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1.
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
2.
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
3.
BMC Evol Biol ; 19(1): 90, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975084

RESUMO

BACKGROUND: Different population trajectories are expected to impact the signature of neutral and adaptive processes at multiple levels, challenging the assessment of the relative roles of different microevolutionary forces. Here, we integrate adaptive and neutral variability patterns to disentangle how adaptive diversity is driven under different demographic scenarios within the Iberian wolf (Canis lupus) range. We studied the persistent, the expanding and a small, isolated group within the Iberian wolf population, using 3 MHC class II genes (DRB1, DQA1, and DQB1), which diversity was compared with 39 microsatellite loci. RESULTS: Both the persistent and the expanding groups show evidence of balancing selection, revealed by a significant departure from neutrality at MHC loci, significant higher observed and expected heterozygosity and lower differentiation at MHC than at neutral loci, and signs of positive selection. However, despite exhibiting a significantly higher genetic diversity than the isolated group, the persistent group did not show significant excess of MHC heterozygotes. The expanding group, while showing a similar level of genetic diversity than the persistent group, displays by contrast a significant excess of MHC heterozygotes, which is compatible with the heterozygote advantage mechanism. Results are not clear regarding the role of drift and selection in the isolated group due to the small size of this population. Although diversity indices of MHC loci correspond to neutral expectations in the isolated group, accelerated MHC divergence, revealed by a higher differentiation at MHC than neutral loci, may indicate diversifying selection. CONCLUSION: Different selective pressures were observed in the three different demographic scenarios, which are possibly driven by different selection mechanisms to maintain adaptive diversity.


Assuntos
Variação Genética , Seleção Genética , Lobos/genética , Alelos , Animais , Demografia , Genes MHC da Classe II , Geografia , Haplótipos/genética , Heterozigoto , Repetições de Microssatélites/genética , Análise de Componente Principal
4.
Dev Comp Immunol ; 96: 126-134, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30853539

RESUMO

The major histocompatibility complex (MHC) genes show high polymorphisms in vertebrates depending on animal immunity status. Herein, MHC class IIA gene in Aeromonas hydrophila-challenged Nile tilapia was screened for presence of polymorphisms using sequencing. Twelve nucleotides deletion polymorphism was determined with a PCR product size of 267 bp in the resistant fish and 255 bp in the control and susceptible/diseased fish. Additionally, a non-synonymous right frameshift c.712 T > G (P. 238 * > G) SNP was detected at the stop codon (*). SNP-susceptibility association analysis revealed that fish carrying GG genotype and allele G were high susceptible (risk) for A. hydrophila, and had lower immune response as indicated by significant reduction in non-specific immune parameters (total protein, globulin, IgM, phagocytic activity, phagocytic index, and lysosome activity) and mRNA level of MHC IIA, interleukin 1 beta (IL1ß), tumor necrosis factor alfa (TNFα), and toll-like receptor 7 (TLR7) in the spleen and head kidney. Thus, G allele could be considered as a risk (recessive or mutant) allele for c. 712 T > G (P. 238 * > G) SNP and so selection of Nile tilapia with protective allele (T) for this SNP could improve the disease resistant of the fish.


Assuntos
Aeromonas hydrophila/patogenicidade , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Genes MHC da Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Aeromonas hydrophila/imunologia , Alelos , Animais , Ciclídeos/genética , Ciclídeos/microbiologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Doenças dos Peixes/genética , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas , Rim Cefálico/imunologia , Rim Cefálico/metabolismo , Rim Cefálico/microbiologia , Antígenos de Histocompatibilidade Classe II/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Polimorfismo Genético/imunologia , Baço/imunologia , Baço/metabolismo , Baço/microbiologia
5.
Genome Biol Evol ; 11(4): 1019-1032, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30903183

RESUMO

The Chinese forest musk deer (Moschus berezovskii; FMD) is an artiodactyl mammal and is both economically valuable and highly endangered. To investigate the genetic mechanisms of musk secretion and adaptive immunity in FMD, we compared its genome to nine other artiodactyl genomes. Comparative genomics demonstrated that eight positively selected genes (PSGs) in FMD were annotated in three KEGG pathways that were related to metabolic and synthetic activity of musk, similar to previous transcriptome studies. Functional enrichment analysis indicated that many PSGs were involved in the regulation of immune system processes, implying important reorganization of the immune system in FMD. FMD-specific missense mutations were found in two PSGs (MHC class II antigen DRA and ADA) that were classified as deleterious by PolyPhen-2, possibly contributing to immune adaptation to infectious diseases. Functional assessment showed that the FMD-specific mutation enhanced the ADA activity, which was likely to strengthen the immune defense against pathogenic invasion. Single nucleotide polymorphism-based inference showed the recent demographic trajectory for FMD. Our data and findings provide valuable genomic resources not only for studying the genetic mechanisms of musk secretion and adaptive immunity, but also for facilitating more effective management of the captive breeding programs for this endangered species.


