and types of data analysis and experimental results. RESULTS: Aligned with the Basic Formal Ontology, OHMI comprises over 1000 terms, including terms imported from more than 10 existing ontologies together with some 500 OHMI-specific terms. A specific OHMI design pattern was generated to represent typical host-microbiome interaction studies. As one major OHMI use case, drawing on data from over 50 peer-reviewed publications, we identified over 100 bacteria and fungi from the gut, oral cavity, skin, and airway that are associated with six rheumatic diseases including rheumatoid arthritis. Our ontological study identified new high-level microbiota taxonomical structures. Two microbiome-related competency questions were also designed and addressed. We were also able to use OHMI to represent statistically significant results identified from a large existing microbiome database data analysis. CONCLUSION: OHMI represents entities and relations in the domain of HMIs. It supports shared knowledge representation, data and metadata standardization and integration, and can be used in formulation of advanced queries for purposes of data analysis.


Assuntos
Ontologias Biológicas , Interações Hospedeiro-Patógeno , Microbiota
6.
J Biomed Semantics ; 7(1): 53, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27627881

RESUMO

BACKGROUND: Statistics play a critical role in biological and clinical research. However, most reports of scientific results in the published literature make it difficult for the reader to reproduce the statistical analyses performed in achieving those results because they provide inadequate documentation of the statistical tests and algorithms applied. The Ontology of Biological and Clinical Statistics (OBCS) is put forward here as a step towards solving this problem. RESULTS: The terms in OBCS including 'data collection', 'data transformation in statistics', 'data visualization', 'statistical data analysis', and 'drawing a conclusion based on data', cover the major types of statistical processes used in basic biological research and clinical outcome studies. OBCS is aligned with the Basic Formal Ontology (BFO) and extends the Ontology of Biomedical Investigations (OBI), an OBO (Open Biological and Biomedical Ontologies) Foundry ontology supported by over 20 research communities. Currently, OBCS comprehends 878 terms, representing 20 BFO classes, 403 OBI classes, 229 OBCS specific classes, and 122 classes imported from ten other OBO ontologies. We discuss two examples illustrating how the ontology is being applied. In the first (biological) use case, we describe how OBCS was applied to represent the high throughput microarray data analysis of immunological transcriptional profiles in human subjects vaccinated with an influenza vaccine. In the second (clinical outcomes) use case, we applied OBCS to represent the processing of electronic health care data to determine the associations between hospital staffing levels and patient mortality. Our case studies were designed to show how OBCS can be used for the consistent representation of statistical analysis pipelines under two different research paradigms. Other ongoing projects using OBCS for statistical data processing are also discussed. The OBCS source code and documentation are available at: https://github.com/obcs/obcs . CONCLUSIONS: The Ontology of Biological and Clinical Statistics (OBCS) is a community-based open source ontology in the domain of biological and clinical statistics. OBCS is a timely ontology that represents statistics-related terms and their relations in a rigorous fashion, facilitates standard data analysis and integration, and supports reproducible biological and clinical research.


Assuntos
Ontologias Biológicas , Estatística como Assunto , Mineração de Dados , Padrões de Referência , Reprodutibilidade dos Testes , Vacinas/imunologia
7.
J Biomed Semantics ; 7: 23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27148435

RESUMO

BACKGROUND: Biobanking necessitates extensive integration of data to allow data analysis and specimen sharing. Ontologies have been demonstrated to be a promising approach in fostering better semantic integration of biobank-related data. Hitherto no ontology provided the coverage needed to capture a broad spectrum of biobank user scenarios. METHODS: Based in the principles laid out by the Open Biological and Biomedical Ontologies Foundry two biobanking ontologies have been developed. These two ontologies were merged using a modular approach consistent with the initial development principles. The merging was facilitated by the fact that both ontologies use the same Upper Ontology and re-use classes from a similar set of pre-existing ontologies. RESULTS: Based on the two previous ontologies the Ontology for Biobanking (http://purl.obolibrary.org/obo/obib.owl) was created. Due to the fact that there was no overlap between the two source ontologies the coverage of the resulting ontology is significantly larger than of the two source ontologies. The ontology is successfully used in managing biobank information of the Penn Medicine BioBank. CONCLUSIONS: Sharing development principles and Upper Ontologies facilitates subsequent merging of ontologies to achieve a broader coverage.


