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1.
Sci Rep ; 11(1): 4243, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608566

RESUMO

SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. This prompted investigation of whether or not asymptomatic disease results in measurable immune activation post-infection. Immune activation following asymptomatic SARS-CoV-2 infection was characterized through a comparative investigation of the immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals from the same community 4-6 weeks following a superspreading event. Few of the 95 individuals had underlying health issues. One seropositive individual reported Cystic Fibrosis and one individual reported Incontinentia pigmenti. No evidence of immune activation was found in asymptomatic seropositive individuals with the exception of the Cystic Fibrosis patient. There were no statistically significant differences in immune transcriptomes between asymptomatic seropositive and highly exposed seronegative individuals. Four positive controls, mildly symptomatic seropositive individuals whose blood was examined 3 weeks following infection, showed immune activation. Negative controls were four seronegative individuals from neighboring communities without COVID-19. All individuals remained in their usual state of health through a five-month follow-up after sample collection. In summary, whole blood transcriptomes identified individual immune profiles within a community population and showed that asymptomatic infection within a super-spreading event was not associated with enduring immunological activation.


Assuntos
/imunologia , Transcriptoma/imunologia , Imunidade Adaptativa/genética , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/isolamento & purificação , Infecções Assintomáticas , Áustria , /diagnóstico , /estatística & dados numéricos , Criança , Pré-Escolar , Busca de Comunicante/estatística & dados numéricos , Características da Família , Feminino , Seguimentos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata/genética , Lactente , Masculino , Pessoa de Meia-Idade , RNA-Seq/estatística & dados numéricos , Adulto Jovem
2.
Life Sci ; 271: 119152, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33548285

RESUMO

Long non-coding RNAs (lncRNAs) were considered as accumulated genetic waste until they were found to be gene expression regulators by highly sensitive modern genomics platforms. It is a huge class of non-coding transcripts with an arbitrary length of >200 nucleotides, which has gained much attention in the past few years. Increasing evidence from several experimental studies unraveled the expression of lncRNA linked to immune response and disease progression. However, only a small number of lncRNAs have robust evidence of their function. Differential expression of lncRNAs in different immune cells is also evident. In this review, we focused on how lncRNAs expression assist in shaping immune cells (Macrophages, Dendritic cells, NK cells, T cells, B cells, eosinophils, neutrophils, and microglial cells) function and their response to the diseased conditions. Emerging evidence revealed lncRNAs may serve as key regulators in the innate and adaptive immune response system. So, the molecular mechanism insight into the function of lncRNAs in immune response may contribute to the development of potential therapeutic targets for various disease treatments. Therefore, it is imperative to explore the expression of lncRNAs and understand its relevance associated with the immune system.


Assuntos
Imunidade Celular/genética , Imunidade Celular/imunologia , Mediadores da Inflamação/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Animais , Células Dendríticas/imunologia , Humanos , Macrófagos/imunologia , Linfócitos T/imunologia
4.
Methods Mol Biol ; 2193: 111-120, 2021.
Artigo | MEDLINE | ID: mdl-32808263

RESUMO

The immune system depends on two major paths-the innate and the adaptive immunity. Macrophage, with its unique features as the first line of immune defense to engulf and digest invaders, serves as the key effector cells integrating those two paths. The dynamic plasticity of macrophage activation during wound repair, inflammation resolution, and tissue remodeling are emerging biomedical and bioengineering hot topics in immune function studies such as the various secretions of cytokines and chemokines and the signaling pathways with ligands and their cognate receptors. Better knowledge on how physical/mechanical and multicellular microenvironment on the modulation of macrophage functions will create innovative therapies to boost host defense mechanism and assist wound healing. In this, we describe an easy method to measure functions (gene expressions) of human and mouse macrophages in response to mechanical microenvironment changes by embedding isolated macrophages in polymerized hyaluronan gel with different wound matrix stiffness.