Assuntos
Imunidade Adaptativa , Cervos/fisiologia , Ácidos Graxos Monoinsaturados/metabolismo , Filogenia , Sequência de Aminoácidos , Animais , Genes MHC da Classe II , Genoma , Masculino , Família Multigênica , Mutação de Sentido Incorreto , Dinâmica Populacional , Seleção Genética
6.
Immunogenetics ; 71(5-6): 383-393, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796497

RESUMO

The ovine MHC class IIa is known to consist of six to eight loci located in close proximity on chromosome 20, forming haplotypes that are typically inherited without recombination. Here, we characterise the class IIa haplotypes within the Soay sheep (Ovis aries) on St. Kilda to assess the diversity present within this unmanaged island population. We used a stepwise sequence-based genotyping strategy to identify alleles at seven polymorphic MHC class IIa loci in a sample of 118 Soay sheep from four cohorts spanning 15 years of the long-term study on St. Kilda. DRB1, the most polymorphic MHC class II locus, was characterised first in all 118 sheep and identified six alleles. Using DRB1 homozygous animals, the DQA (DQA1, DQA2 and DQA2-like) and DQB (DQB1, DQB2 and DQB2-like) loci were sequenced, revealing eight haplotypes. Both DQ1/DQ2 and DQ2/DQ2-like haplotype configurations were identified and a single haplotype carrying three DQB alleles. A test sample of 94 further individuals typed at the DRB1 and DQA loci found no exceptions to the eight identified haplotypes and a haplotype homozygosity of 21.3%. We found evidence of historic positive selection at DRB1, DQA and DQB. The limited variation at MHC class IIa loci in Soay sheep enabled haplotype characterisation but showed that no single locus could capture the full extent of the expressed variation in the region.


Assuntos
Alelos , Genes MHC da Classe II , Genética Populacional , Haplótipos , Ovinos/genética , Animais , Frequência do Gene , Filogenia , Recombinação Genética , Seleção Genética , Análise de Sequência de DNA
7.
Nat Commun ; 10(1): 391, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674883

RESUMO

Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous GWAS. Aiming to define vitiligo subtypes, we discovered that age-of-onset is bimodal; one-third of cases have early onset (mean 10.3 years) and two-thirds later onset (mean 34.0 years). In the early-onset subgroup we found novel association with MHC class II region indel rs145954018, and independent association with the principal MHC class II locus from previous GWAS, represented by rs9271597; greatest association was with rs145954018del-rs9271597A haplotype (P = 2.40 × 10-86, OR = 8.10). Both rs145954018 and rs9271597 are located within lymphoid-specific enhancers, and the rs145954018del-rs9271597A haplotype is specifically associated with increased expression of HLA-DQB1 mRNA and HLA-DQ protein by monocytes and dendritic cells. Thus, for vitiligo, MHC regulatory variation confers extreme risk, more important than HLA coding variation. MHC regulatory variation may represent a significant component of genetic risk for other autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Genes MHC da Classe II/imunologia , Predisposição Genética para Doença , Haplótipos/imunologia , Vitiligo/genética , Vitiligo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Células Dendríticas , Feminino , Regulação da Expressão Gênica/genética , Genes MHC da Classe II/genética , Loci Gênicos , Genótipo , Antígenos HLA-DQ/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Monócitos , Fenótipo , RNA Mensageiro/metabolismo , Regulação para Cima , Adulto Jovem
8.
Cell ; 176(1-2): 334-347.e12, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30580966

RESUMO

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.


