Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.623
Filtrar
1.
Nat Commun ; 11(1): 4414, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887877

RESUMO

CD4+ helper T cells contribute important functions to the immune response during pathogen infection and tumor formation by recognizing antigenic peptides presented by class II major histocompatibility complexes (MHC-II). While many computational algorithms for predicting peptide binding to MHC-II proteins have been reported, their performance varies greatly. Here we present a yeast-display-based platform that allows the identification of over an order of magnitude more unique MHC-II binders than comparable approaches. These peptides contain previously identified motifs, but also reveal new motifs that are validated by in vitro binding assays. Training of prediction algorithms with yeast-display library data improves the prediction of peptide-binding affinity and the identification of pathogen-associated and tumor-associated peptides. In summary, our yeast-display-based platform yields high-quality MHC-II-binding peptide datasets that can be used to improve the accuracy of MHC-II binding prediction algorithms, and potentially enhance our understanding of CD4+ T cell recognition.


Assuntos
Epitopos de Linfócito T/genética , Oligopeptídeos , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Técnicas de Visualização da Superfície Celular , Bases de Dados de Proteínas , Epitopos de Linfócito T/química , Epitopos de Linfócito T/metabolismo , Genes MHC da Classe II , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Oligopeptídeos/química , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Ligação Proteica/genética , Receptores de Antígenos de Linfócitos T , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/metabolismo
2.
Life Sci ; 256: 118026, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615187

RESUMO

AIM: We aimed to determine the biological processes and pathways involved in cervical carcinogenesis associated with high-risk human papillomavirus (HPV) infection. MATERIALS AND METHODS: Total RNA was extracted from three formalin-fixed paraffin-embedded (FFPE) samples each of normal cervix, HPV-infected low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL) and squamous cell carcinoma (SCC). Transcriptomic profiling by microarrays was conducted followed by downstream Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. RESULTS: We examined the difference in GOs enriched for each transition stage from normal cervix to LSIL, HSIL, and SCC, and found 307 genes to be differentially expressed. In the transition from normal cervix to LSIL, the extracellular matrix (ECM) genes were significantly downregulated. The MHC class II genes were significantly upregulated in the LSIL to HSIL transition. In the final transition from HSIL to SCC, the immunoglobulin heavy locus genes were significantly upregulated and the ECM pathway was implicated. CONCLUSION: Deregulation of the immune-related genes including MHC II and immunoglobulin heavy chain genes were involved in the transitions from LSIL to HSIL and SCC, suggesting immune escape from host anti-tumour response. The extracellular matrix plays an important role during the early and late stages of cervical carcinogenesis.


Assuntos
Genes de Cadeia Pesada de Imunoglobulina/genética , Genes MHC da Classe II/genética , Infecções por Papillomavirus/complicações , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Regulação para Baixo , Matriz Extracelular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Infecções por Papillomavirus/genética , Lesões Intraepiteliais Escamosas Cervicais/genética , Lesões Intraepiteliais Escamosas Cervicais/virologia , Transcriptoma , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia
3.
Nucleic Acids Res ; 48(15): 8332-8348, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32633757

RESUMO

Negative cofactor 2 (NC2), including two subunits NC2α and NC2ß, is a conserved positive/negative regulator of class II gene transcription in eukaryotes. It is known that NC2 functions by regulating the assembly of the transcription preinitiation complex. However, the exact role of NC2 in transcriptional regulation is still unclear. Here, we reveal that, in Neurospora crassa, NC2 activates catalase-3 (cat-3) gene transcription in the form of heterodimer mediated by histone fold (HF) domains of two subunits. Deletion of HF domain in either of two subunits disrupts the NC2α-NC2ß interaction and the binding of intact NC2 heterodimer to cat-3 locus. Loss of NC2 dramatically increases histone variant H2A.Z deposition at cat-3 locus. Further studies show that NC2 recruits chromatin remodeling complex INO80C to remove H2A.Z from the nucleosomes around cat-3 locus, resulting in transcriptional activation of cat-3. Besides HF domains of two subunits, interestingly, C-terminal repression domain of NC2ß is required not only for NC2 binding to cat-3 locus, but also for the recruitment of INO80C to cat-3 locus and removal of H2A.Z from the nucleosomes. Collectively, our findings reveal a novel mechanism of NC2 in transcription activation through recruiting INO80C to remove H2A.Z from special H2A.Z-containing nucleosomes.


