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1.
Immunogenetics ; 72(4): 263-274, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32300829

RESUMO

Reticulated flatwoods salamander (Ambystoma bishopi) populations began decreasing dramatically in the 1900s. Contemporary populations are small, isolated, and may be susceptible to inbreeding and reduced adaptive potential because of low genetic variation. Genetic variation at immune genes is especially important as it influences disease susceptibility and adaptation to emerging infectious pathogens, a central conservation concern for declining amphibians. We collected samples from across the extant range of this salamander to examine genetic variation at major histocompatibility complex (MHC) class Iα and IIß exons as well as the mitochondrial control region. We screened tail or toe tissue for ranavirus, a pathogen associated with amphibian declines worldwide. Overall, we found low MHC variation when compared to other amphibian species and did not detect ranavirus at any site. MHC class Iα sequencing revealed only three alleles with a nucleotide diversity of 0.001, while MHC class IIß had five alleles with a with nucleotide diversity of 0.004. However, unique variation still exists across this species' range with private alleles at three sites. Unlike MHC diversity, mitochondrial variation was comparable to levels estimated for other amphibians with nine haplotypes observed, including one haplotype shared across all sites. We hypothesize that a combination of a historic disease outbreak and a population bottleneck may have contributed to low MHC diversity while maintaining higher levels of mitochondrial DNA variation. Ultimately, MHC data indicated that the reticulated flatwoods salamander may be at an elevated risk from infectious diseases due to low levels of immunogenetic variation necessary to combat novel pathogens.


Assuntos
Ambystoma/genética , Complexo Principal de Histocompatibilidade/genética , Ambystoma/virologia , Animais , Espécies em Perigo de Extinção , Éxons , Florida , Variação Genética , Georgia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Ranavirus
2.
Medicine (Baltimore) ; 99(15): e19820, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282748

RESUMO

Acute respiratory distress syndrome (ARDS) is characterized as a neutrophil-dominant disorder without effective pharmacological interventions. Knowledge of neutrophils in ARDS patients at the transcriptome level is still limited. We aimed to identify the hub genes and key pathways in neutrophils of patients with ARDS. The transcriptional profiles of neutrophils from ARDS patients and healthy volunteers were obtained from the GSE76293 dataset. The differentially expressed genes (DEGs) between ARDS and healthy samples were screened using the limma R package. Subsequently, functional and pathway enrichment analyses were performed based on the database for annotation, visualization, and integrated discovery (DAVID). The construction of a protein-protein interaction network was carried out using the search tool for the retrieval of interacting genes (STRING) database and the network was visualized by Cytoscape software. The Cytoscape plugins cytoHubba and MCODE were used to identify hub genes and significant modules. Finally, 136 upregulated genes and 95 downregulated genes were identified. Gene ontology analyses revealed MHC class II plays a major role in functional annotations. SLC11A1, ARG1, CHI3L1, HP, LCN2, and MMP8 were identified as hub genes, and they were all involved in the neutrophil degranulation pathway. The MAPK and neutrophil degranulation pathways in neutrophils were considered as key pathways in the pathogenesis of ARDS. This study improves our understanding of the biological characteristics of neutrophils and the mechanisms underlying ARDS, and key pathways and hub genes identified in this work can serve as targets for novel ARDS treatment strategies.


Assuntos
Biologia Computacional/instrumentação , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neutrófilos/metabolismo , Síndrome do Desconforto Respiratório do Adulto/genética , Degranulação Celular/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética/estatística & dados numéricos , Humanos , Complexo Principal de Histocompatibilidade/genética , Neutrófilos/patologia , Mapas de Interação de Proteínas/genética , Melhoria de Qualidade , Síndrome do Desconforto Respiratório do Adulto/patologia , Software , Transcriptoma/genética , Regulação para Cima/genética
3.
Immunogenetics ; 72(4): 225-239, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112172

