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1.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064383

RESUMO

Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Receptores Purinérgicos P2Y/metabolismo , Estresse Fisiológico/imunologia , Animais , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/imunologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Vigilância Imunológica/imunologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Camundongos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Agonistas do Receptor Purinérgico P2Y/farmacologia , Agonistas do Receptor Purinérgico P2Y/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946558

RESUMO

Colorectal cancer (CRC) remains one of the deadliest malignancies worldwide despite recent progress in treatment strategies. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC patients with high microsatellite instability. In general, heterogenous cell groups in the tumor microenvironment are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding the immune contexture of cancer. In this review, we assimilate current knowledge and recent studies examining anti-tumor immunity in CRC. We also discuss the utilization of novel immune contexture assessment methods that have not been used in CRC research to date.


Assuntos
Neoplasias Colorretais/imunologia , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Biologia Computacional , Humanos , Imunidade , Vigilância Imunológica , Imunoterapia , Microambiente Tumoral
3.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920983

RESUMO

Ovarian cancer is an aggressive gynaecological cancer with extremely poor prognosis, due to late diagnosis as well as the development of chemoresistance after first-line therapy. Research advances have found stem-like cells present in ovarian tumours, which exist in a dynamic niche and persist through therapy. The stem cell niche interacts extensively with the immune and non-immune components of the tumour microenvironment. Significant pathways associated with the cancer stem cell niche have been identified which interfere with the immune component of the tumour microenvironment, leading to immune surveillance evasion, dysfunction and suppression. This review aims to summarise current evidence-based knowledge on the cancer stem cell niche within the ovarian cancer tumour microenvironment and its effect on immune surveillance. Furthermore, the review seeks to understand the clinical consequences of this dynamic interaction by highlighting current therapies which target these processes.


Assuntos
Vigilância Imunológica , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Nicho de Células-Tronco/imunologia , Animais , Feminino , Humanos , Inflamação/patologia , Neoplasias Ovarianas/terapia , Transdução de Sinais
4.
Nat Commun ; 12(1): 2237, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854047

RESUMO

Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/imunologia , Proteínas de Membrana/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Animais , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada , Humanos , Vigilância Imunológica , Pulmão/imunologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Camundongos
5.
Int J Hematol ; 113(5): 642-647, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33651270

RESUMO

Chronic myeloid leukemia (CML) is caused by the reciprocal translocation t(9;22)(q34;q11), resulting in the BCR-ABL1 fusion gene. BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve overall survival in patients with chronic phase CML (CML-CP). Approximately half of the patients who achieve a durable deep molecular response can achieve sustained treatment-free remission (TFR) after TKI discontinuation; thus TFR is now a therapeutic goal for most patients with CML-CP. Sensitive BCL-ABL1 transcript detection methods reveal that evidence of residual CML cells remains in patients who achieve sustained TFR, indicating that the host immune system protects against CML relapse. The human immune system is composed of innate and adaptive arms. Natural killer cells are major components of the innate immune system, while T cells are major components of the adaptive immune system. Myeloid-derived suppressor cells and regulatory T cells, both suppressors of the immune response, have important roles in the regulation of CML. Here, we review the current understanding of the immune response in CML, especially in TFR.


Assuntos
Antineoplásicos/uso terapêutico , Imunidade/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Humanos , Vigilância Imunológica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Indução de Remissão , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
6.
Anticancer Res ; 41(3): 1327-1339, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788724

RESUMO

BACKGROUND: Colonic cancer is associated with a low incidence of peritoneal metastasis compared with gastric cancer; however, the reason for this remains unclear. In this study, a model of peritoneal dissemination using the CT26 murine colon cancer cell line was used to analyze the physiological roles of cancer-derived exosomes. MATERIALS AND METHODS: Exosomes were collected from the supernatant of CT26 cell culture by ultracentrifugation. The number of peritoneal disseminations in two mouse models of colonic cancer pre-administered exosomes or phosphate-buffered saline were compared. RESULTS: Cancer-derived exosomes suppressed peritoneal dissemination compared to phosphate-buffered saline. After administration of exosomes, the number of intraperitoneal macrophages and the expression of inducible nitric oxide synthase increased. Furthermore, cancer-derived exosomes increased activated natural killer cells and interferon-γ expression. CONCLUSION: Tumor-derived exosomes from colonic cancer may suppress peritoneal metastasis via an immunological mechanism.