Assuntos
Catalase/genética , Fosfoproteínas/genética , Fatores de Transcrição/genética , Transcrição Genética , Núcleo Celular/genética , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica/genética , Genes MHC da Classe II/genética , Histonas/genética , Neurospora crassa/genética , Nucleossomos/genética , Nucleossomos/ultraestrutura , Fosfoproteínas/ultraestrutura , Ligação Proteica/genética , Fatores de Transcrição/ultraestrutura , Ativação Transcricional/genética
4.
Proc Natl Acad Sci U S A ; 117(25): 14405-14411, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518111

RESUMO

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.


Assuntos
Síndrome de Behçet/genética , Febre/genética , Predisposição Genética para Doença , Linfadenite/genética , Faringite/genética , Estomatite Aftosa/genética , Alelos , Síndrome de Behçet/imunologia , Criança , Estudos de Coortes , Febre/imunologia , Genes MHC Classe I/genética , Genes MHC Classe I/imunologia , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Loci Gênicos/imunologia , Humanos , Linfadenite/imunologia , Faringite/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estomatite Aftosa/imunologia , Síndrome
5.
PLoS One ; 15(2): e0228112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040512

RESUMO

Neoantigens can be predicted and in some cases identified using the data obtained from the whole exome sequencing and transcriptome sequencing of tumor cells. These sequencing data can be coupled with single-cell RNA sequencing for the direct interrogation of the transcriptome, surfaceome, and pairing of αß T-cell receptors (TCRαß) from hundreds of single T cells. Using these 2 large datasets, we established a platform for identifying antigens recognized by TCRαßs obtained from single T cells. Our approach is based on the rapid expression of cloned TCRαß genes as Sleeping Beauty transposons and the determination of the introduced TCRαßs' antigen specificity and avidity using a reporter cell line. The platform enables the very rapid identification of tumor-reactive TCRs for the bioengineering of T cells with redirected specificity.


Assuntos
Engenharia Celular/métodos , Clonagem Molecular/métodos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/citologia , Linfócitos T/metabolismo , Expressão Gênica , Biblioteca Gênica , Genes MHC Classe I/genética , Genes MHC da Classe II/genética , Células HEK293 , Humanos , Cinética , Receptores de Antígenos de Linfócitos T alfa-beta/genética
7.
Parasite Immunol ; 42(2): e12690, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31802508

RESUMO

AIMS: Pregnant BALB/c mice infected with a Toxoplasma gondii type II strain were used to determine how pregnancy interferes with the development of maternal immunity to T gondii and how infection disrupts pregnancy and foetal development. METHODS: Maternal and foetal parasite loads were assessed by amplification of T gondii SAG1 using qPCR. Adverse effects of infection were evaluated on foetal-placental development by quantification of implantation units undergoing resorption and by histopathological analyses. Serum progesterone levels were quantified by immunoassay. The effect of T gondii infection on maternal immunity was determined by assessing the cellular composition of spleens by flow cytometry. RESULTS: Infected pregnant mice exhibited clinical signs of infection, inflammation and necrosis at the maternal-foetal interface and decreased serum progesterone levels. In infected mice, there was a clear effect of pregnancy and infection on macrophage cell numbers. However, no differences in the parasite load were detected between non-pregnant and pregnant mice. CONCLUSIONS: Maternal T gondii infection induced adverse effects at the maternal-foetal interface. Alterations were found in immune spleen cells, dependent on the day of pregnancy, relative to nonpregnant animals. The results obtained suggest a pregnancy-dependent mechanism during T gondii infection able to interfere with macrophage numbers.


Assuntos
Gravidez/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Modelos Animais de Doenças , Feminino , Genes MHC da Classe II , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Placenta/imunologia , Progesterona/sangue , Baço/imunologia , Toxoplasmose Animal/parasitologia
8.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31753848

RESUMO

Super enhancers (SEs) play critical roles in cell type-specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/metabolismo , Genes MHC da Classe II/genética , Cadeias alfa de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Linfócitos B , Sítios de Ligação/genética , Doadores de Sangue , Linfoma de Burkitt/patologia , Fator de Ligação a CCCTC/metabolismo , Linfócitos T CD4-Positivos , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Deleção de Genes , Loci Gênicos , Cadeias alfa de HLA-DQ/metabolismo , Cadeias HLA-DRB1/metabolismo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética
9.
Immunogenetics ; 71(10): 647-663, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31761978