Assuntos
Antígenos CD/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , Animais , Antígenos CD/imunologia , Linhagem Celular , Fibrinogênio/imunologia , Fibrinogênio/metabolismo , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoterapia , Ligantes , Fígado/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia
9.
Mol Ecol ; 28(4): 833-846, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582649

RESUMO

To increase fitness, a wide range of vertebrates preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) or that have high MHC diversity. Although MHC often can be assessed through olfactory cues, the mechanism by which MHC genes influence odour remains largely unclear. MHC class IIB molecules, which enable recognition and elimination of extracellular bacteria, have been suggested to influence odour indirectly by shaping odour-producing microbiota, i.e. bacterial communities. However, there is little evidence of the predicted covariation between an animal's MHC genotype and its bacterial communities in scent-producing body surfaces. Here, using high-throughput sequencing, we tested the covariation between MHC class IIB genotypes and feather microbiota in the blue petrel (Halobaena caerulea), a seabird with highly developed olfaction that has been suggested to rely on oduor cues during an MHC-based mate choice. First, we show that individuals with similar MHC class IIB profiles also have similar bacterial assemblages in their feathers. Then, we show that individuals with high MHC diversity have less diverse feather microbiota and also a reduced abundance of a bacterium of the genus Arsenophonus, a genus in which some species are symbionts of avian ectoparasites. Our results, showing that feather microbiota covary with MHC, are consistent with the hypothesis that individual MHC genotype may shape the semiochemical-producing microbiota in birds.


Assuntos
Aves/metabolismo , Aves/microbiologia , Microbiota/fisiologia , Animais , Genes MHC da Classe II/genética , Genes MHC da Classe II/fisiologia , Genótipo , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/fisiologia , Microbiota/genética
10.
Curr Opin Nephrol Hypertens ; 28(1): 70-76, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30451735

RESUMO

PURPOSE OF REVIEW: Despite major advances in since the discovery of the phospholipase A2 receptor (PLA2R) as the major autoantigen on podocytes in primary membranous nephropathy, there are still several unanswered questions as highlighted here. RECENT FINDINGS: A substantial body of literature, included in more than 680 articles since 2009, has documented genetic susceptibility to primary membranous nephropathy involving PLA2R1 and class II MHC alleles, the clinical value of anti-PLA2R assays, the significance of epitope spreading of the anti-PLA2R response, discovery of thrombospondin type I domain-containing 7A (THSD7A) as a minor antigen in primary membranous nephropathy, and the ability to transfer disease into mice by infusion of anti-THSD7A sera. However, the normal physiology and pathophysiology of PLA2R and THSD7A in podocytes is still unknown and the genetic influence on disease susceptibility is unexplained. We still do not know what causes loss of self-tolerance to PLA2R and THSD7A or how the autoantibodies, which are predominantly of the IgG4 subclass, cause podocyte injury and proteinuria. Complement deposits are prominent in membranous nephropathy but we are still uncertain how the complement system is activated and whether or not it plays a role in podocyte damage. Notwithstanding the advances over the past decade, our treatments have not changed substantially. SUMMARY: This review identifies opportunities to extend the advances that have been made to better understand the immunopathogenesis and genetic basis of primary membranous nephropathy and apply the knowledge to design more specific therapies.


Assuntos
Glomerulonefrite Membranosa/etiologia , Autoanticorpos/imunologia , Proteínas do Sistema Complemento , Genes MHC da Classe II , Glomerulonefrite Membranosa/imunologia , Humanos , Podócitos/imunologia , Proteinúria/etiologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia
11.
Vet Res ; 49(1): 96, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30241566

RESUMO

Primary porcine alveolar macrophages (PAM) are useful for studying viral infections and immune response in pigs; however, long-term use of these cells is limited by the cells' short lifespan. We immortalized primary PAMs by transfecting them with both hTERT and SV40LT and established two immortalized cell lines (iPAMs) actively proliferating even after 35 passages. These cells possessed the characteristics of primary PAMs, including strong expression of swine leukocyte antigen (SLA) class II genes and the inability to grow anchorage-independently. We characterized their SLA genes and subsequently performed peptide-SLA binding assays using a peptide from porcine circovirus type 2 open reading frame 2 to experimentally measure the binding affinity of the peptide to SLA class II. The number of peptides bound to cells measured by fluorescence was very low for PK15 cells (7.0% ± 1.5), which are not antigen-presenting cells, unlike iPAM61 (33.7% ± 3.4; SLA-DQA*0201/0303, DQB1*0201/0901, DRB1*0201/1301) and iPAM303 (73.3% ± 5.4; SLA DQA*0106/0201, DQB1*0202/0701, DRB1*0402/0602). The difference in peptide binding between the two iPAMs was likely due to the allelic differences between the SLA class II molecules that were expressed. The development of an immortal PAM cell panel harboring diverse SLA haplotypes and the use of an established method in this study can become a valuable tool for evaluating the interaction between antigenic peptides and SLA molecules and is important for many applications in veterinary medicine including vaccine development.