Assuntos
Neoplasias do Colo/imunologia , Exossomos/imunologia , Vigilância Imunológica/imunologia , Neoplasias Peritoneais/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Exossomos/metabolismo , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Neoplasias Peritoneais/secundário , Células RAW 264.7
7.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546395

RESUMO

Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.


Assuntos
Envelhecimento/metabolismo , Senescência Celular , Proteína bcl-X/metabolismo , Envelhecimento/genética , Animais , Apoptose/genética , Apoptose/imunologia , Biomarcadores , Senescência Celular/genética , Dano ao DNA , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Vigilância Imunológica , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Ligação Proteica , Transdução de Sinais , Estresse Fisiológico , Proteína bcl-X/genética
8.
J Hematol Oncol ; 14(1): 7, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407739

RESUMO

Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Neoplasias/terapia , Animais , Ensaios Clínicos como Assunto , Humanos , Vigilância Imunológica , Células Matadoras Naturais/citologia , Ativação Linfocitária , Neoplasias/imunologia , Evasão Tumoral
9.
Science ; 371(6526)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446526

RESUMO

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Imunidade nas Mucosas/imunologia , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunidade nas Mucosas/genética , Vigilância Imunológica/genética , Vigilância Imunológica/imunologia , Interferon gama/genética , Interleucinas/genética , Janus Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Receptores de Interleucina-17/genética , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Adulto Jovem
10.
Infect Genet Evol ; 88: 104701, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33387692

RESUMO

Given the pertinence and acceleration of the spread of COVID-19, there is an increased need for the replicability of data models to verify the veracity of models and visualize important data. Most of these visualizations lack reproducibility, credibility, or accuracy, and are static, which makes it difficult to analyze the spread over time. Furthermore, most current visualizations depicting the spread of COVID-19 are at a global or country level, meaning there is a dearth of regional analysis within a country. Keeping these issues in mind, a replicable, efficient, and simple method to generate regional COVID-19 visualizations mapped with time was created by using the KNIME software, an open-source data analytics platform that can create user-friendly applications or workflows. For this analysis, Albania, Sweden, Ukraine, Denmark, Russia, India, and Australia were closely observed. Among the maps generated for the aforementioned countries, it was noticed that regions with a high population or high population density were often the epicenters within their respective country. The regions caused the virus to spread to their neighboring regions: kickstarting the "domino effect", leading to the infection of another region until the country is overwhelmed with cases-what we call a proximity trend. These dynamic maps are crucial to fighting the pandemic because they can provide insight as to how COVID-19 spreads by providing researchers or officials with an accurate and insightful tool to aid their analysis. By being able to visualize the spread, health and government officials can dive deeper to identify the sources of transmission and attempt to stop or reverse them accordingly.


Assuntos
/epidemiologia , Modelos Estatísticos , Pandemias , Software , Austrália/epidemiologia , /virologia , Europa (Continente)/epidemiologia , Humanos , Vigilância Imunológica , Índia/epidemiologia , Densidade Demográfica , Fluxo de Trabalho
11.
J Immunol ; 206(2): 282-291, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33397742

RESUMO

The CNS is tightly regulated to maintain immune surveillance and efficiently respond to injury and infections. The current appreciation that specialized "brain-adjacent" regions in the CNS are in fact not immune privileged during the steady state, and that immune cells can take up residence in more immune-privileged areas of the CNS during inflammation with consequences on the adjacent brain parenchyma, beg the question of what cell types support CNS immunity. As they do in secondary lymphoid organs, we provide evidence in this review that stromal cells also underpin brain-resident immune cells. We review the organization and function of stromal cells in different anatomical compartments of the CNS and discuss their capacity to rapidly establish and elaborate an immune-competent niche that further sustains immune cells entering the CNS from the periphery. In summary, we argue that stromal cells are key cellular agents that support CNS-compartmentalized immunity.