Assuntos
Ontologias Biológicas , Bancos de Espécimes Biológicos
9.
PLoS One ; 10(3): e0122978, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25894391

RESUMO

The Protein Ontology (PRO) provides terms for and supports annotation of species-specific protein complexes in an ontology framework that relates them both to their components and to species-independent families of complexes. Comprehensive curation of experimentally known forms and annotations thereof is expected to expose discrepancies, differences, and gaps in our knowledge. We have annotated the early events of innate immune signaling mediated by Toll-Like Receptor 3 and 4 complexes in human, mouse, and chicken. The resulting ontology and annotation data set has allowed us to identify species-specific gaps in experimental data and possible functional differences between species, and to employ inferred structural and functional relationships to suggest plausible resolutions of these discrepancies and gaps.


Assuntos
Ontologias Biológicas , Biologia Computacional/métodos , Transdução de Sinais , Receptores Toll-Like/metabolismo , Animais , Galinhas , Evolução Molecular , Humanos , Camundongos , Anotação de Sequência Molecular , Transporte Proteico
10.
Nucleic Acids Res ; 42(Database issue): D415-21, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24270789

RESUMO

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to UniProtKB in that PRO's organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO's representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments.


Assuntos
Ontologias Biológicas , Bases de Dados de Proteínas , Proteínas/classificação , Animais , Humanos , Internet , Camundongos , Proteínas/química
11.
PLoS One ; 8(1): e54156, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326591

RESUMO

The Toll-like receptors represent a largely evolutionarily conserved pathogen recognition machinery responsible for recognition of bacterial, fungal, protozoan, and viral pathogen associated microbial patterns and initiation of inflammatory response. Structurally the Toll-like receptors are comprised of an extracellular leucine rich repeat domain and a cytoplasmic Toll/Interleukin 1 receptor domain. Recognition takes place in the extracellular domain where as the cytoplasmic domain triggers a complex signal network required to sustain appropriate immune response. Signal transduction is regulated by the recruitment of different intracellular adaptors. The Toll-like receptors can be grouped depending on the usage of the adaptor, MyD88, into MyD88-dependent and MyD88 independent subsets. Herein, we present a unique phylogenetic analysis of domain regions of these receptors and their cognate signaling adaptor molecules. Although previously unclear from the phylogeny of full length receptors, these analyses indicate a separate evolutionary origin for the MyD88-dependent and MyD88-independent signaling pathway and provide evidence of a common ancestor for the vertebrate and invertebrate orthologs of the adaptor molecule MyD88. Together these observations suggest a very ancient origin of the MyD88-dependent pathway Additionally we show that early duplications gave rise to several adaptor molecule families. In some cases there is also strong pattern of parallel duplication between adaptor molecules and their corresponding TLR. Our results further support the hypothesis that phylogeny of specific domains involved in signaling pathway can shed light on key processes that link innate to adaptive immune response.


Assuntos
Evolução Molecular , Fator 88 de Diferenciação Mieloide , Filogenia , Receptores Toll-Like , Adaptação Fisiológica/genética , Adaptação Fisiológica/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Duplicação Gênica , Imunidade Inata/genética , Imunidade Inata/fisiologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
12.
BMC Bioinformatics ; 12: 6, 2011 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-21208450