RESUMO

The classical class I and class II molecules of the major histocompatibility complex (MHC) play crucial roles in immune responses to infectious pathogens and vaccines as well as being important for autoimmunity, allergy, cancer and reproduction. These classical MHC genes are the most polymorphic known, with roughly 10,000 alleles in humans. In chickens, the MHC (also known as the BF-BL region) determines decisive resistance and susceptibility to infectious pathogens, but relatively few MHC alleles and haplotypes have been described in any detail. We describe a typing protocol for classical chicken class I (BF) and class II B (BLB) genes based on a hybridization method called reference strand-mediated conformational analysis (RSCA). We optimize the various steps, validate the analysis using well-characterized chicken MHC haplotypes, apply the system to type some experimental lines and discover a new chicken class I allele. This work establishes a basis for typing the MHC genes of chickens worldwide and provides an opportunity to correlate with microsatellite and with single nucleotide polymorphism (SNP) typing for approaches involving imputation.


Assuntos
Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Hibridização de Ácido Nucleico/métodos , Polimorfismo Genético , Análise de Sequência de DNA/normas , Animais , Galinhas , Polimorfismo Conformacional de Fita Simples , Padrões de Referência , Análise de Sequência de DNA/métodos
10.
Immunogenetics ; 71(10): 605-615, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31776588

RESUMO

Immunogenicity of biomolecules is one of the largest concerns in biological therapeutic drug development. Adverse immune responses as a result of immunogenicity to biotherapeutics range from mild hypersensitivity reactions to potentially life-threatening anaphylactic reactions and can negatively impact human health and drug efficacy. Numerous confounding patient-, product- or treatment-related factors can influence the development of an immune reaction against therapeutic proteins. The goal of this study was to investigate the relationship between pre-existing drug reactivity (PE-ADA), individual immunogenetics (MHC class II haplotypes), and development of treatment-induced antidrug antibodies (TE-ADA) in cynomolgus macaque. PE-ADA refers to the presence of antibodies immunoreactive against the biotherapeutic in treatment-naïve individuals. We observed that PE-ADA frequency against four different bispecific antibodies in naïve cynomolgus macaque is similar to that reported in humans. Additionally, we report a trend towards an increased incidence of TE-ADA development in macaques with high PE-ADA levels. In order to explore the relationship between MHC class II alleles and risk of ADA development, we obtained full-length MHC class II sequences from 60 cynomolgus macaques in our colony. We identified a total of 248 DR, DP, and DQ alleles and 236 unique haplotypes in our cohort indicating a genetically complex set of animals potentially reflective of the human population. Based on our observations, we propose the evaluation of the magnitude/frequency of pre-existing reactivity and consideration of MHC class II genetics as additional useful tools to understand the immunogenic potential of biotherapeutics.


Assuntos
Anticorpos Biespecíficos/imunologia , Hipersensibilidade a Drogas/imunologia , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Imunogenética , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/sangue , Hipersensibilidade a Drogas/genética , Frequência do Gene , Haplótipos , Macaca fascicularis , Masculino , Filogenia
11.
Proc Natl Acad Sci U S A ; 116(47): 23643-23652, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31672911

RESUMO

The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.


Assuntos
Epiderme/microbiologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Interações entre Hospedeiro e Microrganismos/imunologia , Queratinócitos/imunologia , Microbiota/imunologia , Células Th1/imunologia , Animais , Apresentação do Antígeno , Candida albicans/imunologia , Epiderme/imunologia , Genes MHC da Classe II , Interferon gama/biossíntese , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Quimera por Radiação , Organismos Livres de Patógenos Específicos , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Simbiose , Células Th1/metabolismo
12.
Methods Mol Biol ; 2024: 269-285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364056

RESUMO

Aberrant glycosylation is a hallmark of cancer that contributes to the disease's ability to evade the immune system. As the MHC processing pathways communicate cellular health to circulating CD8+ and CD4+ T-cells, MHC-associated glycopeptides are likely a source of neoantigens in cancer. In fact, recent advances in mass spectrometry have allowed for the detection and sequencing of tumor-specific glycopeptides from the MHC class I and class II processing pathways. Here, we describe methods for detecting, sequencing, and modeling these MHC-associated glycopeptides.