Assuntos
Encéfalo/imunologia , Sistema Nervoso Central/imunologia , Células Estromais/fisiologia , Animais , Compartimento Celular , Microambiente Celular , Humanos , Imunidade Celular , Vigilância Imunológica
12.
J Immunol ; 206(2): 264-272, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33397740

RESUMO

Lymphatic vessels provide an anatomical framework for immune surveillance and adaptive immune responses. Although appreciated as the route for Ag and dendritic cell transport, peripheral lymphatic vessels are often not considered active players in immune surveillance. Lymphatic vessels, however, integrate contextual cues that directly regulate transport, including changes in intrinsic pumping and capillary remodeling, and express a dynamic repertoire of inflammatory chemokines and adhesion molecules that facilitates leukocyte egress out of inflamed tissue. These mechanisms together contribute to the course of peripheral tissue immunity. In this review, we focus on context-dependent mechanisms that regulate fluid and cellular transport out of peripheral nonlymphoid tissues to provide a framework for understanding the effects of afferent lymphatic transport on immune surveillance, peripheral tissue inflammation, and adaptive immunity.


Assuntos
Inflamação/imunologia , Vasos Linfáticos/imunologia , Imunidade Adaptativa , Animais , Movimento Celular , Microambiente Celular , Humanos , Vigilância Imunológica
13.
Nat Neurosci ; 24(1): 19-23, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33318667

RESUMO

Microglial surveillance is a key feature of brain physiology and disease. Here, we found that Gi-dependent microglial dynamics prevent neuronal network hyperexcitability. By generating MgPTX mice to genetically inhibit Gi in microglia, we show that sustained reduction of microglia brain surveillance and directed process motility induced spontaneous seizures and increased hypersynchrony after physiologically evoked neuronal activity in awake adult mice. Thus, Gi-dependent microglia dynamics may prevent hyperexcitability in neurological diseases.


Assuntos
Receptor Quinase 1 Acoplada a Proteína G/fisiologia , Microglia/fisiologia , Rede Nervosa/fisiologia , Animais , Sinalização do Cálcio , Movimento Celular , Convulsivantes , Eletroencefalografia , Vigilância Imunológica , Camundongos , Microglia/enzimologia , Microglia/ultraestrutura , Doenças do Sistema Nervoso/fisiopatologia , Fenômenos Fisiológicos do Sistema Nervoso , Pilocarpina , Convulsões/fisiopatologia , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo
14.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33352944

RESUMO

Neuroinflammation in Alzheimer's disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aß), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aß with high affinity, α7 nAChR may play a role in Aß-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aß uptake through the α7 nAChR. Despite the lower Aß uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.


Assuntos
Alarminas/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Microglia/imunologia , Microglia/metabolismo , Padrões Moleculares Associados a Patógenos/metabolismo , Doença de Alzheimer/patologia , Movimento Celular , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Imunidade Inata , Vigilância Imunológica , Microglia/citologia , NF-kappa B/metabolismo , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
15.
Science ; 369(6510)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32943500

RESUMO

Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1ß (IL-1ß) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1ß conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.


Assuntos
Desacetilase 6 de Histona/metabolismo , Vigilância Imunológica , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Desacetilase 6 de Histona/genética , Humanos , Inflamassomos/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Centro Organizador dos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transporte Proteico
16.
Nat Commun ; 11(1): 4740, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958755

RESUMO

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.