Assuntos
Inflamação/terapia , Ativação de Macrófagos/genética , Biologia Molecular/métodos , Cicatrização/genética , Imunidade Adaptativa/genética , Animais , Citocinas/genética , Humanos , Ácido Hialurônico/farmacologia , Inflamação/genética , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Transdução de Sinais/genética , Cicatrização/fisiologia
5.
Front Immunol ; 11: 2147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983176

RESUMO

The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Imunidade Adaptativa/genética , Infecções por Coronavirus/virologia , Feminino , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/imunologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/genética , Masculino , Microbiota/imunologia , Pandemias , Pneumonia Viral/virologia , Fatores Sexuais
6.
Proc Natl Acad Sci U S A ; 117(40): 24964-24973, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958663

RESUMO

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Inflamação/genética , Vírus da Influenza A/genética , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Feminino , Feto/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Vírus da Influenza A/patogenicidade , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Glicoproteínas de Membrana/genética , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Placenta/irrigação sanguínea , Placenta/imunologia , Placenta/virologia , Gravidez , Linfócitos T/imunologia , Linfócitos T/virologia , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética
7.
Physiol Genomics ; 52(9): 401-407, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32809918

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1ß and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Perfilação da Expressão Gênica , Ocitocina/análogos & derivados , Pneumonia Viral/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Imunidade Adaptativa/genética , Betacoronavirus/imunologia , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Interações Hospedeiro-Patógeno , Humanos , Ocitocina/farmacologia , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Linfócitos T/imunologia , Linfócitos T/virologia , Transcriptoma
9.
J Autoimmun ; 114: 102506, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32563547

RESUMO

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.


Assuntos
Doenças Autoimunes/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Imunidade Adaptativa/genética , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Doenças Autoimunes/virologia , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Estado Terminal , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/virologia , Feminino , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Imunização Passiva/métodos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais
10.
Nat Immunol ; 21(5): 501-512, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284591

RESUMO

Protection from harmful pathogens depends on activation of the immune system, which relies on tight regulation of gene expression. Recently, the RNA modification N6-methyladenosine (m6A) has been found to play an essential role in such regulation. Here, we summarize newly discovered functions of m6A in controlling various aspects of immunity, including immune recognition, activation of innate and adaptive immune responses, and cell fate decisions. We then discuss some of the current challenges in the field and describe future directions for uncovering the immunological functions of m6A and its mechanisms of action.


Assuntos
Processamento Pós-Transcricional do RNA/imunologia , RNA/genética , Imunidade Adaptativa/genética , Adenosina/análogos & derivados , Adenosina/genética , Animais , Diferenciação Celular , Humanos , Sistema Imunitário , Imunidade Inata/genética , Imunomodulação
11.
Gene ; 745: 144636, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32244056

RESUMO

Since the discovery of the double helix and the introduction of genetic engineering, the possibility to develop new strategies to manipulate the genome has fascinated scientists around the world. Currently scientists have the knowledge andabilitytoedit the genomes. Several methodologies of gene editing have been established, all of them working like "scissor", creating double strand breaks at specific spots. The introduction of a new technology, which was adapted from the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas bacterial immune system, has revolutionized the genetic therapy field, as it allows a much more precise editing of gene than the previously described tools and, therefore, to prevent and treat disease in humans. This review aims to revisit the genome editing history that led to the rediscovery of the CRISPR/Cas technology and to explore the technical aspects, applications and perspectives of this fascinating, powerful, precise, simpler and cheaper technology in different fields.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Terapia Genética/métodos , Imunidade Adaptativa/genética , Animais , Bactérias/genética , Bactérias/imunologia , Sistemas CRISPR-Cas/imunologia , Contenção de Riscos Biológicos , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Modelos Animais de Doenças , Terapia Genética/efeitos adversos , Humanos , RNA Guia/genética
12.
PLoS One ; 15(4): e0231498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287290

RESUMO

The Polycomb group (PcG) proteins are chromatin factors underlying the process of transcriptional memory to preserve developmental decisions and keep cellular identities. However, not only developmental signals need to be memorized and thus maintained during the life of an organism. For host protection against pathogens, also a memory of previous exposures to an immunogenic stimulus is crucial to mount a more protective immune response upon re-exposure. The antigen-specific adaptive immunity in vertebrates is an example of such a memory to previous immunogenic stimulation. Recently, adaptive characteristics were also attributed to innate immunity, which was classically seen to lack memory. However, the mechanistic details of an adaptive innate immune response are yet to be fully understood and chromatin-based epigenetic mechanisms seem to play an important role in this phenomenon. Possibly, PcG proteins can contribute to such an epigenetic innate immune memory. In this study, we analyzed whether the PcG system can mediate a transcriptional memory of exposure to lipopolysaccharides (LPS). To this end, various forms of LPS pre-treatment were applied to reporter cells and expression kinetics of PcG target genes were analyzed after a second LPS exposure. Neither single nor multiple LPS pre-treatment affected the induction of endogenous LPS-responsive transcripts upon re-exposure. Altogether, our extensive analyses did not provide any evidence for a PcG system-mediated memory of LPS stimulation.