RESUMO

Many medical advancements-including improvements to anti-rejection therapies in transplantation and vaccine development-rely on preclinical studies conducted in cynomolgus macaques (Macaca fascicularis). Major histocompatibility complex (MHC) class I and class II genes of cynomolgus macaques are orthologous to human leukocyte antigen complex (HLA) class I and class II genes, respectively. Both encode cell-surface proteins involved in cell recognition and rejection of non-host tissues. MHC class I and class II genes are highly polymorphic, so comprehensive genotyping requires the development of complete databases of allelic variants. Our group used PacBio circular consensus sequencing of full-length cDNA amplicons to characterize MHC class I and class II transcript sequences for a cohort of 293 Indonesian cynomolgus macaques (ICM) in a large, pedigreed breeding colony. These studies allowed us to expand the existing database of Macaca fascicularis (Mafa) alleles by identifying an additional 141 MHC class I and 61 class II transcript sequences. In addition, we defined co-segregating combinations of allelic variants as regional haplotypes for 70 Mafa-A, 78 Mafa-B, and 45 Mafa-DRB gene clusters. Finally, we defined class I and class II transcripts that are associated with 100 extended MHC haplotypes in this breeding colony by combining our genotyping analyses with short tandem repeat (STR) patterns across the MHC region. Our sequencing analyses and haplotype definitions improve the utility of these ICM for transplantation studies as well as infectious disease and vaccine research.


Assuntos
Haplótipos , Macaca fascicularis/genética , Complexo Principal de Histocompatibilidade/genética , Animais , Cruzamento , Indonésia , Repetições de Microssatélites
4.
Poult Sci ; 99(3): 1267-1274, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32111304

RESUMO

The chicken major histocompatibility B complex (MHC-B) region is of great interest owing to its very strong association with resistance to many diseases. Variation in the MHC-B was initially identified by hemagglutination of red blood cells with specific alloantisera. New technologies, developed to identify variation in biological materials, have been applied to the chicken MHC. Protein variation encoded by the MHC genes was examined by immunoprecipitation and 2-dimensional gel electrophoresis. Increased availability of DNA probes, PCR, and sequencing resulted in the application of DNA-based methods for MHC detection. The chicken reference genome, completed in 2004, allowed further refinements in DNA methods that enabled more rapid examination of MHC variation and extended such analyses to include very diverse chicken populations. This review progresses from the inception of MHC-B identification to the present, describing multiple methods, plus their advantages and disadvantages.


Assuntos
Técnicas de Química Analítica/veterinária , Galinhas/genética , Complexo Principal de Histocompatibilidade/genética , Animais , Técnicas de Química Analítica/métodos
5.
Proc Biol Sci ; 287(1921): 20192706, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32097586

RESUMO

Major histocompatibility complex (MHC)-based mating rules can evolve as a way to avoid inbreeding or to increase offspring immune competence. While the role of mating preference in shaping the MHC diversity in vertebrates has been acknowledged, its impact on individual MHC diversity has not been considered. Here, we use computer simulations to investigate how simple mating rules favouring MHC-dissimilar partners affect the evolution of the number of MHC variants in individual genomes, accompanying selection for resistance to parasites. We showed that the effect of such preferences could sometimes be dramatic. If preferences are aimed at avoiding identical alleles, the equilibrium number of MHC alleles is much smaller than under random mating. However, if the mating rule minimizes the ratio of shared to different alleles in partners, MHC number is higher than under random mating. Additionally, our simulations revealed that a negative correlation between the numbers of MHC variants in mated individuals can arise from simple rules of MHC-disassortative mating. Our results reveal unexpected potential of MHC-based mating preferences to drive MHC gene family expansions or contractions and highlight the need to study the mechanistic basis of such preferences, which is currently poorly understood.


Assuntos
Complexo Principal de Histocompatibilidade/genética , Preferência de Acasalamento Animal , Alelos , Animais , Feminino , Endogamia , Masculino
6.
Cancer Treat Rev ; 84: 101950, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31918022

RESUMO

Recent advances in our understanding of the molecular biology of gastric and oesophageal cancers have shown that gastroesophageal adenocarcinoma should be considered as one disease spectrum. Clinical management of these cancers is challenging, with poor outcomes in both early and late disease settings. Certain molecular subsets of gastroesophageal adenocarcinoma demonstrate features that suggest immunotherapy could be an effective treatment. Immunogenetic markers, including mismatch repair deficiency, PD-L1 status and tumour infiltrating lymphocytes influence overall prognosis. They may also determine the response to adjuvant and neoadjuvant conventional chemotherapy. Initial results from immunotherapy trials for gastroesophageal cancer have however been mixed, with poor overall responses in the first- and second-line settings. This review aims to discuss how better understanding of these immune and genetic interactions may lead to better selection of patients for conventional and immune based therapies, and therefore improve patient outcomes. We also discuss the challenges in implementing this new understanding in routine practice, and the current limitations of immune based treatments for gastroesophageal cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Quimioterapia Adjuvante , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Humanos , Fenômenos Imunogenéticos , Linfócitos do Interstício Tumoral/imunologia , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Instabilidade de Microssatélites , Terapia Neoadjuvante , Seleção de Pacientes , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
7.
Nat Rev Immunol ; 20(1): 25-39, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570880

RESUMO

'Immune checkpoint blockade' for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT-ß-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.