Assuntos
Mutação da Fase de Leitura , Repetições de Microssatélites/genética , Neoplasias/genética , Neoplasias/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antígenos HLA/genética , Humanos , Mutação INDEL , Vigilância Imunológica , Instabilidade de Microssatélites , Taxa de Mutação , Seleção Genética , Microglobulina beta-2/genética
17.
Brasília, D.F.; OPAS; 2020-09-22.
em Português | PAHO-IRIS | ID: phr2-52718

RESUMO

O Manual de Vigilância de Pneumonia Bacteriana e Meningite em Menores de 5 anos: Guia Prático tornou-se referência de destaque para os profissionais de saúde da Região das Américas que lidam com atividades de vigilância epidemiológica. Abrange doenças, principais agentes etiológicos, vacinas disponíveis, procedimentos laboratoriais e de vigilância para captura e monitoramento de casos, bem como análise de dados para a produção de informações relevantes. Esta segunda edição introduz novos conceitos e procedimentos de atualização para refletir a introdução de testes de biologia molecular em diagnósticos laboratoriais e a disponibilidade de novas vacinas.


Assuntos
Saúde da Criança , Meningites Bacterianas , Pneumonia Bacteriana , Imunização , Vacinação , Vigilância Imunológica , Vigilância em Saúde Pública
18.
Science ; 369(6500)2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32646971

RESUMO

The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in a tissue- and organ-specific manner during homeostasis and in multiple disease processes. This Review discusses recent advances to understand previously unidentified functions of adult mammalian lymphatic vessels, including immunosurveillance and immunomodulation upon pathogen invasion, transport of dietary fat, drainage of cerebrospinal fluid and aqueous humor, possible contributions toward neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies.


Assuntos
Vigilância Imunológica , Vasos Linfáticos/imunologia , Animais , Sistema Nervoso Central/imunologia , Infecções do Sistema Nervoso Central/imunologia , Líquido Cefalorraquidiano/imunologia , Encefalite/imunologia , Homeostase/imunologia , Humanos , Intestinos/imunologia , Vasos Linfáticos/microbiologia , Camundongos , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia
19.
Nat Commun ; 11(1): 2860, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503978

RESUMO

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.


Assuntos
Linfoma de Burkitt/imunologia , Células Matadoras Naturais/imunologia , Linfoma de Células T/imunologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transferência Adotiva , Animais , Linfoma de Burkitt/mortalidade , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Vigilância Imunológica/genética , Interferon Tipo I/farmacologia , Interferon Tipo I/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Camundongos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
20.
Mol Immunol ; 124: 153-160, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32580073

RESUMO

Patients with Huntington's diseases display reduced tumor incidence mediated by unclear mechanisms. Besides, the effects of characteristic overexpression of 97 polyglutamine protein (polyQ protein) on tumor surveillance by the host immune system have not been investigated. NK cells are cytotoxic innate lymphocytes that sense and kill stressed and transformed cells through recognition of abnormal molecular patterns. Here, we found that polyQ protein induced the accumulation of misfolded proteins in tumor cells and sensitized these tumor cells to NK cell cytolysis in vitro. Transcriptome analysis showed that polyQ protein overexpression caused an abnormal transcriptome changes in tumor cells, which might predispose these tumor cells to death upon NK cell cytolysis. However, on the other hand, polyQ protein in NK cells compromised NK cell cytolytic activity through forcing the accumulation of misfolded proteins. Furthermore, polyQ overexpression enriched oxidative phosphorylation related gene set in NK cells, which might lead to an exhaustion-like status of NK cells with reduced cytolytic activity. Therefore, our study shows that polyQ protein overexpression in tumors alone, but not in both tumor cells and NK cells, might result in increased tumor rejection by NK cells, revealing a dual role of polyQ protein on tumor surveillance by the immune system.


Assuntos
Citotoxicidade Imunológica/imunologia , Vigilância Imunológica/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Peptídeos/metabolismo , Linhagem Celular Tumoral , Humanos , Dobramento de Proteína
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