RESUMO

BACKGROUND: The Cell Ontology (CL) is an ontology for the representation of in vivo cell types. As biological ontologies such as the CL grow in complexity, they become increasingly difficult to use and maintain. By making the information in the ontology computable, we can use automated reasoners to detect errors and assist with classification. Here we report on the generation of computable definitions for the hematopoietic cell types in the CL. RESULTS: Computable definitions for over 340 CL classes have been created using a genus-differentia approach. These define cell types according to multiple axes of classification such as the protein complexes found on the surface of a cell type, the biological processes participated in by a cell type, or the phenotypic characteristics associated with a cell type. We employed automated reasoners to verify the ontology and to reveal mistakes in manual curation. The implementation of this process exposed areas in the ontology where new cell type classes were needed to accommodate species-specific expression of cellular markers. Our use of reasoners also inferred new relationships within the CL, and between the CL and the contributing ontologies. This restructured ontology can be used to identify immune cells by flow cytometry, supports sophisticated biological queries involving cells, and helps generate new hypotheses about cell function based on similarities to other cell types. CONCLUSION: Use of computable definitions enhances the development of the CL and supports the interoperability of OBO ontologies.


Assuntos
Células Sanguíneas/classificação , Biologia Computacional/métodos , Bases de Dados Factuais , Armazenamento e Recuperação da Informação/métodos , Vocabulário Controlado
13.
J Biomed Inform ; 44(1): 75-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20123131

RESUMO

The Cell Ontology (CL) aims for the representation of in vivo and in vitro cell types from all of biology. The CL is a candidate reference ontology of the OBO Foundry and requires extensive revision to bring it up to current standards for biomedical ontologies, both in its structure and its coverage of various subfields of biology. We have now addressed the specific content of one area of the CL, the section of the ontology dealing with hematopoietic cells. This section has been extensively revised to improve its content and eliminate multiple inheritance in the asserted hierarchy, and the groundwork has been laid for structuring the hematopoietic cell type terms as cross-products incorporating logical definitions built from relationships to external ontologies, such as the Protein Ontology and the Gene Ontology. The methods and improvements to the CL in this area represent a paradigm for improvement of the entire ontology over time.


Assuntos
Células Sanguíneas/citologia , Hematopoese , Informática Médica , Vocabulário Controlado , Animais , Humanos
14.
PLoS One ; 5(6): e11052, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20548796

RESUMO

BACKGROUND: HIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively). These drugs demonstrated a differential ability to sustain the generation of immature DCs (iDCs) with an altered phenotype, including low levels of CD1a, CD86, CD36 and CD209. DCs generated in the presence of rtv also failed to acquire the typical phenotype of mature DCs (mDCs), and secreted lower amounts of IL-12 and IL-15. Accordingly, these aberrant mDCs failed to support activation of autologous Natural Killer (NK) cells, and resulted highly susceptible to NK cell-mediated cytotoxicity. CONCLUSIONS/SIGNIFICANCE: Our findings uncover novel functional properties of PIs within the DC-NK cell cross-talk, unveiling the heterogeneous ability of members of this class drugs to drive the generation of atypical monocyte-derived DCs (MDDCs) showing an aberrant phenotype, a failure to respond appropriately to bacterial endotoxin, a weak ability to prime autologous NK cells, and a high susceptibility to NK cell killing. These unexpected properties might contribute to limit inflammation and viral spreading in HIV-1 infected patients under PIs treatment, and open novel therapeutical perspectives for this class drugs as immunomodulators in autoimmunity and cancer.


Assuntos
Células Dendríticas/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Proliferação de Células , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia
15.
BMC Bioinformatics ; 10: 70, 2009 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-19243617

RESUMO

BACKGROUND: Recent increases in the volume and diversity of life science data and information and an increasing emphasis on data sharing and interoperability have resulted in the creation of a large number of biological ontologies, including the Cell Ontology (CL), designed to provide a standardized representation of cell types for data annotation. Ontologies have been shown to have significant benefits for computational analyses of large data sets and for automated reasoning applications, leading to organized attempts to improve the structure and formal rigor of ontologies to better support computation. Currently, the CL employs multiple is_a relations, defining cell types in terms of histological, functional, and lineage properties, and the majority of definitions are written with sufficient generality to hold across multiple species. This approach limits the CL's utility for computation and for cross-species data integration. RESULTS: To enhance the CL's utility for computational analyses, we developed a method for the ontological representation of cells and applied this method to develop a dendritic cell ontology (DC-CL). DC-CL subtypes are delineated on the basis of surface protein expression, systematically including both species-general and species-specific types and optimizing DC-CL for the analysis of flow cytometry data. We avoid multiple uses of is_a by linking DC-CL terms to terms in other ontologies via additional, formally defined relations such as has_function. CONCLUSION: This approach brings benefits in the form of increased accuracy, support for reasoning, and interoperability with other ontology resources. Accordingly, we propose our method as a general strategy for the ontological representation of cells. DC-CL is available from http://www.obofoundry.org.