Assuntos
Memória Imunológica/genética , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Animais , Linhagem Celular , Cromatina/genética , Drosophila/imunologia , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Epigênese Genética/genética , Imunidade Inata/genética , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Lipopolissacarídeos/genética , Lipopolissacarídeos/imunologia , Proteínas do Grupo Polycomb/metabolismo
13.
Tissue Cell ; 63: 101320, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223948

RESUMO

Multipotent mesenchymal stromal cells (MSCs) are characterized by immunomodulatory properties along with the high proliferative and paracrine activity, as well as multilineage potency. The effects of MSCs on the T cell adaptive immunity are of a special interest. Low O2 level (1-7 %) is known to be typical for the putative site of the MSC - T cell interactions. A comparative evaluation of the effects of adipose tissue derived MSC (ASCs) on the mitogen-stimulated T cells at the ambient (20 %) and tissue-related (5 %) O2 levels demonstrated reduced T cell activation by the HLA-DR expression, decreased pro-inflammatory and increased anti-inflammatory cytokine production in co-culture, inhibited T cell proliferation, with the effects increased at hypoxia. T cell interactions with ASCs resulted in the up-regulation of PDCD1, Foxp3, and TGFß1 known to play an important role in the immune response suppression, and in the down-regulation of genes involved in the inflammatory reaction (IL2, IFNG). These changes were significantly increased under hypoxia. At the same time, neither ASCs nor the reduced O2 level had negative effects on the viability of T cells.


Assuntos
Imunidade Adaptativa/genética , Células-Tronco Mesenquimais/metabolismo , Oxigênio/metabolismo , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Adipócitos/imunologia , Adipócitos/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Comunicação Celular/genética , Hipóxia Celular/genética , Proliferação de Células/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Antígenos HLA-DR/genética , Humanos , Interferon gama/genética , Interleucina-2/genética , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Oxigênio/imunologia , Comunicação Parácrina/genética , Receptor de Morte Celular Programada 1/genética , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta1/genética
14.
PLoS One ; 15(4): e0226661, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240171

RESUMO

CD47 is an immune checkpoint protein that downregulates both the innate and adaptive anti-tumor immune response via its counter receptor SIRPα. Biologics, including humanized CD47 monoclonal antibodies and decoy SIRPα receptors, that block the SIRPα-CD47 interaction, are currently being developed as cancer immunotherapy agents. However, adverse side effects and limited penetration of tumor tissue associated with their structure and large size may impede their clinical application. We recently developed a quantitative high throughput screening assay platform to identify small molecules that disrupt the binding of SIRPα and CD47 as an alternative approach to these protein-based therapeutics. Here, we report on the development and optimization of a cell-based binding assay to validate active small molecules from our biochemical screening effort. This assay has a low volume, high capacity homogenous format that relies on laser scanning cytometry (LSC) and associated techniques to enhance signal to noise measurement of cell surface binding. The LSC assay is specific, concentration dependent, and validated for the two major human SIRPα variants (V1 and V2), with results that parallel those of our biochemical data as well as published studies. We also utilized the LSC assay to confirm published studies showing that the inhibition of amino-terminal pyroglutamate formation on CD47 using the glutaminyl cyclase inhibitor SEN177 disrupts SIRPα binding. The SIRPα-CD47 interaction could be quantitatively measured in live and fixed tumor cells. Use of fixed cells reduces the burden of cell maintenance and provides stable cell standards to control for inter- and intra-assay variations. We also demonstrate the utility of the assay to characterize the activity of the first reported small molecule antagonists of the SIRPα-CD47 interaction. This assay will support the screening of thousands of compounds to identify or validate active small molecules as hits, develop structure activity relationships and assist in the optimization of hits to leads by a typical iterative medicinal chemistry campaign.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Antígenos de Diferenciação/genética , Antígeno CD47/genética , Neoplasias/tratamento farmacológico , Receptores Imunológicos/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Imunidade Adaptativa/genética , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/química , Antígenos de Diferenciação/química , Antígeno CD47/química , Desenvolvimento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imunoterapia/métodos , Células Jurkat , Citometria de Varredura a Laser , Ligantes , Oncologia/tendências , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Fagocitose/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Receptores Imunológicos/química , Bibliotecas de Moléculas Pequenas/química
16.
Nat Rev Immunol ; 20(6): 375-388, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32132681

RESUMO

Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.