Assuntos
Genes MHC da Classe II , Genes MHC Classe I , Glicopeptídeos/análise , Glicosilação , Espectrometria de Massas
13.
J Immunol ; 203(6): 1619-1628, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31391235

RESUMO

Proteins are composed of α-amino acid residues. This consistency in backbone structure likely serves an important role in the display of an enormous diversity of peptides by class II MHC (MHC-II) products, which make contacts with main chain atoms of their peptide cargo. Peptides that contain residues with an extra carbon in the backbone (derived from ß-amino acids) have biological properties that differ starkly from those of their conventional counterparts. How changes in the structure of the peptide backbone affect the loading of peptides onto MHC-II or recognition of the resulting complexes by TCRs has not been widely explored. We prepared a library of analogues of MHC-II-binding peptides derived from OVA, in which at least one α-amino acid residue was replaced with a homologous ß-amino acid residue. The latter contain an extra methylene unit in the peptide backbone but retain the original side chain. We show that several of these α/ß-peptides retain the ability to bind tightly to MHC-II, activate TCR signaling, and induce responses from T cells in mice. One α/ß-peptide exhibited enhanced stability in the presence of an endosomal protease relative to the index peptide. Conjugation of this backbone-modified peptide to a camelid single-domain Ab fragment specific for MHC-II enhanced its biological activity. Our results suggest that backbone modification offers a method to modulate MHC binding and selectivity, T cell stimulatory capacity, and susceptibility to processing by proteases such as those found within endosomes where Ag processing occurs.


Assuntos
Aminoácidos/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação/fisiologia , Linhagem Celular Tumoral , Genes MHC da Classe II/fisiologia , Ligantes , Camundongos , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/fisiologia , Receptores de Antígenos de Linfócitos T/metabolismo , Relação Estrutura-Atividade , Linfócitos T/metabolismo
14.
Infect Genet Evol ; 74: 103933, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229664

RESUMO

Genetic control of host susceptibility to M. avium, an important lung pathogen of immune-compromised individuals, remains incompletely defined. Apart from the slc11a1 (Nramp1) gene, which plays a pivotal role in genetic control of a few intracellular pathogens, including M. avium, in mice, we know nothing about genetic loci determining susceptibility to and/or severity of M. avium-triggered disease. Previously, our lab developed a panel of H2-congenic, recombinant mouse strains for identification of the MHC genes involved in the control of M. tuberculosis infection. In the present study, we applied a few recombinant strains from this panel to study $ possible influence of allelic variations in classical Class II genes on the development of M. avium infection. Our results demonstrate a clear difference in lung pathology, post-infection survival time, lung neutrophil influx and corresponding chemokine/cytokine responses, as well as the degree of lung T lymphocyte activation, between mouse strains differing by the alleles of a single highly polymorphic Class II H2-Aß gene. Paradoxically, mice carrying the H2-Aßb allele, which provides a notable protective effect against M. tuberculosis compared to the H2-Aßj allele, were more susceptible to M. avium infection as indicated by several parameters of the disease. We discuss possible reasons for such a reciprocal expression of phenotypes determined by a single allelic variant during two "similar" infections that may concern differences in virulence, NO-sensitivity, intracellular life style and antigenic composition between these two mycobacterial species.


Assuntos
Genes MHC da Classe II , Mycobacterium avium/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Tuberculose/patologia , Animais , Citocinas/metabolismo , Variação Genética , Ativação Linfocitária , Camundongos , Camundongos Congênicos , Mycobacterium avium/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/genética , Tuberculose/imunologia
15.
Proc Natl Acad Sci U S A ; 116(21): 10441-10446, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31040209

RESUMO

Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage "don't-eat me" signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale.