Assuntos
Biologia Computacional/métodos , Células Dendríticas/classificação , Bases de Dados Factuais , Armazenamento e Recuperação da Informação/métodos , Terminologia como Assunto , Vocabulário Controlado
16.
Blood ; 111(2): 723-31, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17909078

RESUMO

Microbial products, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DCs) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulin-dependent kinase IV (CaMKIV) in this survival program. The pharmacologic inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decrease the viability of monocyte-derived DCs exposed to bacterial LPS. The defect in TLR4 signaling includes a failure to accumulate the phosphorylated form of the cAMP response element-binding protein (pCREB), Bcl-2, and Bcl-xL. CaMKIV null mice have a decreased number of DCs in lymphoid tissues and fail to accumulate mature DCs in spleen on in vivo exposure to LPS. Although isolated Camk4-/- DCs are able to acquire the phenotype typical of mature cells and release normal amounts of cytokines in response to LPS, they fail to accumulate pCREB, Bcl-2, and Bcl-xL and therefore do not survive. The transgenic expression of Bcl-2 in CaMKIV null mice results in full recovery of DC survival in response to LPS. These results reveal a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival.


Assuntos
Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/imunologia , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Células Dendríticas/metabolismo , Monócitos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/imunologia , Proteína de Ligação a CREB/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/imunologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Humanos , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Knockout , Monócitos/citologia , Monócitos/imunologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Baço/citologia , Baço/imunologia , Baço/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Proteína bcl-X/genética , Proteína bcl-X/imunologia , Proteína bcl-X/metabolismo
17.
Tumori ; 91(4): 361-3, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16277106

RESUMO

Thymoma is a rare tumor characterized by an association with autoimmune diseases. Immunological abnormalities are increasingly being recognized in thymoma patients and are the cause of a peculiar susceptibility to infections. The authors present the clinical history of a thymoma patient affected by fatal immunodeficiency.


Assuntos
Agamaglobulinemia/complicações , Timoma/complicações , Neoplasias do Timo/complicações , Agamaglobulinemia/imunologia , Evolução Fatal , Humanos , Síndromes de Imunodeficiência/complicações , Masculino , Pessoa de Meia-Idade , Timoma/imunologia , Neoplasias do Timo/imunologia
18.
J Leukoc Biol ; 78(2): 372-82, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15923217

RESUMO

We have described previously that hypervariable region 1 (HVR1) variants of hepatitis C virus (HCV) frequently act as T cell receptor (TCR) antagonists for HVR1-specific helper T cells. These naturally occurring HVR1-antagonistic sequences interfered with the effects of HVR1-agonistic sequences such as TCR down-regulation and early activatory signals. By taking advantage of these findings, in this paper, we have analyzed the fate of these HVR1-specific antagonized CD4+ T cells. We present the evidence that TCR antagonism renders agonist-activated T cells susceptible to bystander CD95-mediated killing by suppressing the expression of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-like inhibitor proteins. To verify whether the TCR repertoire of a HVR1-specific T cell population could be modified consequently, we used a HVR1-agonistic sequence to induce in vitro CD4+ T cells and another HVR1 sequence with antagonistic property to mediate suppressive phenomena. HVR1-specific T cells were cultured with the agonist alone or with the agonist plus the antagonist. HVR1 specificity and T cell repertoires were followed over time by analyzing TCR beta-variable gene segment by "spectratyping". The results showed that the specificity for the agonist was rapidly spoiled after culture in the presence of the antagonist, and the TCR repertoire was strongly modified as a result of CD95-mediated apoptosis of agonist-specific clonal expansions. These data support the hypothesis that in HCV infection, the generation of TCR antagonists may reshape the T cell repertoire, representing an efficacious immune evasion strategy of a highly mutant pathogen.