Assuntos
Imunoterapia , Neoplasias/terapia , Animais , Biomarcadores Tumorais/imunologia , Resistência à Doença/imunologia , Humanos , Interferon gama/imunologia , Complexo Principal de Histocompatibilidade , Transdução de Sinais , Linfócitos T/imunologia
8.
Immunogenetics ; 72(1-2): 5-8, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31522238

RESUMO

The laboratory rat (Rattus norvegicus) has a long tradition as experimental animal in transplantation and autoimmunity research and, hence, there has been an inherent interest in its major histocompatibility complex (MHC), the RT1 complex. Available inbred rat strains and their derived RT1-congenic and intra-RT1 recombinant congenic strains were crucial for definition and characterization of RT1 genes and alleles and essentially advanced elucidation of the RT1 genomic organization in the past. The Immuno Polymorphism Database (IPD) harbors a section for rat MHC genes and alleles (IPD-MHC RT1) since 2005. The curator for IPD-MHC RT1 provides official designations for newly described genes and alleles of RT1. This is the first nomenclature report of RT1 genes and alleles that are currently included in IPD-MHC RT1.


Assuntos
Bases de Dados Factuais , Complexo Principal de Histocompatibilidade/genética , Polimorfismo Genético , Terminologia como Assunto , Alelos , Animais , Ratos
9.
Immunogenetics ; 72(1-2): 49-55, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31641782

RESUMO

The Immuno Polymorphism Database (IPD), https://www.ebi.ac.uk/ipd/, is a set of specialist databases that enable the study of polymorphic genes which function as part of the vertebrate immune system. The major focus is on the hyperpolymorphic major histocompatibility complex (MHC) genes and the killer-cell immunoglobulin-like receptor (KIR) genes, by providing the official repository and primary source of sequence data. Databases are centred around humans as well as animals important for food security, for companionship and as disease models. The IPD project works with specialist groups or nomenclature committees who provide and manually curate individual sections before they are submitted for online publication. To reflect the recent advance of allele sequencing technologies and the increasing demands of novel tools for the analysis of genomic variation, the IPD project is undergoing a progressive redesign and reorganisation. In this review, recent updates and future developments are discussed, with a focus on the core concepts to better future-proof the project.


Assuntos
Antígenos de Plaquetas Humanas/genética , Complexo Principal de Histocompatibilidade/genética , Biologia Computacional/métodos , Bases de Dados como Assunto , Bases de Dados Factuais , Bases de Dados Genéticas , Epitopos de Linfócito T/genética , Antígenos HLA/genética , Humanos , Imunidade/genética , Polimorfismo Genético/genética , Alinhamento de Sequência/estatística & dados numéricos
10.
Immunogenetics ; 72(1-2): 89-100, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31713647

RESUMO

The IPD-MHC Database represents the official repository for non-human major histocompatibility complex (MHC) sequences, overseen and supported by the Comparative MHC Nomenclature Committee, providing access to curated MHC data and associated analysis tools. IPD-MHC gathers allelic MHC class I and class II sequences from classical and non-classical MHC loci from various non-human animals including pets, farmed and experimental model animals. So far, Atlantic salmon and rainbow trout are the only teleost fish species with MHC class I and class II sequences present. For the remaining teleost or ray-finned species, data on alleles originating from given classical locus is scarce hampering their inclusion in the database. However, a fast expansion of sequenced genomes opens for identification of classical loci where high-throughput sequencing (HTS) will enable typing of allelic variants in a variety of new teleost or ray-finned species. HTS also opens for large-scale studies of salmonid MHC diversity challenging the current database nomenclature and analysis tools. Here we establish an Illumina approach to identify allelic MHC diversity in Atlantic salmon, using animals from an endangered wild population, and alter the salmonid MHC nomenclature to accommodate the expected sequence expansions.