Assuntos
Engenharia Genética/métodos , Células-Tronco Pluripotentes/imunologia , Sistemas CRISPR-Cas , Linhagem Celular , Técnicas de Inativação de Genes , Genes MHC Classe I , Genes MHC da Classe II , Humanos
16.
Infect Genet Evol ; 73: 197-204, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31051273

RESUMO

Major histocompatibility complex (MHC) genes code for membrane-embedded proteins that are involved in parasite/pathogen recognition. The link between the MHC and immunity makes these genes important genetic markers to evaluate in systems where infectious disease is associated with population declines. As human impacts on wildlife populations continue to increase, it is also essential to evaluate the role of MHC and immunity in the context of anthropogenic change. Amphibians are an ideal model to test the role of the MHC in infectious disease resistance, as parasites and anthropogenic disturbances currently threaten populations worldwide. We characterized the diversity of MHC class IIß peptide binding region alleles, 13 microsatellite loci, and population-level trematode resistance in 14 populations of wood frogs (Lithobates sylvaticus) in northwestern Pennsylvania with varying geographic distances to agriculture. To assess local adaptation in the MHC IIß, we compared genetic differentiation of MHC IIß and microsatellite markers (FST). We also tested for an effect of isolation by distance on genetic differentiation of MHC IIß and microsatellite markers. In addition, we evaluated whether population-level MHC IIß diversity and common allele frequencies correlate with distance to agriculture and trematode resistance. We found no evidence for genetic structure based on microsatellite analysis nor an effect of isolation by distance on neutral and immunogenetic markers. However, we did detect structure based on the MHC IIß locus, suggesting that it is under local selection. The MHC IIß allele Lisy-DAB*1 was more common in populations living near agricultural sites. Populations with higher MHC IIß diversity showed increased resistance to trematodes. Our results suggest that wood frog populations experience immunogenetic differences at a small scale. In addition, agriculture may disturb natural associations between hosts and parasites through its influence on immunocompetence, underscoring the importance of examining the effects of environmental context on host-parasite interactions.


Assuntos
Adaptação Fisiológica/genética , Genes MHC da Classe II/genética , Ranidae/genética , Agricultura , Animais , Variação Genética , Genótipo
17.
Hum Immunol ; 80(9): 714-722, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31101373

RESUMO

Umbilical cord blood stem cell transplantation is an important choice for treating a variety of hematopoietic, neoplastic, and genetic disorders. The optimal size for a cord blood bank to provide matching units for 80% of patients requiring a stem cell transplantation procedure depends on the particular characteristics of each population. In this study, we analyzed the immunogenetic diversity of a sample set of Mexican patients suffering from blood, hematopoietic, and immunological diseases, to assess the best strategy for cord blood banking. For achieving that, we analyzed HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 genotype and allele frequencies of both units from the bioarchive of the Umbilical Cord Blood Bank from La Raza and patients requiring a stem cell transplant and compared these variables with data from the same geographic and genetic context. We were able to detect significant differences for at least half of the alleles were observed for HLA class I and class II genes between units and patients. Five Native American haplotypes had lower frequencies in patients sample than in the cord blood units. Genetic admixture estimations for both groups showed a higher contribution of Native American component in the cord blood units. Differences in ancestral components in the Umbilical Cord Blood Bank from La Raza and six virtual banks modeled from a pool of Mexican mixed ancestry individuals show that genetic background is important in cord blood collection. In conclusion, increasing diversity over quantity of new cord blood units will improve the cost effectiveness of cord blood banking and health policies regarding hematopoietic stem cell transplantation in admixed populations such as those present in Latin American countries.


Assuntos
Bancos de Sangue , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal/imunologia , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Transplantados , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene/genética , Genes MHC Classe I , Genes MHC da Classe II , Variação Genética , Haplótipos/genética , Humanos , Masculino , México , Adulto Jovem
18.
Microb Pathog ; 132: 243-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075428

RESUMO

Ebola virus (EBOV), a non-segmented single-stranded RNA virus, is often-most transmitted through body fluids like sweat, tears, saliva, and nasal secretions. Till date, there is no licensed vaccine of EBOV is available in the market; however, the world is increasingly vulnerable to this emerging threat. Hence, it is the need of time to develop a vaccine for EBOV to hinder its dissemination. The current study has been designed for identification and characterization of the potential B and T-cell epitopes using the Immuno-informatics tools, and it helped in finding the potent vaccine candidates against EBOV. Prediction, antigenicity and allergenicity testing of predicted B and T cells' epitopes was done as well to identify their potential as a vaccine candidate and to measure their safety level respectively. Among B-cell epitopes "WIPAGIGVTGVIIA" showed a high antigenicity score and it would play an important role in evoking the immune response. In T-cell epitopes, peptides "AIGLAWIPY" and "IRGFPRCRY" presented high antigenicity score, which binds to MHC class-I and MHC class-II alleles respectively. All predicted epitopes were analyzed and compared with already reported peptides carefully. Comparatively, Peptides predicted in the present study showed more immunogenicity score than already reported peptides, used as positive control, and are more immunogenic as compared to them. Peptides reported in the present study do not target only Zaire EBOV (ZEBOV), as in previous studies, but also other species, i.e. Tai Forest EBOV (TAFV), Sudan EBOV (SUDV), Bundibugyo EBOV (BDBV), and Reston EBOV (RESTV) and would bring the promising results as potent vaccine candidates.