Assuntos
Antígenos Virais/imunologia , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Hepacivirus/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores , Subpopulações de Linfócitos T/imunologia , Proteínas Virais/imunologia , Receptor fas/imunologia , Proliferação de Células , Células Cultivadas , Regulação para Baixo/imunologia , Epitopos de Linfócito T , Hepacivirus/patogenicidade , Humanos , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Serpinas/biossíntese , Serpinas/imunologia , Proteínas Virais/biossíntese
19.
J Leukoc Biol ; 76(3): 634-40, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15197238

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation, which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the absence of all GPI-linked proteins on the membrane of the clonal-defective cells. The presence of a consistent GPI-defective monocyte compartment is a common feature in PNH patients. To investigate the functional behavior of this population, we analyzed its in vitro differentiation ability toward functional dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH patients are unable to undergo full DC differentiation in vitro after granulocyte macrophage-colony stimulating factor and recombinant interleukin (IL)-4 treatment. In this context, the GPI-defective DC population shows mannose receptor expression, high levels of the CD86 molecule, and impaired CD1a up-regulation. The analysis of lipopolysaccharide and CD40-dependent, functional pathways in these DCs revealed a strong decrease in tumor necrosis factor alpha and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in delivering accessory signals for T cell receptor-dependent T cell proliferation.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Glicosilfosfatidilinositóis/deficiência , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/imunologia , Monócitos/imunologia , Adulto , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Antígeno B7-2 , Antígenos CD40/imunologia , Diferenciação Celular/genética , Divisão Celular/imunologia , Células Dendríticas/citologia , Feminino , Glicosilfosfatidilinositóis/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hemoglobinúria Paroxística/genética , Humanos , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-4/farmacologia , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Lectinas de Ligação a Manose/imunologia , Lectinas de Ligação a Manose/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Monócitos/citologia , Mutação/genética , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
20.
J Biol Chem ; 279(31): 32507-14, 2004 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-15166249

RESUMO

Immature dendritic cells (iDCs) can be instructed to polarize the immune response toward a noninflammatory pathway by mediators that increase the intracellular concentration of cAMP. This phenomenon is associated with the ability of the cyclic nucleoside to inhibit the release of pro-inflammatory cytokines without affecting the differentiation process of the dendritic cells (DCs). Here we investigated the ability of cAMP to modulate the endotoxin signaling by exposing DCs to exogenous 8-bromium-cyclic AMP in the presence or absence of H89, a selective inhibitor of the protein kinase A, one of the major molecular targets of the cyclic nucleoside. cAMP affects the early lipopolysaccharide-induced signaling cascade dissociating the activation of NF-kappa B, p38, and ERK pathways from the stimulation of c-Src and Lyn kinases. This phenomenon was prevented by H89. The pharmacological block of Src-like tyrosine kinases induces comparable results confirming the involvement of this family of enzymes in the mechanism controlling the release of cytokines in human monocyte-derived iDCs. We propose that the cAMP-protein kinase A-dependent pathway regulates the functional plasticity of iDCs by gating the Toll-like receptor signaling at the level of Src-like kinases.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Células Dendríticas/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/metabolismo , Western Blotting , Diferenciação Celular , Divisão Celular , Células Cultivadas , Quimiotaxia , Células Dendríticas/citologia , Endotoxinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Inflamação , Interleucina-12/metabolismo , Lipopolissacarídeos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fenótipo , Proteína Quinase C/metabolismo , Proteínas Tirosina Quinases/metabolismo , Linfócitos T/metabolismo , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno
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