Assuntos
Complexo Principal de Histocompatibilidade/genética , Salmo salar/genética , Salmo salar/imunologia , Alelos , Animais , Bases de Dados Factuais , Evolução Molecular , Variação Genética , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Análise de Sequência de Proteína
11.
Nat Rev Immunol ; 20(2): 113-127, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31666730

RESUMO

The coordinated activities of innate and adaptive immunity are critical for effective protection against viruses. To counter this, some viruses have evolved sophisticated strategies to circumvent immune cell recognition. In particular, cytomegaloviruses encode large arsenals of molecules that seek to subvert T cell and natural killer cell function via a remarkable array of mechanisms. Consequently, these 'immunoevasins' play a fundamental role in shaping the nature of the immune system by driving the evolution of new immune receptors and recognition mechanisms. Here, we review the diverse strategies adopted by cytomegaloviruses to target immune pathways and outline the host's response.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Proteínas Virais/imunologia , Animais , Betaherpesvirinae/patogenicidade , Proteínas do Capsídeo/imunologia , Infecções por Herpesviridae/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Camundongos , Muromegalovirus/patogenicidade , Proteínas de Ligação a RNA/imunologia , Proteínas do Envelope Viral/imunologia
12.
Nucleic Acids Res ; 48(D1): D948-D955, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31667505

RESUMO

The IPD-IMGT/HLA Database, http://www.ebi.ac.uk/ipd/imgt/hla/, currently contains over 25 000 allele sequence for 45 genes, which are located within the Major Histocompatibility Complex (MHC) of the human genome. This region is the most polymorphic region of the human genome, and the levels of polymorphism seen exceed most other genes. Some of the genes have several thousand variants and are now termed hyperpolymorphic, rather than just simply polymorphic. The IPD-IMGT/HLA Database has provided a stable, highly accessible, user-friendly repository for this information, providing the scientific and medical community access to the many variant sequences of this gene system, that are critical for the successful outcome of transplantation. The number of currently known variants, and dramatic increase in the number of new variants being identified has necessitated a dedicated resource with custom tools for curation and publication. The challenge for the database is to continue to provide a highly curated database of sequence variants, while supporting the increased number of submissions and complexity of sequences. In order to do this, traditional methods of accessing and presenting data will be challenged, and new methods will need to be utilized to keep pace with new discoveries.


Assuntos
Alelos , Biologia Computacional , Bases de Dados Genéticas , Antígenos de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/genética , Software , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Navegador
13.
Immunogenetics ; 72(1-2): 25-36, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31624862

RESUMO

The major histocompatibility complex (MHC) is central to the innate and adaptive immune responses of jawed vertebrates. Characteristic of the MHC are high gene density, gene copy number variation, and allelic polymorphism. Because apes and monkeys are the closest living relatives of humans, the MHCs of these non-human primates (NHP) are studied in depth in the context of evolution, biomedicine, and conservation biology. The Immuno Polymorphism Database (IPD)-MHC NHP Database (IPD-MHC NHP), which curates MHC data of great and small apes, as well as Old and New World monkeys, has been upgraded. The curators of the database are responsible for providing official designations for newly discovered alleles. This nomenclature report updates the 2012 report, and summarizes important nomenclature issues and relevant novel features of the IPD-MHC NHP Database.


Assuntos
Bases de Dados Genéticas , Complexo Principal de Histocompatibilidade/genética , Primatas/genética , Primatas/imunologia , Alelos , Animais , Cercopithecidae/genética , Hominidae/genética , Complexo Principal de Histocompatibilidade/fisiologia , Filogenia , Platirrinos/genética , Polimorfismo Genético , Terminologia como Assunto
14.
Immunogenetics ; 72(1-2): 85-88, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31735991

RESUMO

Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Celíaca/imunologia , Epitopos de Linfócito T/imunologia , Glutens/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Animais , Humanos , Terminologia como Assunto
15.
Immunogenetics ; 72(1-2): 9-24, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31741010

RESUMO

Among the genes with the highest allelic polymorphism and sequence diversity are those encoding the classical class I and class II molecules of the major histocompatibility complex (MHC). Although many thousands of MHC sequences have been deposited in general sequence databases like GenBank, the availability of curated MHC sequences with agreed nomenclature has been enormously beneficial. Along with the Immuno Polymorphism Database-IMunoGeneTics/human leukocyte antigen (IPD-IMGT/HLA) database, a collection of databases for curated sequences of immune importance has been developed. A recent addition is an IPD-MHC database for chickens. For many years, the nomenclature system for chicken MHC genes has been based on a list of standard, presumed to be stable, haplotypes. However, these standard haplotypes give different names to identical sequences. Moreover, the discovery of new recombinants between haplotypes and a rapid increase in newly discovered alleles leaves the old system untenable. In this review, a new nomenclature is considered, for which alleles of different loci are given names based on the system used for other MHCs, and then haplotypes are named according to the alleles present. The new nomenclature system is trialled, first with standard haplotypes and then with validated sequences from the scientific literature. In the trial, some class II B sequences were found in both class II loci, presumably by gene conversion or inversion, so that identical sequences would receive different names. This situation prompts further suggestions to the new nomenclature system. In summary, there has been progress, but also problems, with the new IPD-MHC system for chickens.


Assuntos
Galinhas/genética , Bases de Dados Factuais , Imunogenética , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Polimorfismo Genético , Terminologia como Assunto , Animais
16.
Scand J Immunol ; 91(3): e12853, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31793005

RESUMO

What is the evolutionary mechanism for the TCR-MHC-conserved interaction? We extend Dembic's model (Dembic Z. In, Scand J Immunol e12806, 2019) of thymus positive selection for high-avidity anti-self-MHC Tregs among double (CD4 + CD8+)-positive (DP) developing thymocytes. This model is based on competition for self-MHC (+ Pep) complexes presented on cortical epithelium. Such T cells exit as CD4 + CD25+FoxP3 + thymic-derived Tregs (tTregs). The other positively selected DP T cells are then negatively selected on medulla epithelium removing high-avidity anti-self-MHC + Pep as T cells commit to CD4 + or CD8 + lineages. The process is likened to the competitive selection and affinity maturation in Germinal Centre for the somatic hypermutation (SHM) of rearranged immunoglobulin (Ig) variable region (V[D]Js) of centrocytes bearing antigen-specific B cell receptors (BCR). We now argue that the same direct SHM processes for TCRs occur in post-antigenic Germinal Centres, but now occurring in peripheral pTregs. This model provides a potential solution to a long-standing problem previously recognized by Cohn and others (Cohn M, Anderson CC, Dembic Z. In, Scand J Immunol e12790, 2019) of how co-evolution occurs of species-specific MHC alleles with the repertoire of their germline TCR V counterparts. We suggest this is not by 'blind', slow, and random Darwinian natural selection events, but a rapid structured somatic selection vertical transmission process. The pTregs bearing somatic TCR V mutant genes then, on arrival in reproductive tissues, can donate their TCR V sequences via soma-to-germline feedback as discussed in this journal earlier. (Steele EJ, Lindley RA. In, Scand J Immunol e12670, 2018) The high-avidity tTregs also participate in the same process to maintain a biased, high-avidity anti-self-MHC germline V repertoire.


Assuntos
Alelos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Evolução Molecular , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Mamíferos , Mutação , Ligação Proteica , Receptores de Antígenos de Linfócitos T/genética , Timócitos/imunologia , Timócitos/metabolismo
17.
BMC Evol Biol ; 19(1): 218, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791241

RESUMO

BACKGROUND: Lymphotoxin-α (LTα), located in the Major Histocompatibility Complex (MHC) class III region on chromosome 6, encodes a cytotoxic protein that mediates a variety of antiviral responses among other biological functions. Furthermore, several genotypes at this gene have been implicated in the onset of a number of complex diseases, including myocardial infarction, autoimmunity, and various types of cancer. However, little is known about levels of nucleotide variation and linkage disequilibrium (LD) in and near LTα, which could also influence phenotypic variance. To address this gap in knowledge, we examined sequence variation across ~ 10 kilobases (kbs), encompassing LTα and the upstream region, in 2039 individuals from the 1000 Genomes Project originating from 21 global populations. RESULTS: Here, we observed striking patterns of diversity, including an excess of intermediate-frequency alleles, the maintenance of multiple common haplotypes and a deep coalescence time for variation (dating > 1.0 million years ago), in global populations. While these results are generally consistent with a model of balancing selection, we also uncovered a signature of positive selection in the form of long-range LD on chromosomes with derived alleles primarily in Eurasian populations. To reconcile these findings, which appear to support different models of selection, we argue that selective sweeps (particularly, soft sweeps) of multiple derived alleles in and/or near LTα occurred in non-Africans after their ancestors left Africa. Furthermore, these targets of selection were predicted to alter transcription factor binding site affinity and protein stability, suggesting they play a role in gene function. Additionally, our data also showed that a subset of these functional adaptive variants are present in archaic hominin genomes. CONCLUSIONS: Overall, this study identified candidate functional alleles in a biologically-relevant genomic region, and offers new insights into the evolutionary origins of these loci in modern human populations.


