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1.
Nat Commun ; 11(1): 4794, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963235

RESUMO

Most human genomes are characterized by aligning individual reads to the reference genome, but accurate long reads and linked reads now enable us to construct accurate, phased de novo assemblies. We focus on a medically important, highly variable, 5 million base-pair (bp) region where diploid assembly is particularly useful - the Major Histocompatibility Complex (MHC). Here, we develop a human genome benchmark derived from a diploid assembly for the openly-consented Genome in a Bottle sample HG002. We assemble a single contig for each haplotype, align them to the reference, call phased small and structural variants, and define a small variant benchmark for the MHC, covering 94% of the MHC and 22368 variants smaller than 50 bp, 49% more variants than a mapping-based benchmark. This benchmark reliably identifies errors in mapping-based callsets, and enables performance assessment in regions with much denser, complex variation than regions covered by previous benchmarks.


Assuntos
Diploide , Complexo Principal de Histocompatibilidade/genética , Benchmarking , Linhagem Celular , Variação Genética , Genoma Humano , Haplótipos , Humanos
2.
Nat Commun ; 11(1): 4128, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807809

RESUMO

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.


Assuntos
Mutação/genética , Neoplasias/genética , Neoplasias/imunologia , Fatores Etários , Alelos , Feminino , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Fatores Sexuais
3.
PLoS One ; 15(8): e0237765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804960

RESUMO

The failure of the maternal immune system to recognize fetal antigens and vice versa due to MHC similarity between the foal and its dam might result in the lack of placental separation during parturition in mares. The aim of the study was to investigate the influence of MHC similarity between a mare and a foal on the incidence of retained fetal membranes (RFM) in post-partum mares. DNA was sampled from 43 draft mares and their foals. Mares which failed to expel fetal membranes within three hours after foal expulsion were considered the RFM group (n = 14) and mares that expelled fetal membranes during the above period were the control group (n = 29). Nine MHC microsatellites of MHC I and MHC II were amplified for all mares and foals. MHC compatibility and MHC genetic similarity between mares and their foals was determined based on MHC microsatellites. The inbreeding coefficient was also calculated for all horses. The incidence of RFM in the studied population was 33%. Compatibility in MHC I and MHC II did not increase the risk of RFM in the studied population of draft mares (P>0.05). Differences in MHC similarity at the genetic level were not observed between mare-foal pairs in RFM and control group (P>0.05). We suspect that RFM in draft mares may not be associated with MHC similarity between a foal and its dam. Despite the above, draft horses could be genetically predisposed to the disease.


Assuntos
Doenças dos Cavalos/imunologia , Cavalos/imunologia , Endogamia , Complexo Principal de Histocompatibilidade/imunologia , Placenta Retida/veterinária , Animais , Estudos Transversais , Feminino , Técnicas de Genotipagem , Doenças dos Cavalos/epidemiologia , Cavalos/genética , Incidência , Complexo Principal de Histocompatibilidade/genética , Repetições de Microssatélites/genética , Repetições de Microssatélites/imunologia , Placenta Retida/epidemiologia , Placenta Retida/imunologia , Período Pós-Parto , Gravidez
4.
Immunogenetics ; 72(5): 325-332, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32488290

RESUMO

Described here is a new, more efficient method for defining major histocompatibility complex-Y (MHC-Y) genotypes in chickens. The MHC-Y region is genetically independent from the classical MHC (MHC-B) region. MHC-Y is highly polymorphic and potentially important in the genetics of disease resistance. MHC-Y haplotypes contain variable numbers of specialized MHC class I-like genes, along with members of four additional gene families. Previously, MHC-Y haplotypes were defined by patterns of restriction fragments (RF) generated in labor-intensive procedures that were difficult to use to define MHC-Y genotypes for large numbers of samples. The method reported here is much simpler. MHC-Y genotypes are distinguished via patterns of PCR products generated from heritable short tandem repeat (STR) regions found immediately upstream of the MHC class I-like genes located throughout MHC-Y haplotypes. To validate the method, fully pedigreed families were analyzed for STR-defined haplotypes in light of haplotypes defined previously by RF patterns. STR-defined MHC-Y patterns segregate in fully pedigreed families as expected and correspond with haplotypes assigned by RF patterns. The patterns provided in STR chromatograms generated by capillary electrophoresis are distinct for different haplotypes and can be scored easily. Investigations into the influence of MHC-Y genetics on immune responses can now realistically be conducted with large sample sets.


Assuntos
Galinhas/genética , Complexo Principal de Histocompatibilidade/genética , Repetições de Microssatélites/genética , Animais , Genótipo , Haplótipos , Família Multigênica/genética , Reação em Cadeia da Polimerase/veterinária , Reprodutibilidade dos Testes , Fatores de Tempo
5.
Mol Immunol ; 124: 83-90, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32544655

RESUMO

Major histocompatibility complex (MHC) genes are critical for disease resistance or susceptibility responsible for host-pathogen interactions determined mainly by extensive polymorphisms in the MHC genes. Here, we examined the diversity and phylogenetic pattern of MHC haplotypes reconstructed using three MHC-linked microsatellite markers in 55 populations of five Bovidae species and compared them with those based on neutral autosomal microsatellite markers (NAMs). Three-hundred-and-forty MHC haplotypes were identified in 1453 Bovidae individuals, suggesting significantly higher polymorphism and heterozygosity compared with those based on NAMs. The ambitious boundaries in population differentiation (phylogenetic network, pairwise FST and STRUCTURE analyses) within and between species assessed using the MHC haplotypes were different from those revealed by NAMs associated closely with speciation, geographical distribution, domestication and management histories. In addition, the mean FST was significantly correlated negatively with the number of observed alleles (NA), observed (HO) and expected (HE) heterozygosity and polymorphism information content (PIC) (P < 0.05) in the MHC haplotype dataset while there was no correction of the mean FST estimates (P> 0.05) between the MHC haplotype and NAMs datasets. Analysis of molecular variance (AMOVA) revealed a lower percentage of total variance (PTV) between species/groups based on the MHC-linked microsatellites than NAMs. Therefore, it was inferred that individuals within populations accumulated as many MHC variants as possible to increase their heterozygosity and thus the survival rate of their affiliated populations and species, which eventually reduced population differentiation and thereby complicated their classification and phylogenetic relationship inference. In summary, host-pathogen coevolution and heterozygote advantage, rather than demographic history, act as key driving forces shaping the MHC diversity within the populations and determining the interspecific MHC diversity.


Assuntos
Animais Domésticos/genética , Evolução Biológica , Interações Hospedeiro-Patógeno/genética , Complexo Principal de Histocompatibilidade/genética , Animais , Animais Domésticos/imunologia , Bovinos , Variação Genética , Haplótipos , Heterozigoto , Interações Hospedeiro-Patógeno/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Repetições de Microssatélites , Filogenia
6.
Nature ; 582(7813): 577-581, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499649

RESUMO

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.


Assuntos
Complemento C3/genética , Complemento C4/genética , Lúpus Eritematoso Sistêmico/genética , Caracteres Sexuais , Síndrome de Sjogren/genética , Adulto , Alelos , Complemento C3/análise , Complemento C3/líquido cefalorraquidiano , Complemento C4/análise , Complemento C4/líquido cefalorraquidiano , Feminino , Predisposição Genética para Doença , Antígenos HLA/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/líquido cefalorraquidiano , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/sangue , Síndrome de Sjogren/líquido cefalorraquidiano , Adulto Jovem
7.
Avian Dis ; 64(1): 36-45, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32267123

RESUMO

The chicken major histocompatibility complex (MHC) B locus has been linked to resistance to infectious diseases. We have previously provided evidence that the MHC congenic chicken lines 331/B2 and 335/B19 differ in susceptibility to infectious bronchitis virus (IBV) strains M41 and ArkDPI in in vivo challenge experiments. Innate immune responses can be difficult to measure in vivo because they are nonspecific and can be triggered by environmental factors. In an attempt to address this issue, we used tracheal organ cultures derived from 331/B2 and 335/B19 birds to study local cytokine production after in vitro challenge with IBV M41. Interferon (IFN)-ß, interleukin (IL)-1ß, IL-6, and IL-10 gene expression and production were assessed. Tracheal organ cultures derived from 335/B19 birds presented an increased inflammatory response compared to 331/B2. However, it was not possible to discriminate between cytokine responses in IBV-infected and phosphate-buffered saline-treated tracheal organ cultures. Because tracheal processing entails physical damage to the trachea, it is possible that the tracheal organ cultures presented high levels of inflammation regardless of the IBV challenge. To demonstrate the effects of IBV on innate immune responses in the MHC congenic chicken lines, we performed an additional in vivo experiment that focused on cytokine gene expression and production in tracheas up to 60 hr after a challenge with IBV M41. Our results corroborate previous in vivo observations that suggest that detrimental local inflammatory responses in 335/B19 birds might be associated with their susceptibility to IBV and that inflammation does not necessarily lead to the assembly of an appropriate adaptive immune response. This work provides further insight into the increased susceptibility of 335/B19 birds to infectious bronchitis.


Assuntos
Proteínas Aviárias/genética , Galinhas , Infecções por Coronavirus/veterinária , Citocinas/genética , Expressão Gênica , Vírus da Bronquite Infecciosa/fisiologia , Doenças das Aves Domésticas/fisiopatologia , Animais , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Complexo Principal de Histocompatibilidade/genética , Doenças das Aves Domésticas/virologia
8.
Clin Immunol ; 214: 108405, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32247832

RESUMO

Psoriatic arthritis (PsA) is a heterogeneous disease that affects multiple organ systems including the peripheral and axial joints, entheses and nails. PsA is associated with significant comorbidities including cardiovascular, metabolic, and psychiatric diseases. The pathogenesis of PsA is complex and involves genetic, immunologic and environmental factors. Recent evidence suggests the heritability for PsA to be stronger and distinct from that of PsC. Prominent genes identified via GWAS for PsA include HLA-B/C, HLAB, IL12B, IL23R, TNP1, TRAF3IP3, and REL. We review the genetics of psoriatic arthritis and discuss the role of the innate immune system as important in the pathogenesis of PsA by focusing on key signaling pathways and cellular makeup. Understanding the candidate genes identified in PsA highlights pathways of critical importance to the pathogenesis of psoriatic disease including the key role of the innate immune response, mediated through IL-23/IL-17 axis, RANK and NFκB signaling pathways.


Assuntos
Artrite Psoriásica/imunologia , Imunidade Inata/genética , Artrite Psoriásica/genética , Células Dendríticas/imunologia , Estudo de Associação Genômica Ampla , Humanos , Interleucinas/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/imunologia , Complexo Principal de Histocompatibilidade/genética , Monócitos/imunologia , Herança Multifatorial , NF-kappa B/fisiologia , Neutrófilos/imunologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Transdução de Sinais/genética
9.
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
10.
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
11.
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
12.
J Immunol ; 204(7): 1982-1987, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122998

RESUMO

GFP is frequently used as a marker for tracking donor cells adoptively transplanted into recipient animals. The human ubiquitin C promoter (UBC)-driven-GFP transgenic mouse is a commonly used source of donor cells for this purpose. This mouse was initially generated in the C57BL/6 inbred strain and has been backcrossed into the BALB/cBy strain for over 11 generations. Both the C57BL/6 inbred and BALB/cBy congenic UBC-GFP lines are commercially available and have been widely distributed. These UBC-GFP lines can be a convenient resource for tracking donor cells in both syngenic MHC-matched and in allogenic MHC-mismatched studies as C57BL/6 (H-2b) and BALB/cBy (H-2d) have disparate MHC haplotypes. In this report, we surprisingly discover that the UBC-GFP BALB/cBy congenic mice still retain the H-2b MHC haplotype of their original C57BL/6 founder, suggesting that the UBC-GFP transgene integration site is closely linked to the MHC locus on chromosome 17. Using linear amplification-mediated PCR, we successfully map the UBC-GFP transgene to the MHC locus. This study highlights the importance and urgency of mapping the transgene integration site of transgenic mouse strains used in biomedical research. Furthermore, this study raises the possibility of alternative interpretations of previous studies using congenic UBC-GFP mice and focuses attention on the necessity for rigor and reproducibility in scientific research.


Assuntos
Cromossomos/genética , Proteínas de Fluorescência Verde/genética , Complexo Principal de Histocompatibilidade/genética , Mutagênese Insercional/genética , Transgenes/genética , Ubiquitina C/genética , Animais , Haplótipos/genética , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Reprodutibilidade dos Testes
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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