Assuntos
Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Glicoproteínas/imunologia , Alelos , Sequência de Aminoácidos , Vacinas contra Ebola/genética , Ebolavirus/genética , Genes MHC Classe I , Genes MHC da Classe II , Glicoproteínas/química , Glicoproteínas/genética , Antígeno HLA-B7 , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Estrutura Secundária de Proteína
19.
Arq Neuropsiquiatr ; 77(4): 239-247, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31090804

RESUMO

OBJECTIVE: To study the genetic susceptibility to neuromyelitis optica (NMO) as well as the relationship between HLA genotypes and susceptibility to the disease in the southern Brazilian population. METHODS: We analyzed patients with NMO, who met criteria for Wingerchuk's diagnosis of NMO, with detected serum anti-AQP4-IgG antibody. The HLA genotyping was performed by high-resolution techniques (Sanger sequencing) in patients and controls. The HLA genotypes were statistically compared with a paired control population. RESULTS: The HLA genotyping revealed the diversity of the southern Brazilian population whose HLA profile resembled European and Asian populations. Some alleles had statistical correlations with a positive association (increased susceptibility) with NMO, particularly the HLA-DRB1*04:05 and *16:02. CONCLUSIONS: In our study, the HLA genotype was different to that previously reported for other Brazilian populations. Although our study had a small cohort, HLA genotypes were associated with increased susceptibility to NMO for HLA-DRB1*04:05 and *16:02. The alleles of HLA class I HLA-A*02:08 and *30:09, HLA-B*08:04 and *35:04 showed an association before the Bonferroni correction.


Assuntos
Alelos , Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Neuromielite Óptica/genética , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valores de Referência , Adulto Jovem
20.
J Immunol Res ; 2019: 7026067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949517

RESUMO

Aim: The RelB gene plays an important role in guiding the progression of arthritis. We have previously demonstrated that the expression of the RelB gene is decreased significantly in bone marrow DCs of CD38-/- mice. In this study, we demonstrate that the cluster of the differentiation (CD38) gene could be a potentially therapeutic target for autoimmune arthritis. Method: Collagen-induced arthritis (CIA) models were generated with both the wild-type (WT) C57BL/6 and CD38-/- mice. The expression of the RelB gene and maturation of bone marrow-derived dendritic cells (DCs) from the WT and CD38-/- mice were detected. Antigen-specific T cell responses, joint damage, and expression of proinflammatory cytokines were assessed. The effects of the Nuclear Factor Kappa B (NF-κB) transcription factor and its mechanisms were characterized. Results: We demonstrated that in CD38-/- mice, the expression of the RelB gene and major histocompatibility complex II (MHC II) was decreased, accompanied with the inhibited T cell reaction in a mixed lymphocyte reaction (MLR) in bone marrow-derived DCs. Compared to the serious degeneration of the cartilage and the enlarged gap of the cavum articular in WT CIA mice, joint pathological changes of the CD38-/- CIA mice revealed marked attenuation, while the joint structures were well preserved. The preserved effects were observed by the inhibition of proinflammatory cytokines and promotion of anti-inflammatory cytokines. Furthermore, decreased phosphorylation of NF-κB was also observed in CD38-/- CIA mice. Conclusion: We demonstrate that CD38 could regulate CIA through NF-κB and this regulatory molecule could be a novel target for the treatment of autoimmune inflammatory joint disease.


Assuntos
ADP-Ribosil Ciclase 1/genética , Artrite Experimental/fisiopatologia , Glicoproteínas de Membrana/genética , NF-kappa B/metabolismo , Transdução de Sinais , ADP-Ribosil Ciclase 1/imunologia , Animais , Artrite Experimental/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Diferenciação Celular , Colágeno , Citocinas/imunologia , Regulação para Baixo , Genes MHC da Classe II , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Fosforilação , Linfócitos T/imunologia , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA