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1.
Parasitol Res ; 119(1): 203-214, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31845020

RESUMO

Infection with helminth parasites or the administration of their antigens can prevent or attenuate autoimmune diseases. To date, the specific molecules that prime the amelioration are only limited. In this study, recombinant Schistosoma japonicum cystatin (rSjcystatin) and fructose-1,6-bisphosphate aldolase (rSjFBPA) were administered to female NOD mice via intraperitoneal (i.p.) injection to characterize the immunological response by the recombinant proteins. We have shown that the administration of rSjcystatin or rSjFBPA significantly reduced the diabetes incidence and ameliorated the severity of type 1 diabetes mellitus (T1DM). Disease attenuation was associated with suppressed interferon-gamma (IFN-γ) production in autoreactive T cells and with a switch to the production of Th2 cytokines. Following rSjcystatin or rSjFBPA injection, regulatory T cells (Tregs) were remarkably increased, which was accompanied by increased expression of interleukin-10 (IL-10) and transforming growth factor beta (TGF-ß). Our study suggests that helminth-derived proteins may be useful in strategies to limit pathology by promoting the Th2 response and upregulating Tregs during the inflammatory tissue-damage process in T1DM.


Assuntos
Cistatinas/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Frutose-Bifosfato Aldolase/administração & dosagem , Proteínas de Helminto/administração & dosagem , Fatores Imunológicos/administração & dosagem , Schistosoma japonicum/enzimologia , Animais , Cistatinas/genética , Cistatinas/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Feminino , Frutose-Bifosfato Aldolase/genética , Frutose-Bifosfato Aldolase/metabolismo , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia
2.
Elife ; 82019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478832

RESUMO

Genetic polymorphism in the interferon lambda (IFN-λ) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to interferon-based treatment. Here, we evaluate associations between IFN-λ polymorphism and HCV variation in 8729 patients (Europeans 77%, Asians 13%, Africans 8%) infected with various viral genotypes, predominantly 1a (41%), 1b (22%) and 3a (21%). We searched for associations between rs12979860 genotype and variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations in all tested proteins, including in the interferon-sensitivity determining region of NS5A. We also assessed the combined impact of human and HCV variation on pretreatment viral load and report amino acids associated with both IFN-λ polymorphism and HCV load across multiple viral genotypes. By demonstrating that IFN-λ variation leaves a large footprint on the viral proteome, we provide evidence of pervasive viral adaptation to innate immune pressure during chronic HCV infection.


Assuntos
Adaptação Biológica , Hepacivirus/genética , Hepatite C/imunologia , Hepatite C/virologia , Fatores Imunológicos/genética , Interferons/genética , Proteínas não Estruturais Virais/genética , África , Ásia , Europa (Continente) , Genótipo , Humanos , Carga Viral
3.
Appl Microbiol Biotechnol ; 103(19): 7931-7941, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456001

RESUMO

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD) characterized by superficial mucosal inflammation, rectal bleeding, diarrhea, and abdominal pain. Anti-inflammatory and immunosuppressive drugs have been used in the therapy of human UC. Interleukin (IL)-35, which functions as an anti-inflammatory cytokine, has been shown to play a potential therapeutic role in a UC-like mouse colitis induced by dextran sodium sulfate (DSS). However, the contribution of IL-35 via oral administration to colitis prevention has not been determined. In order to explore its preventative potentiality, a dairy Lactococcus lactis NZ9000 strain was engineered to express murine IL-35 (NZ9000/IL-35), and this recombinant bacteria was applied to prevent and limit the development of DSS-induced mouse colitis. We found that oral administration of NZ9000/IL-35 induced the accumulation of IL-35 in the gut lumen of normal mice. When administrated preventatively, NZ9000/IL-35-gavaged mice exhibited decreased weight loss, DAI score, colon shortening as well as colitis-associated histopathological changes in colon, indicating that the oral administration of NZ9000/35 contributed to the suppression of DSS-induced colitis progression. Moreover, much less Th17 cells and higher level of Treg cells in lamina propria, as well as increased colon and serum levels of IL-10 with a concomitant reduced pro-inflammatory cytokines, IL-6, IL-17A, IFN-γ, and TNF-α were apparently regulated by NZ9000/IL-35 in colitis mice. Together, we put forward direct evidence pinpointing the effectiveness of NZ9000/IL-35 in preventing UC-like mouse colitis, implying a potential candidate of this recombinant Lactococcus lactis that prevent the progression of IBD.


Assuntos
Colite Ulcerativa/prevenção & controle , Fatores Imunológicos/metabolismo , Interleucinas/metabolismo , Lactococcus lactis/metabolismo , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fatores Imunológicos/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Lactococcus lactis/genética , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Resultado do Tratamento
4.
Artigo em Inglês | MEDLINE | ID: mdl-31293981

RESUMO

The M3 protein (M3) encoded by murine gammaherpesvirus 68 (MHV-68) is a unique viral immunomodulator with a high-affinity for a broad spectrum of chemokines, key mediators responsible for the migration of immune cells to sites of inflammation. M3 is currently being studied as a very attractive and desirable tool for blocking the chemokine signaling involved in some inflammatory diseases and cancers. In this study, we elucidated the role of M3 residues E70 and T272 in binding to chemokines by examining the effects of the E70A and T272G mutations on the ability of recombinant M3, prepared in Escherichia coli cells, to bind the human chemokines CCL5 and CXCL8. We found that the E70A mutation enhanced binding of M3 to CCL5 two-fold but had little effect on its binding to CXCL8. In contrast, the T272G mutation was found to be important for the thermal stability of M3 and significantly decreased M3's binding to both CCL5 (by about 4×) and CXCL8 (by about 5×). We also constructed in silico models of the wild-type M3-CCL5 and M3-CCL8 complexes and found substantial differences in their physical and chemical properties. M3 models with single mutation E70A and T272G suggested the role of E70 and T272 in binding M3 protein to chemokines. In sum, we have confirmed that site-directed mutagenesis could be an effective tool for modulating the blockade of particular chemokines by M3, as desired in therapeutic treatments for severe inflammatory illnesses arising from chemokine network dysregulation.


Assuntos
Quimiocinas/metabolismo , Mutação , Ligação Proteica , Rhadinovirus/genética , Proteínas Virais/genética , Proteínas Virais/imunologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Quimiocina CCL5/metabolismo , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/imunologia , Interleucina-8 , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Virais/química
5.
Biomed Res Int ; 2019: 8103142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312661

RESUMO

Neoantigens are optimal tumor-specific targets for T-cell based immunotherapy, especially for patients with "undruggable" mutated driver genes. T-cell immunotherapy can be a "universal" treatment for HLA genotype patients sharing same oncogenic mutations. To identify potential neoantigens for therapy in gastric cancer, 32 gastric cancer patients were enrolled in our study. Whole exome sequencing data from these patients was processed by TSNAD software to detect cancer somatic mutations and predict neoantigens. The somatic mutations between different patients suggested a high interpatient heterogeneity. C>A and C>T substitutions are common, suggesting an active nucleotide excision repair. The number of predicted neoantigens was significantly higher in patients at stage T1a compared to in patients at T2 or T4b. Six genes (PIK3CA, FAT4, BRCA2, GNAQ, LRP1B, and PREX2) were found as recurrently mutated driver genes in our study. Combining with highly frequent HLA alleles, several neoantigens derived from six recurrently mutated genes were considered as potential targets for further immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Medicina de Precisão , Neoplasias Gástricas/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/isolamento & purificação , Antígenos de Neoplasias/uso terapêutico , Bases de Dados Genéticas , Exoma/genética , Exoma/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/uso terapêutico , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
6.
J Cancer Res Clin Oncol ; 145(8): 2013-2025, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177386

RESUMO

PURPOSE: FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women. METHODS: HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case-control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data. RESULTS: The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (ORAj: 0.60; 95% CI 0.36-0.99; p = 0.049) and was an independent predictor of protection against HSIL development (ORAdj: 0.28; 95% CI 0.11-0.68; p = 0.006). In addition, the homozygous genotype (G/G) of the rs2232365 variants (related to increased FOXP3 expression) was independently associated with the HPV infection (ORAdj: 2.10; 95% CI 1.06-4.15; p = 0.033). Haplotype analysis revealed no significant associations in our study. CONCLUSIONS: Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management.


