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1.
Nat Med ; 25(10): 1576-1588, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591603

RESUMO

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4+ T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1ß signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.


Assuntos
Aterosclerose/imunologia , Interleucina-1beta/genética , Placa Aterosclerótica/metabolismo , Análise de Célula Única , Imunidade Adaptativa/genética , Idoso , Aterosclerose/genética , Aterosclerose/patologia , Diferenciação Celular/genética , Endarterectomia das Carótidas , Feminino , Humanos , Imunidade Inata/genética , Interleucina-1beta/imunologia , Leucócitos Mononucleares , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Proteoma/genética , Proteoma/imunologia , Transdução de Sinais/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
2.
Nat Commun ; 10(1): 4364, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554793

RESUMO

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.


Assuntos
Imunidade Adaptativa/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Síndromes de Imunodeficiência/imunologia , Inflamação/imunologia , Microbiota/imunologia , Imunidade Adaptativa/genética , Animais , Células Cultivadas , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
DNA Cell Biol ; 38(11): 1257-1268, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553224

RESUMO

Recent analyses suggest bacterial and/or mitochondrion-like ancestry for giant viruses (Megavirales sensu latu): amoeban mitochondrial gene arrangements resemble those of their candidate homologs in megaviral genomes. This presumed ancestral synteny decreases with genome size across megaviral families at large and within Poxviridae. In this study, analyses focus on Phycodnaviridae, a polyphyletic group of giant viruses infecting Haplophyta, Stramenopiles, and other algae, using syntenies between algal mitogene arrangements and chloroplast genomes and Rickettsia prowazekii as positive controls. Mitogene alignment qualities with Rickettsia are much higher than with viral genomes. Mitogenome synteny with some viruses is higher, for others lower than with Rickettsia, despite lower alignments qualities. In some algae, syntenies among cohosted chloroplast, virus, and mitochondrion are higher, in others lower than expected. This suggests gene order coevolution in cohosted genomes, different coregulations of organelle metabolisms for different algae, and viral mitogenome mimicry, to hijack organelle-committed cellular resources and/or escape cellular defenses/genetic immunity systems. This principle might explain high synteny between human mitochondria and the pathogenic endocellular alphaproteobacterium R. prowazekii beyond common ancestry. Results indicate that putative bacteria/mitochondrion-like genomic ancestors of Phycodnaviridae originated before or at the mitochondrion-bacteria split, and ulterior functional constraints on gene arrangements of cohosted genomes.


Assuntos
Cloroplastos/genética , Evolução Molecular , Mitocôndrias/genética , Mimetismo Molecular/fisiologia , Phycodnaviridae/genética , Sintenia/genética , Imunidade Adaptativa/genética , Genoma Mitocondrial/genética , Genoma Viral/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Evasão da Resposta Imune/genética , Organelas/genética , Filogenia , Análise de Sequência de DNA
4.
DNA Cell Biol ; 38(11): 1170-1177, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31502877

RESUMO

Host response to viral infection is a highly regulated process involving engagement of various host factors, cytokines, chemokines, and stimulatory signals that pave the way for an antiviral immune response. The response is manifested in terms of viral sequestration, phagocytosis, and inhibition of genome replication, and, finally, if required, lymphocyte-mediated clearance of virally infected cells. During this process, cross-talk between viral and host factors can shape disease outcomes and immunopathology. Bone marrow stromal antigen 2 (BST-2), also know as tetherin, is induced by type I interferon produced in response to viral infections, as well as in certain cancers. BST-2 has been shown to be a host restriction factor of virus multiplication through its ability to physically tether budding virions and restrict viral spread. However, BST-2 has other roles in the host antiviral response. This review focuses on the diverse functions of BST-2 and its downstream signaling pathways in regulating host immune responses.


Assuntos
Antígenos CD/fisiologia , Imunomodulação/genética , Vírion/imunologia , Vírion/metabolismo , Imunidade Adaptativa/genética , Animais , Antígenos CD/genética , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação/imunologia , Viroses/genética , Viroses/imunologia
5.
Fish Shellfish Immunol ; 93: 781-788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326588

RESUMO

Nile tilapia (Oreochromis niloticus) is a pivotal economic fish that has been plagued by Streptococcus infections. Tumor necrosis factor receptor-associated factor 5 (TRAF5) is a crucial adaptor molecule, which can trigger downstream signaling cascades involved in immune pathway. In this study, Nile tilapia TRAF5 coding sequence (named OnTRAF5) was obtained, which contained typical functional domains, such as RING, zinc finger, coiled-coil and MATH domain. Different from other TRAF molecules, OnTRAF5 had shown relatively low identify with its homolog, and it was clustered into other teleost TRAF5 proteins. qRT-PCR was used to analysis the expression level of OnTRAF5 in gill, skin, muscle, head kidney, heart, intestine, thymus, liver, spleen and brain, In healthy Nile tilapia, the expression level of OnTRAF5 in intestine, gill and spleen were significantly higher than other tissues. While under Streptococcus agalactiae infection, the expression level of OnTRAF5 was improved significantly in all detected organs. Additionally, over-expression WT OnTRAF5 activated NF-κB, deletion of RING or zinc finger caused the activity impaired. In conclusion, OnTRAF5 participate in anti-bacteria immune response and is crucial for the signaling transduction.


Assuntos
Imunidade Adaptativa/genética , Ciclídeos/genética , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Fator 5 Associado a Receptor de TNF/genética , Sequência de Aminoácidos , Animais , Ciclídeos/imunologia , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Filogenia , Alinhamento de Sequência/veterinária , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/fisiologia , Fator 5 Associado a Receptor de TNF/química , Fator 5 Associado a Receptor de TNF/imunologia
6.
Microbiol Immunol ; 63(9): 379-391, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310013

RESUMO

The immune system with large number of molecules protects the host against a plethora of continuously evolving microbes. Major histocompatibility complex (MHC) molecules serve as cardinal elements of the adaptive immune system responsible for the activation of the adaptive immunity in the host. The present study reports MHCI molecule in freshwater carp, Catla catla, and its differential expression in immunologically relevant tissues post-infection with Gram-negative and Gram-positive bacteria. The MHCI sequence of C. catla had 502 bp nucleotides encoding putative 146 amino acids. The phylogenetic analysis exhibited its evolutionary conservation within the Cyprinidae family and formed a different clade with the higher vertebrates. Simultaneously, CXCR3 and CXCR4 chemokines were cloned and characterized for their expression in infected tissues. Analysis of immunologically relevant tissues of the infected fish exhibited an increase of MHCI gene expression and the down-regulation of CXCR3 and CXCR4 chemokines, indicating a tricky interaction between the innate and adaptive immune system. It was found that intestine, skin and spleen played a crucial role in the contribution of the defense activity which instigated the self-immunity. These immune activities can provide useful information to understand the interaction of self and non-self- immune system in freshwater fish, Catla catla.


Assuntos
Carpas/genética , Quimiocinas/genética , Clonagem Molecular/métodos , Cyprinidae/genética , Genes MHC Classe I/genética , Receptores CXCR3/genética , Receptores CXCR4/genética , Imunidade Adaptativa/genética , Sequência de Aminoácidos , Animais , Carpas/imunologia , Cyprinidae/imunologia , Regulação para Baixo , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Água Doce , Expressão Gênica , Filogenia , Alinhamento de Sequência , Pele/imunologia , Baço/imunologia
7.
Nat Commun ; 10(1): 3001, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278272

RESUMO

Type III-A CRISPR-Cas systems are prokaryotic RNA-guided adaptive immune systems that use a protein-RNA complex, Csm, for transcription-dependent immunity against foreign DNA. Csm can cleave RNA and single-stranded DNA (ssDNA), but whether it targets one or both nucleic acids during transcription elongation is unknown. Here, we show that binding of a Thermus thermophilus (T. thermophilus) Csm (TthCsm) to a nascent transcript in a transcription elongation complex (TEC) promotes tethering but not direct contact of TthCsm with RNA polymerase (RNAP). Biochemical experiments show that both TthCsm and Staphylococcus epidermidis (S. epidermidis) Csm (SepCsm) cleave RNA transcripts, but not ssDNA, at the transcription bubble. Taken together, these results suggest that Type III systems primarily target transcripts, instead of unwound ssDNA in TECs, for immunity against double-stranded DNA (dsDNA) phages and plasmids. This reveals similarities between Csm and eukaryotic RNA interference, which also uses RNA-guided RNA targeting to silence actively transcribed genes.


Assuntos
Imunidade Adaptativa/genética , Sistemas CRISPR-Cas/genética , Staphylococcus epidermidis/genética , Thermus thermophilus/genética , Elongação da Transcrição Genética/imunologia , Bacteriófagos/imunologia , Sistemas CRISPR-Cas/imunologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/imunologia , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/imunologia , DNA de Cadeia Simples/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , Plasmídeos/imunologia , RNA Guia/genética , RNA Guia/imunologia , RNA Guia/metabolismo , Staphylococcus epidermidis/imunologia , Thermus thermophilus/imunologia
8.
Immunol Allergy Clin North Am ; 39(3): 309-319, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284922

RESUMO

The infant's developing immune response is central to establishing a balanced system that reacts appropriately to infectious stimuli, but does not induce altered disease states with potential long-term sequelae. Respiratory syncytial virus may alter the immune system, affecting future responses. Early infection may have direct effects on the lung itself. Other early life processes contribute to the development of immune responses including assembly of the microbiome, which seems to have a particularly important role for establishing the immune environment. This review covers studies that have set up important paradigms and discusses recent data that direct research toward informative hypotheses.


Assuntos
Asma/etiologia , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios , Imunidade Adaptativa/genética , Fatores Etários , Animais , Asma/epidemiologia , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade Inata/genética , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia
9.
PLoS Biol ; 17(6): e3000314, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194732

RESUMO

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR-disease associations. We present Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE), a statistical approach that identifies TCR sequences actively involved in current immune responses from a single RepSeq sample and apply it to repertoires of patients with a variety of disorders - patients with autoimmune disease (ankylosing spondylitis [AS]), under cancer immunotherapy, or subject to an acute infection (live yellow fever [YF] vaccine). We validate the method with independent assays. ALICE requires no longitudinal data collection nor large cohorts, and it is directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.


Assuntos
Imunidade Adaptativa/genética , Regiões Determinantes de Complementaridade/genética , Receptores de Antígenos de Linfócitos T/fisiologia , Análise de Sequência de DNA/métodos , Antígenos , Antígenos Virais , Análise por Conglomerados , Regiões Determinantes de Complementaridade/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunoterapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
10.
BMC Immunol ; 20(1): 18, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164097

RESUMO

BACKGROUND: Mouse models have been extremely valuable in identifying the fundamental mechanisms of airway inflammation that underlie human allergic asthma. Several models are commonly used, employing different methods and routes of sensitisation, and allergens of varying clinical relevance. Although all models elicit similar hallmarks of allergic airway inflammation, including airway eosinophilia, goblet cell hyperplasia and cellular infiltration in lung, it is not established whether they do so by involving the same mechanisms. RESULTS: We compared the impact of inactivation of various innate or adaptive immune genes, as well as sex, in different models of allergic airway inflammation in mice of C57BL/6 background. Chicken ovalbumin (OVA) and house dust mite (HDM) were used as allergens in settings of single or multiple intranasal (i.n.) challenges, after sensitisation in adjuvant or in adjuvant-free conditions. Eosinophil numbers in the broncho-alveolar lavage and lung histopathology were assessed in each model. We found that Major Histocompatibility Complex Class II (MHCII) deficiency and lack of conventional CD4+ T cells had the most profound effect, essentially ablating airway eosinophilia and goblet cell hyperplasia in all models. In contrast, Thymic stromal lymphopoietin receptor (TSLPR) deficiency greatly reduced eosinophilia but had a variable effect on goblet cells. CD1d deficiency and lack of Natural Killer T (NKT) cells moderately impaired inflammation in OVA models but not HDM, whereas sex affected the response to HDM but not OVA. Lastly, defective Toll-like receptor (TLR)4 expression had only a relatively modest overall impact on inflammation. CONCLUSION: All the models studied were comparably dependent on adaptive CD4+ T cell responses and TSLP. In contrast, sex, NKT cells and TLR4 appeared to play subtler and more variable roles that were dependent on the type of allergen and mode of immunization and challenge. These results are consistent with clinical data suggesting a key role of CD4+ T cells and TSLP in patients with allergic asthma.


Assuntos
Alérgenos/imunologia , Eosinofilia/imunologia , Células Caliciformes/patologia , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa/genética , Adjuvantes Imunológicos , Animais , Antígenos de Dermatophagoides/imunologia , Feminino , Humanos , Imunidade Inata/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Ovalbumina/imunologia
11.
Fish Shellfish Immunol ; 92: 536-551, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247320

RESUMO

Phytic acid (PA) is one of the most common anti-nutritional factors in plant-derived protein feeds, and it poses considerable threats to aquaculture production. However, little is known about the effects of PA on fish intestinal health. This study aimed to investigate the impacts of PA on intestinal immune function in on-growing grass carp. To achieve this goal, a growth trial was conducted for 60 days by feeding 540 fish (120.56 ±â€¯0.51 g) with six semi-purified diets containing graded levels of PA (0, 0.8, 1.6, 2.4, 3.2 and 4.0%). Then fish were challenged with Aeromonas hydrophila for 6 days. The results indicated that, compared with the control group (0% PA), PA did the following: (1) suppressed fish growth performance (percentage weight gain and feed efficiency) and reduced their ability to resist enteritis; (2) decreased fish intestinal antimicrobial ability by reducing intestinal lysozyme (LZ) activities, the contents of complement 3 (C3), C4 and immunoglobulin M (IgM), and downregulating the mRNA levels of hepcidin, liver-expressed antimicrobial peptide 2A (LEAP-2A), LEAP-2B, and ß-defensin-1; and (3) aggravated fish intestinal inflammation responses by upregulating the mRNA levels of pro-inflammatory cytokines including tumour necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) (except in the DI), interferon γ2 (IFN-γ2), IL-8, IL-12p40, IL-15 (except in the DI) and IL-17D, which is partly related to the nuclear factor kappa B (NF-κB) signalling pathway, whereas downregulating the mRNA levels of anti-inflammatory cytokines including transforming growth factor ß1 (TGF-ß1), IL-4/13A, IL-4/13B, IL-10 and IL-11, which is partially associated with the target of rapamycin (TOR) signalling pathway. The possible reasons for some distinctive gene expression patterns in fish three intestinal segments were discussed. Finally, based on the percent weight gain, enteritis morbidity, IgM content and LZ activity in the PI, the maximum tolerance levels of PA for on-growing grass carp were estimated to be 2.17, 1.68, 1.47 and 1.18% of the diet, respectively.


Assuntos
Imunidade Adaptativa/genética , Carpas/crescimento & desenvolvimento , Carpas/imunologia , Doenças dos Peixes/imunologia , Imunidade Inata/genética , Intestinos/imunologia , Ácido Fítico/metabolismo , Aeromonas hydrophila/fisiologia , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Infecções por Bactérias Gram-Negativas/imunologia , Ácido Fítico/administração & dosagem , Distribuição Aleatória
12.
Dig Dis Sci ; 64(7): 1759-1769, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073736

RESUMO

Crohn's disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their 'westernization', as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Interação Gene-Ambiente , Variação Genética , Imunidade Adaptativa/genética , Animais , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Fenótipo , Fatores de Risco
13.
BMC Genomics ; 20(1): 432, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138127

RESUMO

BACKGROUND: Accompanied with rapid growth and high density aquaculture, gibel carp has been seriously threatened by Carassius auratus herpesvirus (CaHV) since 2012. In previous study, distinct CaHV resistances and immune responses were revealed in the diseased individuals of three gibel carp gynogenetic clones (A+, F and H). However, little is known about the gene expression changes in the survivors after CaHV challenge, particularly their differences of innate and adaptive immune system between susceptible clone and resistant clone. RESULTS: We firstly confirmed the CaHV carrier state in the survivors of three gibel carp clones after CaHV challenge by evaluating the abundances of five CaHV genes. The assay of viral loads indicated the resistant clone H possessed not only stronger resistance but also higher tolerance to CaHV. Then, 2818, 4047 and 3323 differentially expressed unigenes (DEUs) were screened from the head-kidney transcriptome profiles of survivors compared with controls from clone A+, F and H. GO and KEGG analysis suggested that a persistent immune response might sustain in resistant clone H and F, while susceptible clone A+ had a long-term impact on the circulatory system which was consistent with the major symptoms of bleeding caused by CaHV. Among the top 30 enriched pathways of specifically up-regulated DEUs in respective clones, 26, 7 and 15 pathways in clone H, F and A+ were associated with infections, diseases, or immune-related pathways respectively. In addition, 20 pathways in clone F belonged to "metabolism" or "biogenesis", and 7 pathways involved in "circulatory system" were enriched in clone A+. Significantly, we revealed the differential expression changes of IFN system genes and immunoglobulin (Ig) genes among the survivors of three clones. Finally, myosins and Igs were identified as co-expression modules which were positively or negatively correlated to CaHV viral loads respectively. CONCLUSIONS: Our results revealed the common and distinct gene expression changes in immune and circulatory system in the survivors of three gibel carp gynogenetic clones with different CaHV resistances. The current study represents a paradigm of differential innate and adaptive immune reactions in teleost, and will be beneficial to the disease-resistance breeding of gibel carp.


Assuntos
Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Infecções por Herpesviridae/veterinária , Imunidade Adaptativa/genética , Animais , Carpas/metabolismo , Carpas/virologia , Doenças dos Peixes/genética , Doenças dos Peixes/metabolismo , Genes de Imunoglobulinas , Herpesviridae , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Imunidade Inata/genética , Interferons/metabolismo , Miosinas/genética , Transdução de Sinais
15.
Scand J Immunol ; 90(2): e12776, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069824

RESUMO

The number of the X chromosome-linked genes has been previously suggested to influence immune responses and the development of autoimmune diseases. In the present study, we aimed at evaluating the level of expression of CD40L (an X-linked gene involved in adaptive immunity) and TLR7 (an X-linked gene involved in innate immunity) in a variety of different karyotypes. Those included males, females and patients with X chromosome aneuploidy. Healthy females (46, XX; n = 10) and healthy males (46, XY; n = 10) were compared to females with Turner syndrome (TS) (45, X; n = 11) and males with Klinefelter syndrome (KS) (47, XXY; n = 5). Stimulation of peripheral blood mononuclear cells (PBMCs) with PMA and ionomycin resulted in higher percentage of CD3 + CD40L+ T cells (P < 0.001) and higher level expression of CD40L in T cell (P < 0.001) in female and KS patients compared with male and TS patients. TLR7-mediated IFN-alpha production by HLADR + CD3- CD19- cells was significantly upregulated in healthy women compared with healthy males, TS and KS patients (P < 0.001). TLR7 agonist-stimulated PBMCs from healthy females and KS patients expressed significantly higher levels of TLR7 mRNA than those from male and TS patients (P < 0.05). The increased expression of the X-linked genes TLR7 and CD40L in healthy females and KS patients suggests that the presence of two X chromosomes plays a major role in enhancing both innate and adaptive immune responses. These results may contribute to the explanation of sex-based differences in immune biology and the sex bias in predisposition to autoimmune diseases.


Assuntos
Imunidade Adaptativa/genética , Ligante de CD40/biossíntese , Ligante de CD40/genética , Cromossomos Humanos X/genética , Dosagem de Genes/genética , Imunidade Inata/genética , Receptor 7 Toll-Like/biossíntese , Receptor 7 Toll-Like/genética , Imunidade Adaptativa/imunologia , Antígenos CD19/biossíntese , Complexo CD3/biossíntese , Células Cultivadas , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Imunidade Inata/imunologia , Interferon-alfa/biossíntese , Ionomicina/farmacologia , Síndrome de Klinefelter/genética , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Ácidos Polimetacrílicos/farmacologia , RNA Mensageiro/biossíntese , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Síndrome de Turner/genética
16.
Vet Parasitol ; 269: 34-41, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31079826

RESUMO

The outcome of infection with Leishmania infantum in dogs is variable, which is thought to be due to the nature of the immune response mounted by the host. As a consequence, the clinical signs and severity of canine leishmaniosis vary between individual dogs. Host immunogenetic factors might play an important role in determining the outcome of infection. The aim of this study was to examine polymorphisms in innate and adaptive immune response genes, to determine whether any of these were associated with susceptibility or resistance to L. infantum infection. Genomic DNA was obtained from two groups: pet dogs in endemic regions of Europe and a group of Beagles exposed to sand fly infection as part of a vaccine study. Genotyping was performed using a SNP (single nucleotide polymorphism) array for selected immune response genes. The first part of the study compared 62 clinical cases with 101 clinically unaffected dogs that were seronegative for Leishmania antibodies. One SNP in the CIITA gene demonstrated a significantly higher minor allele frequency in the case group, compared with the control group at the individual SNP level after permutation, but was not significant after correction for multiple testing. The second part of the study examined 48 Beagle dogs exposed to L. infantum over two transmission seasons. Twenty-seven dogs with a resistant phenotype (no evidence of clinical disease, seronegative at the end of the study period, negative on lymph node culture and only transiently PCR positive in bone marrow) were compared with 21 dogs demonstrating a susceptible phenotype (clinical disease, seropositive, positive lymph node culture and consistently PCR positive in bone marrow). Three SNPs in TLR3, two SNPs in PTPN22 and one SNP in TLR4 and IL1A were associated with the susceptible phenotype in the Beagle group at the individual SNP level after permutation analysis, but were not significant after correction for multiple testing. Further validation of these SNPs is required in a larger cohort of dogs, ideally with extreme phenotypes to confirm an association with the outcome of L. infantum infection.


Assuntos
Resistência à Doença/genética , Doenças do Cão/imunologia , Leishmania infantum/imunologia , Leishmaniose/veterinária , Polimorfismo de Nucleotídeo Único/genética , Psychodidae/parasitologia , Imunidade Adaptativa/genética , Animais , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Doenças Endêmicas/veterinária , Europa (Continente)/epidemiologia , Imunidade Inata/genética , Leishmania infantum/genética , Leishmaniose/epidemiologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Reação em Cadeia da Polimerase/veterinária
17.
Fish Shellfish Immunol ; 92: 151-164, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31108176

RESUMO

IL-12 is an important cytokine that connects the innate and adaptive immune systems. The complete gene structure of olive flounder IL-12 and its characteristics have not yet been formally reported. Here, we report the complete sequences of both subunits of olive flounder IL-12 (IL-12p35 and IL-12p40). In addition, its function was analyzed by generating the single-chain rIL-12 of which subunits were fused by a GS linker and the rIL-12-specific mouse antibody. The cDNA sequences of IL-12p35 and IL-12p40 were 1059 nucleotides and 1319 nucleotides, respectively. The analyses of their gene structures, deduced amino acid sequences, protein model structures, and phylogenetic trees confirmed the accurate identification of olive flounder IL-12. The protein structure model suggested that an inter-subunit disulfide bond might be formed between the Cys177 of p35 and Cys74 of p40 to link the subunits. Olive flounder expressed IL-12p40 at higher levels than IL-12p35 in the various tissues under natural conditions although both expression levels were low. However, when infected by Edwardsiella tarda or stimulated by LPS, the flounder expressed both of the subunit genes at similar maximized levels in 6 h and gradually reduced thereafter. Olive flounder PBMC induced with the rIL-12 increased IFN-γ and TNF-α expression but decreased IL-10 expression as did treatment with LPS. However, when the LPS-treated PBMC were neutralized with the rIL-12-specific antibody, the pattern of cytokine expression was precisely reversed. In conclusion, we have formally identified the gene structure and function of olive flounder IL-12.


Assuntos
Imunidade Adaptativa/genética , Doenças dos Peixes/imunologia , Linguados/genética , Linguados/imunologia , Imunidade Inata/genética , Interleucina-12/genética , Interleucina-12/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Edwardsiella tarda/fisiologia , Infecções por Enterobacteriaceae/imunologia , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Linguado/genética , Linguado/imunologia , Perfilação da Expressão Gênica/veterinária , Interleucina-12/química , Lipopolissacarídeos/farmacologia , Filogenia , Alinhamento de Sequência/veterinária
18.
PLoS Comput Biol ; 15(5): e1007015, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095555

RESUMO

MHC genes, which code for proteins responsible for presenting pathogen-derived antigens to the host immune system, show remarkable copy-number variation both between and within species. However, the evolutionary forces driving this variation are poorly understood. Here, we use computer simulations to investigate whether evolution of the number of MHC variants in the genome can be shaped by the number of pathogen species the host population encounters (pathogen richness). Our model assumed that while increasing a range of pathogens recognised, expressing additional MHC variants also incurs costs such as an increased risk of autoimmunity. We found that pathogen richness selected for high MHC copy number only when the costs were low. Furthermore, the shape of the association was modified by the rate of pathogen evolution, with faster pathogen mutation rates selecting for increased host MHC copy number, but only when pathogen richness was low to moderate. Thus, taking into account factors other than pathogen richness may help explain wide variation between vertebrate species in the number of MHC genes. Within population, variation in the number of unique MHC variants carried by individuals (INV) was observed under most parameter combinations, except at low pathogen richness. This variance gave rise to positive correlations between INV and host immunocompetence (proportion of pathogens recognised). However, within-population variation in host immunocompetence declined with pathogen richness. Thus, counterintuitively, pathogens can contribute more to genetic variance for host fitness in species exposed to fewer pathogen species, with consequences to predictions from "Hamilton-Zuk" theory of sexual selection.


Assuntos
Evolução Molecular , Dosagem de Genes , Complexo Principal de Histocompatibilidade , Imunidade Adaptativa/genética , Alelos , Animais , Apresentação do Antígeno/genética , Biologia Computacional , Simulação por Computador , Variação Genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Modelos Genéticos , Modelos Imunológicos , Mutação , Seleção Genética
19.
Medicine (Baltimore) ; 98(21): e15774, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124967

RESUMO

BACKGROUND: Melanoma-associated antigen-A (MAGE-A) was recognized as high-expressed in many solid tumors including esophageal carcinoma (EC), nevertheless, was reported to be low/not-expressed in normal tissues. Thus, it was considered as an extraordinary appropriate target for treatment especially in immunotherapy. Therefore, it demanded more detail knowledge on the precise function of MAGE-A. METHODS: In this study, we used the data from the Cancer Genome Atlas dataset (TCGA-ESCA) to analyze the expression and survival for MAGE A3/4/11 (the subtype of MAGE-A) using the online tool of UALCAN. Furthermore, the high-throughput sequencing data of the patients with esophageal squamous-cell carcinoma (ESCC) from TCGA dataset were performed to analyze the correlation test, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of MAGE A3/4/9/11 using LinkeDomics (online tool) and ClueGO (inner software of Cytoscape). Finally, relative gene expressions of MAGE A3/4/9/11 were verified by quantitative real-time PCR (q-PCR) in the patients with EC. RESULTS: MAGE A3/4/11 was high-expressed in tissues of patients with ESCC, and there was no difference in survival time for patients between the high-expressed with the low/medium-expressed. The Go enrichment analysis showed that the 4 MAGE-A subtypes (MAGE-A3/4/9/11) were enriched in the regulation of the adaptive immune response, translational initiation, interleukin-4 production, response to type I interferon, and skin development, respectively. The KEGG results showed that they were enriched in T cell receptor signaling pathway (MAGE-A3), Th1 and Th2 differentiation, antigen processing and presentation (MAGE-A4), cytokine-cytokine receptor interaction (MAGE-A9), and chemokine signaling pathway (MAGE-A11). CONCLUSION: MAGE A3/4/9/11 was high-expressed in EC, and were enrolled in the regulation of immune response. They may consider as candidate immune target for EC treatment and provided the messages for further research in the function of MAGE-A.


Assuntos
Antígenos de Neoplasias/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas de Neoplasias/genética , Imunidade Adaptativa/genética , Idoso , Antígenos de Neoplasias/imunologia , Biologia Computacional , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Esôfago/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Células Th1/imunologia , Células Th2/imunologia
20.
World J Gastroenterol ; 25(18): 2177-2187, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31143069

RESUMO

The molecular scalpel of clustered regularly interspersed short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology may be sharp enough to begin cutting the genes implicated in inflammatory bowel disease (IBD) and consequently decrease the 6.3 billion dollar annual financial healthcare burden in the treatment of IBD. For the past few years CRISPR technology has drastically revolutionized DNA engineering and biomedical research field. We are beginning to see its application in gene manipulation of sickle cell disease, human immunodeficiency virus resistant embryologic twin gene modification and IBD genes such as Gatm (Glycine amidinotransferase, mitochondrial), nucleotide-binding oligomerization domain-containing protein 2, KRT12 and other genes implicated in adaptive immune convergence pathways have been subjected to gene editing, however there are very few publications. Furthermore, since Crohn's disease and ulcerative colitis have shared disease susceptibility and share genetic gene profile, it is paramount and is more advantageous to use CRISPR technology to maximize impact. Although, currently CRISPR does have its limitations due to limited number of specific Cas enzymes, off-target activity, protospacer adjacent motifs and crossfire between different target sites. However, these limitations have given researchers further insight on how to augment and manipulate enzymes to enable precise gene excision and limit crossfire between target sites.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Terapia Genética/métodos , Doenças Inflamatórias Intestinais/terapia , Imunidade Adaptativa/genética , Edição de Genes/tendências , Terapia Genética/tendências , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia
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