Assuntos
Genes MHC da Classe II/fisiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Macrófagos Alveolares/metabolismo , Suínos/metabolismo , Animais , Linhagem Celular , Peptídeos/metabolismo , Ligação Proteica
12.
Toxicol Lett ; 296: 106-113, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30099064

RESUMO

Intensive research during the past decade has highlighted the impact of the regulatory function of the aryl hydrocarbon receptor (AhR) in immunity. In this study, we focused on the influence of AhR activation on the differentiation of murine bone marrow-derived myeloid precursor cells into mature macrophages. Our results show that the activation of AhR by subtoxic doses of the AhR ligand benzo(a)pyrene (BaP) impaired the proliferation of bone marrow cells (BMCs) whereas the proportion of resulting adherent cells was not affected. Flow cytometric analysis revealed that the number of mature bone marrow-derived macrophages (BMMs) was significantly decreased by AhR activation. However, expression of the murine macrophage marker F4/80, the major histocompatibility complex class II (MHC-II) and the Fcγ receptor I (FcγRI/CD64) were upregulated on BaP-exposed BMMs in an AhR-dependent manner. Analysis of cytokine secretion after BMM activation with heat-killed (hk) salmonellae showed that BaP exposure resulted in suppressed secretion of interleukin (IL)-1ß, IL-6 and the chemokine CXC motif ligand 1 (CXCL1). In contrast, the release of tumor necrosis factor (TNF)-α and IL-10 was increased following BaP exposure. In addition, the production of antimicrobial nitric oxide (NO) was increased AhR-dependently. Bacterial stimulation of BaP exposed BMMs also induced the expression of MHC-II and CD64, while the expression of F4/80 was dramatically decreased. In summary, this study demonstrates for the first time that sustained exposure over 6 days of bone marrow-derived myeloid precursors to subtoxic doses of BaP critically interferes with differentiation and activation of BMMs. We could convincingly show that AhR-induced gene regulation is crucial for homeostasis of pro- and anti-inflammatory cytokines during macrophage activation.


Assuntos
Benzo(a)pireno/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Células Progenitoras Mieloides/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Antígenos de Diferenciação/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Genes MHC da Classe II/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fenótipo
14.
Fish Shellfish Immunol ; 80: 302-310, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29902561

RESUMO

The major histocompatibility complex (MHC) plays an important role in the vertebrate immune response to antigenic peptides, and it is essential for recognizing foreign pathogens in organisms. In this study, MHC class IIα (Trov-MHC IIα) from the golden pompano (Trachinotus ovatus) was first cloned and identified. The gene structure of Trov-MHC IIα was contained four exons and three introns. High levels of polymorphism were found in the exon 2 of Trov-MHC IIα. A total of 29 different MHC class IIα alleles with high polymorphism were identified from 80 individuals. The ratio of non-synonymous substitutions (dN) to synonymous substitutions (dS) was 3.157 (>1) in the peptide binding regions (PBRs) of Trov-MHC IIα, suggesting positive balancing selection. Six alleles were selected to analyze the association between alleles and resistance/susceptibility to Vibrio harveyi in golden pompano. The results showed that Trov-DAA*6401 and Trov-DAA*6702 alleles were associated with the resistance to V. harveyi in golden pompano, while alleles Trov-DAA*6304 and Trov-DAA*7301 were associated with the susceptibility to V. harveyi in golden pompano. This study confirmed the association between alleles of MHC class IIα and disease resistance, and also detected some alleles which might be correlated with high V. harveyi-resistance. These disease resistance-related MHC alleles could be used as potential genetic markers for molecular marker-assisted selective breeding in the golden pompano.