Assuntos
Linfotoxina-alfa/genética , Complexo Principal de Histocompatibilidade , África , Animais , Evolução Biológica , Cromossomos Humanos Par 6 , Evolução Molecular , Frequência do Gene , Genética Populacional , Haplótipos , Hominidae/genética , Projeto Genoma Humano , Humanos , Desequilíbrio de Ligação , Linfotoxina-alfa/imunologia , Polimorfismo de Nucleotídeo Único
18.
J Hematol Oncol ; 12(1): 139, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852498

RESUMO

Adoptive T cell therapy has achieved dramatic success in a clinic, and the Food and Drug Administration approved two chimeric antigen receptor-engineered T cell (CAR-T) therapies that target hematological cancers in 2018. A significant issue faced by CAR-T therapies is the lack of tumor-specific biomarkers on the surfaces of solid tumor cells, which hampers the application of CAR-T therapies to solid tumors. Intracellular tumor-related antigens can be presented as peptides in the major histocompatibility complex (MHC) on the cell surface, which interact with the T cell receptors (TCR) on antigen-specific T cells to stimulate an anti-tumor response. Multiple immunotherapy strategies have been developed to eradicate tumor cells through targeting the TCR-peptide/MHC interactions. Here, we summarize the current status of TCR-based immunotherapy strategies, with particular focus on the TCR structure, activated signaling pathways, the effects and toxicity associated with TCR-based therapies in clinical trials, preclinical studies examining immune-mobilizing monoclonal TCRs against cancer (ImmTACs), and TCR-fusion molecules. We propose several TCR-based therapeutic strategies to achieve optimal clinical responses without the induction of autoimmune diseases.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Complexo Principal de Histocompatibilidade/imunologia , Mieloma Múltiplo/terapia , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Humanos , Mieloma Múltiplo/imunologia , Prognóstico , Linfócitos T/metabolismo , Linfócitos T/transplante
19.
Elife ; 82019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746734

RESUMO

The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed colonization in Cystic Fibrosis, postulating that downregulation of RNF5 expression is the likely causal mechanism. Our study provides insights into the genetic architecture of the MHC region and pinpoints disease associations that are due to differential expression of HLA genes and non-HLA genes.


Assuntos
Fibrose Cística/genética , Predisposição Genética para Doença , Complexo Principal de Histocompatibilidade/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Mapeamento Cromossômico , Fibrose Cística/patologia , Feminino , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA-Seq , Adulto Jovem
20.
Immunogenetics ; 71(10): 635-645, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31745606

RESUMO

It has become anticipated that regenerative medicine will extend into the field of veterinary medicine as new treatments for various disorders. Although the use of allogeneic stem cells for tissue regeneration is more attractive than that of autologous cells in emergencies, the therapeutic potential of allogeneic transplantation is often limited by allo-immune responses inducing graft rejection. Therefore, a methodology for quantifying and monitoring alloreactive T cells is necessary for evaluating allo-immune responses. The mixed lymphocyte reaction (MLR) is widely used to evaluate T cell alloreactivity. In human, flow cytometric MLR with carboxyfluorescein diacetate succinimidyl ester has been established and used as a more useful assay than conventional MLR with radioisotope labeling. However, the available information about alloreactivity based on the differences of dog major histocompatibility complex (MHC) (dog leukocyte antigen, DLA) is quite limited in dog. In this paper, we describe our established flow cytometric MLR method that can quantify the T cell alloreactivity while distinguishing cell phenotypes in dog, and T cell alloreactivity among DLA-type matched pairs was significantly lower than DLA-mismatched pairs, suggesting that our developed flow cytometric MLR method is useful for quantifying T cell alloreactivity. In addition, we demonstrated the advantage of DLA homozygous cells as a donor (stimulator) for allogeneic transplantation. We also elucidated that the frequency of alloreactive T cell precursors was almost the same as that of mouse and human (1-10%). To our knowledge, this is the first report to focus on the degree of allo-immune responses in dog based on the differences of DLA polymorphisms.


Assuntos
Citometria de Fluxo/métodos , Histocompatibilidade , Teste de Cultura Mista de Linfócitos/métodos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Polimorfismo Genético , Linfócitos T/imunologia , Animais , Cães , Haplótipos , Ativação Linfocitária/imunologia
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