Assuntos
Fatores de Transcrição Forkhead/genética , Fatores Imunológicos/genética , Infecções por Papillomavirus/diagnóstico , Polimorfismo de Nucleotídeo Único , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Adulto , Brasil , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/diagnóstico , Neoplasia Intraepitelial Cervical/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Papillomaviridae/imunologia , Infecções por Papillomavirus/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prognóstico , Fatores de Risco , Lesões Intraepiteliais Escamosas Cervicais/genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Adulto Jovem
7.
Arch Oral Biol ; 103: 55-61, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31136880

RESUMO

OBJECTIVE: The aim of this study was to investigate the effects of Candida albicans on the production of defense effector molecules by human oral mucosal epithelial cells in vitro. DESIGN: Immortalized human oral mucosal epithelial (Leuk-1) cells and C. albicans strain 5314 were cocultured at different cell-to-C. albicans ratios. The viability of Leuk-1 cells was determined by MTT and RTCA measurements. The secretory levels of multiple defense effector molecules were determined by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results indicated that C. albicans significantly decreased the secretion of IgG, cystatin C, lactoferrin, and TGF-ß1 in a dose-dependent manner and remarkably reduced the production of IgA independent of the cell-to-C. albicans ratio. However, C. albicans clearly enhanced the secretion of IgM, galectin-3, P-selectin, granzyme B and perforin. CONCLUSION: These results suggest that C. albicans may exert a regulatory role in the defense response of oral mucosal epithelial cells by altering secretory levels of defense effector molecules.


Assuntos
Candida albicans/imunologia , Candidíase , Imunidade nas Mucosas/genética , Imunidade nas Mucosas/fisiologia , Fatores Imunológicos/genética , Técnicas de Cocultura , Células Epiteliais , Humanos , Mucosa Bucal
8.
J Microbiol Biotechnol ; 29(6): 863-876, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31091863

RESUMO

Farm animals such as piglets are often affected by environmental stress, which can disturb the gut ecosystem. Antibiotics were commonly used to prevent diarrhea in weaned piglets, but this was banned by the European Union due to the development of antibiotic resistance. However, the use of probiotics instead of antibiotics may reduce the risk posed by pathogenic microorganisms and reduce the incidence of gastrointestinal diseases. Therefore, this study was conducted to investigate the effects of Lactobacillus casei Zhang on the mechanical barrier and immune function of early-weaned piglets infected using Escherichia coli K88 based on histomorphology and immunology. Fourteen-day-old weaned piglets were divided into a control group and experimental groups that were fed L. casei Zhang and infected with E. coli K88 with or without prefeeding and/or postfeeding of L. casei Zhang. The L. casei Zhang dose used was 107 CFU/g diet. Jejunum segments were obtained before histological, immunohistochemical, and western blot analyses were performed. In addition, the relative mRNA expression of toll receptors and cytokines was measured. Piglets fed L. casei Zhang showed significantly increased jejunum villus height, villus height-crypt depth ratio, muscle thickness, and expression of proliferating cell nuclear antigen and tight junction proteins ZO-1 and occludin. The use of L. casei Zhang effectively reduced intestinal inflammation after infection. We found that L. casei Zhang feeding prevented the jejunum damage induced by E. coli K88, suggesting that it may be a potential alternative to antibiotics for preventing diarrhea in early-weaned piglets.


Assuntos
Infecções por Escherichia coli/veterinária , Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/fisiologia , Jejuno/efeitos dos fármacos , Lactobacillus casei/fisiologia , Probióticos/administração & dosagem , Doenças dos Suínos/prevenção & controle , Animais , Citocinas/genética , Suplementos Nutricionais , Escherichia coli Enterotoxigênica/fisiologia , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/prevenção & controle , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Jejuno/patologia , Ocludina/genética , Ocludina/metabolismo , Probióticos/farmacologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Suínos , Doenças dos Suínos/patologia , Receptores Toll-Like/genética , Desmame , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
9.
Reprod Biol ; 19(1): 100-111, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30929911