Assuntos
Resistência à Doença , Doenças dos Peixes , Peixes/genética , Peixes/imunologia , Genes MHC da Classe II , Vibrioses , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar/genética , Resistência à Doença/genética , Resistência à Doença/imunologia , Doenças dos Peixes/genética , Doenças dos Peixes/imunologia , Polimorfismo Genético , Análise de Sequência de DNA , Vibrio , Vibrioses/genética , Vibrioses/imunologia , Vibrioses/veterinária
15.
Iran J Immunol ; 15(2): 97-111, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29947339

RESUMO

BACKGROUND: The high polymorphism in the human leukocyte antigen (HLA) genes can be used as an identity of individuals to compare with other populations. This extreme polymorphism in the HLA system is accountable for the differences in alleles and haplotypes among ethnic groups, populations, and the inhabitants of many regions. OBJECTIVE: To define the frequency of HLA alleles and haplotypes among the Sistanis, Sistani/Zaboli population in Iran. METHODS: In this study, genotyping of class I (A, B, C) and class II HLA (DRB1, DQA1, DQB1) loci were determined in 90 unrelated Iraninan Sistani people and the results were compared with 474,892 HLA chromosomes from a diverse worldwide population. RESULTS: The highest frequently observed alleles in this study were A*02:01, B*35:01, C*12:03, C*06:02, DRB1*11, DQA1*05:05, and DQB1*03:01. Furthermore, the most frequent 3-locus haplotypes were A*02:01-B*50:01*C*06:02, DRB1*11-DQB1*03:01-DQA1*05:05, and A*02:01-B*50:01-DRB1*07. The most occurring 4-locus haplotypes were A*02:01-B*50:01-C*06:02-DRB1*07 and A*02:01-B*50:01-DRB1*07-DQB1*02:01. A*02:01-B*50:01-C*06:02-DRB1*07-DQB1*02:01 and A*02:01-B*50:01-C*06:02-DRB1*07-DQB1*02:01-DQA1*02:01 were determined to be the predominant 5- and 6-locus haplotypes, respectively. The heat maps and multiple correspondence analyses based on the frequency of HLA alleles showed that Sistanis share a common genetic inheritance with other Iranian ethnic groups such as the people from Yazd and Fars except some differences with Baluchis, Iranian Jews, Lurs of Kohgiluyeh/Buyerahmad, and Arabs of Fars, which may arise from the admixture of these groups or with foreign subgroups over centuries, and also a close relatedness with some European populations. CONCLUSION: These data could be useful for finding better donor matches for organ transplantation among Sistanis or other related Iranian ethnic groups, epidemiological studies of HLA-associated diseases, handling HLA genomics and mapping the migration pattern of different ethnic group.


Assuntos
Grupos Étnicos/genética , Genes MHC da Classe II , Genes MHC Classe I , Genética Populacional , Alelos , Análise por Conglomerados , Frequência do Gene , Geografia , Antígenos HLA/genética , Haplótipos , Teste de Histocompatibilidade , Humanos , Irã (Geográfico) , Desequilíbrio de Ligação , Polimorfismo Genético
16.
Vet Immunol Immunopathol ; 200: 1-6, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29776607

RESUMO

Mesenchymal stem cells (MSCs) are a promising treatment for equine musculoskeletal injuries because of their ability to regulate the inflammation and to differentiate into other cell types. Since interest in allogeneic therapy is rising, concerns about MSC immunogenicity need to be addressed. Differentiated MSCs from several species increase their expression of immunogenic molecules and induce alloresponses, but equine MSC immunogenic profile after differentiation has not been reported. Therefore, the aim of this study was to assess the gene expression of immunogenic markers in tri-lineage differentiated equine bone marrow derived MSCs (eBM-MSCs). For this purpose, eBM-MSCs (n = 4) were differentiated into osteoblasts, adipocytes and chondrocytes. Differentiation was confirmed by specific staining and gene expression of lineage-related markers. Subsequently, gene expression of MHC-I, MHC-II, CD40 and CD80 was analyzed in undifferentiated (control) and tri-lineage differentiated eBM-MSCs. Osteogenesis and adipogenesis, but not chondrogenesis, significantly upregulated MHC-I; MHC-II expression significantly increased in the three lineages, while CD40 and CD80 expression did not change. Despite this, MHC-I and MHC-II upregulation after differentiation might lead to increased immunogenicity and risk of allorecognition, either eBM-MSCs differentiate in vivo after administration or they are differentiated prior to administration, with potential negative consequences for effectiveness and safety of allogeneic therapy.