Assuntos
Imunidade Adaptativa/imunologia , Epigênese Genética/imunologia , Doenças do Sistema Imunitário/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Imunidade Adaptativa/genética , Animais , Humanos , Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/genética , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Memória Imunológica/genética , Inflamação/genética , Inflamação/imunologia
17.
Immunity ; 52(3): 557-570.e6, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32160523

RESUMO

The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Imunidade Adaptativa/genética , Animais , Citometria de Fluxo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Humanos , Imunidade nas Mucosas/genética , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Intestinos/ultraestrutura , Linfócitos/imunologia , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Varredura , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/ultraestrutura , Análise de Sequência de DNA
18.
Nat Med ; 26(4): 618-629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094927

RESUMO

Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.


Assuntos
Imunidade Adaptativa/genética , Formação de Anticorpos/genética , Vacinas contra Influenza/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transcriptoma , Vacina contra Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Vacinação , Febre Amarela/prevenção & controle , Adulto Jovem
19.
Int J Mol Sci ; 21(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075292

RESUMO

Dendritic cells (DCs) are antigen-presenting cells with a key role in immune responses. They act as a link between the innate and adaptive systems and they can induce and maintain immunologic tolerance. DCs are subdivided into conventional and plasmacytoid DCs. These cell subsets originate from the same bone marrow precursors and their differentiation process is determined by several extrinsic and intrinsic factors, such as cytokines, transcription factors, and miRNAs. miRNAs are small non-coding RNAs that play a crucial role in modulating physiological and pathological processes mediated by DCs. miRNA deregulation affects many inflammatory conditions and diseases. The aim of this review was to underline the importance of miRNAs in inflammatory processes mediated by DCs in physiological and pathological conditions and to highlight their potential application for future therapies.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/metabolismo , Inflamação/genética , MicroRNAs/genética , Imunidade Adaptativa/genética , Diferenciação Celular/genética , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Inflamação/imunologia , MicroRNAs/imunologia
20.
Gene ; 739: 144496, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32088242

RESUMO

Early larval developmental stages of fish are highly susceptible to opportunistic pathogens until the complete maturation of the lymphoid organs. Knowledge of the expression pattern of important markers of adaptive immune system during the ontogenetic development is essential before vaccinating the fish. In the present study, Pterophyllum scalare (angelfish) was taken to explore the relative expression profile of developmental markers of adaptive immunity, recombination activating gene-2 (RAG-2) and immunoglobulin M (IgM). The fishes were bred and early developmental stages (0-45 days post-hatched) were used to assess the expression profile. The genes, RAG-2 and IgM were cloned and sequenced with the base pair lengths of 1958 bp and 225 bp respectively. The mRNA expression of RAG-2 appeared at insignificant level at the first day of hatching, but the expression was significantly increased from 24 dph (days post-hatching) onwards and reached its peak at 27 dph. The results proved that the maturation of lymphoid organs was completed at 27 dph as the respective protein is involved in the V(D)J recombination, important for the maturation of lymphoid organs. A similar trend was also observed in the mRNA transcript levels of IgM gene and a significantly high expression was detected from 27 dph onwards. The present study suggested that the suitable time for vaccination in P. scalare could be taken at 27 dph, as the maturation and development of lymphoid organs is completed thus helps in stimulating the adaptive response of immunity against any pathogen.


Assuntos
Imunidade Adaptativa/genética , Ciclídeos/genética , Proteínas de Ligação a DNA/imunologia , Vacinação/veterinária , Animais , Ciclídeos/imunologia , Clonagem Molecular , Proteínas de Ligação a DNA/genética , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Rim/imunologia , Tecido Linfoide/imunologia , Baço/imunologia
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