RESUMO

Prostaglandins (PGs) are important regulators of the early corpus luteum (CL) in the dog. Whereas, initially, CL is gonadotropin independent, in the second half of its lifespan, hypophyseal support is required. The transition period is marked by decreased availability of PGs, in particular of PGE2. We previously reported that inhibition of COX2/PTGS2 in vivo suppressed luteal production of PGE2, lowered circulating progesterone and negatively affected luteal development. Therefore, bitches were treated with a COX2-specific blocker, firocoxib, for 5, 10, 20 and 30 days after ovulation, leading to suppression of the steroidogenic machinery. Control groups received a placebo for the same periods. Considering the wide range of possible modulatory roles of PGs shown in different organ systems, this follow-up project aimed to understand further possible PG-mediated effects in early canine CL. Thirty-four (34) factors related predominantly to vascularization and immune response were screened (mRNAs and proteins) on samples from the above described in vivo study. Most of the effects were observed during the transitional period (days 20 and 30). The inhibition of COX2 diminished the expression of angiopoietin family members ANGPT1, -2, Tie1 and -2 receptors. The expression of endothelin (ET)-1 was increased. Concerning the immune system, increased expression of the pro-inflammatory cytokines, IL1ß, IL6 and IL12a, and elevated expression levels of CD4, was observed. Cumulatively, besides its involvement in regulating steroidogenesis, our results indicate a broader role of PGs in the canine CL, including modulation of angiogenesis, vascular stabilization and local immunomodulation. Possible cross-species translational effects are strongly implied.


Assuntos
4-Butirolactona/análogos & derivados , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Fatores Imunológicos/metabolismo , Prostaglandinas/farmacologia , Sulfonas/farmacologia , 4-Butirolactona/farmacologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Cães , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/genética , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Transcriptoma
10.
Papillomavirus Res ; 7: 132-134, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954690

RESUMO

Twin and family studies suggest that genetic factors play a role in cervical neoplasia susceptibility. Both rare high penetrant and common low penetrant host genetic variants have been shown to influence the risk of HPV persistence, and common variants have been shown to influence the risk of cervical neoplasia. The strongest associations with cervical neoplasia are with HLA genes, with associations having been demonstrated to both reduce and increase the risk of the disease. Fine-mapping using imputed amino-acid sequences of HLA-types has shown that the HLA associations are driven primarily by the HLA-B amino acid position 156 (B156), and HLA-DRB1 amino acid positions 13 and 71. This is informative about the types of peptides that may be useful for peptide vaccines. As cervical neoplasia is at least moderately heritable, genetics may be able to identify those at high or low disease risk. Using the findings of hundreds of disease-associated SNPs to calculate genetic risk scores, it has been shown that women with genetic risk scores in the bottom 10% of the population have very low risk of cervical neoplasia (<0.17%), whereas those in the top 5% have 22% risk of developing the disease. Further large scale genetic studies would be helpful to better define particularly the non-MHC component of genetic risk.


Assuntos
Predisposição Genética para Doença , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/genética , Feminino , Antígenos HLA/genética , Humanos , Fatores Imunológicos/genética , Polimorfismo de Nucleotídeo Único
11.
Appl Microbiol Biotechnol ; 103(11): 4443-4453, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989251

RESUMO

The availability of preimmune libraries of antibody fragments allows for the fast generation of binders which can be expressed in both eukaryotic and prokaryotic systems. We exploited the recombinant nature of antibody fragments to demonstrate the possibility of expressing them as functional proteins displayed on the surface of Escherichia coli and by such a way to generate living reagents ready-to-use for diagnostics. Such immunoreagents were effectively exploited without the necessity of any purification step to prepare immunocapture surfaces suitable for the diagnostic of both cancer cells and toxic microalgae. The same nanobody-displaying bacteria were also engineered to coexpress GFP in their cytoplasm. Suspensions of such living fluorescent immunoreagents effectively bound to eukaryotic cells making them visible and quantifiable by flow cytometry analysis and using 96-well plate readers. The collected data showed the suitability of such living immunoreagents for reproducible and inexpensive diagnostic applications.


Assuntos
Técnicas de Visualização da Superfície Celular/métodos , Técnicas Citológicas/métodos , Escherichia coli/metabolismo , Proteínas Imobilizadas/metabolismo , Fatores Imunológicos/metabolismo , Proteínas Recombinantes/metabolismo , Anticorpos de Domínio Único/metabolismo , Aderência Bacteriana , Escherichia coli/genética , Proteínas Imobilizadas/genética , Imunoensaio/métodos , Fatores Imunológicos/genética , Proteínas Recombinantes/genética , Anticorpos de Domínio Único/genética , Coloração e Rotulagem/métodos
12.
Fish Shellfish Immunol ; 88: 480-488, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877062

RESUMO

As one of the most important neuropeptides identified only in invertebrates of Mollusca, Annelida and Arthropoda, FMRFamide (Phe-Met-Arg-Phe-NH2) involves in multiple physiological processes, such as mediating cardiac frequency and contraction of somatic and visceral muscles. However, its modulatory role in the immune defense has not been well understood. In the present study, an FMRFamide precursor (designed as CgFMRFamide) was identified in oyster Crassostrea gigas, which could be processed into nineteen FMRFamide peptides. Phylogenetic analysis revealed that CgFMRFamide shared high similarity with other identified FMRFamides in mollusks. The mRNA of CgFMRFamide was mainly concentrated in the tissues of visceral ganglia, hepatopancreas and hemocytes, and a consistent distribution of FMRFamide peptide was confirmed by immunohistochemistry and immunocytochemistry assays. The mRNA expression level of CgFMRFamide in hemocytes was significantly up-regulated after immune stimulation with lipopolysaccharide (LPS). After the concentration of FMRFamide was increased by exogenous injection, the in vivo expressions of pro-inflammatory cytokine CgIL17-5, as well as the apoptosis-related CgCaspase-1 and CgCaspase-3 in hemocytes were promptly increased (p < 0.05), but the concentration of signal molecule nitric oxide (NO) was significantly down-regulated (p < 0.05). Meanwhile, an increased phosphorylation of p38 MAP kinase in hemocytes was also detected after the FMRFamide injection. These results collectively demonstrated that the conserved FMRFamide could not only respond to immune stimulation, but also regulate the expression of immune effectors and apoptosis-related genes, which might be mediated by p38 MAP kinase pathway, thereby effectively involved in clearing pathogens and maintaining homeostasis in oysters.


Assuntos
Crassostrea/imunologia , FMRFamida/imunologia , Fatores Imunológicos/imunologia , Animais , Apoptose , Caspases/metabolismo , Citocinas/metabolismo , FMRFamida/administração & dosagem , FMRFamida/genética , Hemócitos/efeitos dos fármacos , Hemócitos/imunologia , Imunidade Inata , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/genética , Lipopolissacarídeos , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Filogenia , RNA Mensageiro , Regulação para Cima
13.
Nat Commun ; 10(1): 1052, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837455

RESUMO

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.


Assuntos
Loci Gênicos/imunologia , Predisposição Genética para Doença , Fatores Imunológicos/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Úlceras Orais/imunologia , Estomatite Aftosa/imunologia , Linfócitos T/imunologia
14.
Rev Med Virol ; 29(2): e2026, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609190

RESUMO

Respiratory syncytial virus (RSV) infection is the most common cause of bronchiolitis and pneumonia in the pediatric population worldwide. The immunopathology of RSV infection varies considerably and severe disease occurs only in a minority of the population. There are many factors (host, viral, and environmental) that contribute to the complicated disease phenotype. In this regard, host factors are decisive for pulmonary susceptibility to RSV infection. Host genetic diversity certainly affects the balance between control of viral replication and tissue damage during RSV infection, consequently impacting on diseases outcome. In this review, we discuss the role of host genetic variation in disease caused by RSV aiming to highlight genetic risk factors for one of the most common diseases in early childhood. Our findings clearly indicate that the response of each individual to infection is influenced by genetic diversity mainly linked to the regulation of host immune responses. Future genetic association and functional studies using more powerful and consistently reproducible approaches will likely be able to confirm, refine, and expand our developing concept of RSV disease pathogenesis.


Assuntos
Predisposição Genética para Doença , Fatores Imunológicos/genética , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sinciciais Respiratórios/imunologia , Bronquiolite/genética , Bronquiolite/imunologia , Humanos , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia
15.
Mol Cell Biochem ; 451(1-2): 37-42, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29926320

RESUMO

Cross-talk between coding RNAs and regulatory non-coding microRNAs, within human genome, has provided compelling evidence for the existence of flexible checkpoint control of T-Cell activation. The present study attempts to demonstrate that the interplay between miR-2909 and its effector KLF4 gene has the inherent capacity to regulate genes coding for CTLA4, CD28, CD40, CD134, PDL1, CD80, CD86, IL-6 and IL-10 within normal human peripheral blood mononuclear cells (PBMCs). Based upon these findings, we propose a pathway that links miR-2909 RNomics with the genes coding for immune checkpoint regulators required for the maintenance of immune homeostasis.


Assuntos
Antígenos CD/metabolismo , Fatores Imunológicos/metabolismo , Leucócitos Mononucleares/metabolismo , MicroRNAs/genética , Antígenos CD/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Humanos , Fatores Imunológicos/genética , MicroRNAs/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais
16.
Papillomavirus Res ; 7: 11-14, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30092369

RESUMO

OBJECTIVES: While most human papillomavirus (HPV) infection clears on its own, persistent HPV infection can cause genital warts and anal, penile and oropharyngeal cancers in men. We conducted genetic analysis in a sub-cohort of the HPV infection in men (HIM) study to test the hypothesis that differences in host genes influence HPV persistence in men. METHODS: Baseline and longitudinal genital HPV status at the genitals was measured every 6-months using the Linear Array assay amplified HPV L1 gene fragment using the PGMY09/11 L1 consensus primer system. DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) in the customized genome-wide genotyping array, the "TxArray," were examined using logistic regression in a case-control study design to assess the association with HPV16 persistence/clearance. RESULTS: Of the total of 737,742 autosomal SNPs in the array, 605,885 passed basic quality control and were examined between 40 men (cases) with > 18 months persistent genital HPV 16 infection vs. 151 controls who were HPV 16-positive, but whose infections cleared in < 18 months. The logistic regression analysis from this case-control study showed variants in several gene regions associated with genital HPV 16 persistence, with the strongest association detected with SNPs on chromosomes 20 (p < 5.72 × 10-6) and 15 (p < 5.89 × 10-6), after adjusting for age, smoking status, number of sex partners and four principal components (ancestral background). CONCLUSIONS: Our results provide a preliminary basis for understanding the biological mechanism of oncogenic HPV 16 pathogenesis at the genitals in men. Some of the genes flanking the top hit SNPs are consistent with previous findings in both HPV related and non-related cancers but further genetic studies in larger cohorts are warranted to confirm these and identify novel major susceptibility genes involved in the pathogenesis of genital HPV persistence in men.


Assuntos
Predisposição Genética para Doença , Doenças dos Genitais Masculinos/genética , Papillomavirus Humano 16/isolamento & purificação , Fatores Imunológicos/genética , Infecções por Papillomavirus/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Doenças dos Genitais Masculinos/imunologia , Doenças dos Genitais Masculinos/virologia , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
Amino Acids ; 51(2): 345-353, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30353357

RESUMO

The diversity of defensive peptides from skin of amphibians has been demonstrated. These peptides may have resulted from the diversity of microorganisms encountered by amphibians. In this study, peptidomics and RNA sequencing analyses were used to study deeply the defensive peptides of the skin secretions from Polypedates megacephalus. A total of 99 defensive peptides have been identified from the skin secretions. Among these peptides, 3 peptides were myotropical peptides and 34 peptides classified as protease inhibitor peptides. 5 lectins, 8 antimicrobial peptides, 26 immunomodulatory peptides, 10 wound-healing peptides and 13 other bioactive peptides were identified as belonging to the innate immune system. One antimicrobial peptide Pm-amp1 showed high similarity to antimicrobial peptide marcin-18. This peptide was successfully expressed and showed moderate activity against four tested strains. These identified peptides highlight the extensive diversity of defensive peptides and provide powerful tools to understand the defense weapon of frog.


Assuntos
Proteínas de Anfíbios/química , Proteínas de Anfíbios/genética , Venenos de Anfíbios/química , Venenos de Anfíbios/genética , Anuros/fisiologia , Pele/química , Proteínas de Anfíbios/isolamento & purificação , Animais , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Feminino , Fatores Imunológicos/genética , Fatores Imunológicos/isolamento & purificação , Lectinas/genética , Lectinas/isolamento & purificação , Masculino , Espectrometria de Massas , Inibidores de Proteases/química , Inibidores de Proteases/isolamento & purificação , Análise de Sequência de Proteína , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
18.
Med Microbiol Immunol ; 208(5): 631-640, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30306260

RESUMO

Influenza remains an important threat for human health, despite the extensive study of influenza viruses and the production of effective vaccines. In contrast to virus genetics determinants, host genetic factors with clinical impact remained unexplored until recently. The association between three single nucleotide polymorphisms (SNPs) and influenza outcome in a European population was investigated in the present study. All samples were collected during the influenza A(H1N1)pdm09 post-pandemic period 2010-11 and a sufficient number of severe and fatal cases was included. Host genomic DNA was isolated from pharyngeal samples of 110 patients from northern Greece with severe (n = 59) or mild (n = 51) influenza A(H1N1)pdm09 disease, at baseline, and the genotype of CD55 rs2564978, C1QBP rs3786054 and FCGR2A rs1801274 SNPs was investigated. Our findings suggest a relationship between the two complement-related SNPs, namely, the rare TT genotype of CD55 and the rare AA genotype of C1QBP with increased death risk. No significant differences were observed for FCGR2A genotypes neither with fatality nor disease severity. Additional large-scale genetic association studies are necessary for the identification of reliable host genetic risk factors associated with influenza A(H1N1)pdm09 outcome. Prophylactic intervention of additional high-risk populations, according to their genetic profile, will be a key achievement for the fight against influenza viruses.


Assuntos
Proteínas do Sistema Complemento/genética , Predisposição Genética para Doença , Fatores Imunológicos/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/genética , Influenza Humana/virologia , Adolescente , Adulto , Feminino , Genótipo , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Int J Oncol ; 54(2): 515-526, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535430

RESUMO

Glycodelin [gene name, progesterone associated endometrial protein (PAEP)] was initially described as an immune system modulator in reproduction. Today, it is also known to be expressed in several types of cancer, including non­small cell lung cancer (NSCLC). In this cancer type, the feasibility of its usage as a follow­up biomarker and its potential role as an immune system modulator were described. It is assumed that NSCLC tumours secrete glycodelin to overcome immune surveillance. Therefore, targeting glycodelin might be a future approach with which to weaken the immune system defence of NSCLC tumours. In this context, it is important to understand the regulatory pathways of PAEP/glycodelin expression, as these are mostly unknown so far. In this study, we analysed the influence of several inducers and of their downstream pathways on PAEP/glycodelin expression in a human lung adenocarcinoma carcinoma (ADC; H1975) and a human lung squamous cell carcinoma (SQCC) cell line (2106T). PAEP/glycodelin expression was notably stimulated by the canonical transforming growth factor (TGF)­ß pathway in SQCC cells and the PKC signalling cascade in both cell lines. The PI3K/AKT pathway inhibited PAEP/glycodelin expression in the ADC cells and an antagonizing role towards the other investigated signalling cascades is suggested herein. Furthermore, the mitogen­activated protein kinase kinase (MEK)/extracellular­signal regulated kinases (ERK) pathway was, to a lesser extent, found to be associated with increased PAEP/glycodelin amounts. The phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT), MEK/ERK pathway and TGF­ß are targets of NSCLC drugs that are already approved or are currently under investigation. On the whole, the findings of this study provide evidence that inhibiting these targets affects the expression of glycodelin and its immunosuppressive effect in NSCLC tumours. Moreover, understanding the regulation of glycodelin expression may lead to the development of novel therapeutic approaches with which to weaken the immune system defence of NSCLC tumours in the future.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Glicodelina/genética , Fatores Imunológicos/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Glicodelina/imunologia , Humanos , Fatores Imunológicos/imunologia , Fosfatidilinositol 3-Quinases/genética , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética
20.
Zhongguo Fei Ai Za Zhi ; 21(12): 918-923, 2018 Dec 20.
Artigo em Chinês | MEDLINE | ID: mdl-30591100

RESUMO

Small cell lung cancer (SCLC), which accounts for about 15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Despite sensitive to chemotherapy and radiotherapy, SCLC is vulnerable to get resistant and has high recurrence rates. In recent years, immunotherapy has shown good antitumor activity, especially programmed death receptor-1/ligand-L1 (PD-1/L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) Checkpoint inhibitors have changed the pattern of tumor treatment, and SCLC has high immunogenicity, high mutation load and other favorable immune factors, so immuno-checkpoint inhibitors may become an important breakthrough in SCLC treatment. This article will briefly review the clinical research of immunotherapy for small cell lung cancer.
.


Assuntos
Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/imunologia , Imunoterapia/tendências , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia
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