Assuntos
Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Genes MHC da Classe II , Genes MHC Classe I , Células-Tronco Mesenquimais/metabolismo , Adipogenia , Animais , Antígeno B7-1/metabolismo , Antígenos CD40/metabolismo , Condrogênese , Expressão Gênica/genética , Cavalos , Masculino , Osteogênese , Reação em Cadeia da Polimerase em Tempo Real/veterinária
17.
Vet J ; 235: 9-15, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29704945

RESUMO

The clinical outcome of Leishmania infantum infection in dogs varies from subclinical infection to severe disease. Researchers attribute this variability in clinical manifestations to the ability of the immune response to limit pathogen multiplication and dissemination, which is, in part, likely determined by the immune response genes. The aim of this study was to test the hypothesis that MHC class II genes are associated with disease outcome of experimental L. infantum infection in Beagles. Dog leukocyte antigen (DLA) class II haplotypes were characterised by sequence-based typing of Beagle dogs experimentally infected with L. infantum during vaccine challenge studies. Variability of response to infection was determined by clinical score, serology and quantification of L. infantum DNA in the bone marrow over the study period. Dogs showed limited DLA diversity and the DLA profiles of dogs recruited for the different vaccine challenge studies differed. There were variable responses to infection, despite the apparent restriction in genetic diversity. One haplotype DLA-DRB1*001:02-DQA1*001:01-DQB1*002:01 was associated with increased anti-Leishmania antibodies in one infection model, but no DLA associations were found in other groups or with parasite load or clinical score. Examination of this particular DLA haplotype in a larger number of dogs is required to confirm whether an association exists with the immune or clinical responses to L. infantum infection.


Assuntos
Doenças do Cão/parasitologia , Genes MHC da Classe II/imunologia , Leishmania infantum , Leishmaniose Visceral/veterinária , Animais , Anticorpos Antiprotozoários/sangue , Medula Óssea/parasitologia , DNA de Protozoário/análise , Doenças do Cão/imunologia , Cães , Genes MHC da Classe II/genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Leishmania infantum/genética , Leishmania infantum/imunologia , Leishmaniose Visceral/genética , Leishmaniose Visceral/imunologia , Complexo Principal de Histocompatibilidade
18.
Nat Commun ; 9(1): 1102, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29549257

RESUMO

The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11chighMHCII+ cells (Cnb1 CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3+ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11chighMHCII+ cells to express IL-2. Deleting IL-2 in CD11chighMHCII+ cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin-NFAT-IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.


Assuntos
Antígeno CD11c/imunologia , Calcineurina/imunologia , Colite/imunologia , Interleucina-2/imunologia , Intestinos/imunologia , Células Mieloides/imunologia , Animais , Antígeno CD11c/genética , Calcineurina/genética , Colite/genética , Feminino , Genes MHC da Classe II , Homeostase , Humanos , Interleucina-2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/imunologia , Células Th17/imunologia
19.
Acta Neuropathol Commun ; 6(1): 18, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490700

RESUMO

Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Genes MHC da Classe II , Sialiltransferases/metabolismo , Antígenos CD/genética , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Estudos de Coortes , Metilação de DNA , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Melanoma/metabolismo , Melanoma/patologia , Prognóstico , Regiões Promotoras Genéticas , Sialiltransferases/genética , Linfócitos T/metabolismo , Linfócitos T/patologia
20.
Nat Commun ; 9(1): 928, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500348

RESUMO

B cells expressing high affinity antigen receptors are advantaged in germinal centers (GC), perhaps by increased acquisition of antigen for presentation to follicular helper T cells and improved T-cell help. In this model for affinity-dependent selection, the density of peptide/MHCII (pMHCII) complexes on GC B cells is the primary determinant of selection. Here we show in chimeric mice populated by B cells differing only in their capacity to express MHCII (MHCII+/+ and MHCII+/-) that GC selection is insensitive to halving pMHCII density. Alone, both B cell types generate identical humoral responses; in competition, MHCII+/+ B cells are preferentially recruited to early GCs but this advantage does not persist once GCs are established. During GC responses, competing MHCII+/+ and MHCII+/- GC B cells comparably accumulate mutations and have indistinguishable rates of affinity maturation. We conclude that B-cell selection by pMHCII density is stringent in the establishment of GCs, but relaxed during GC responses.


Assuntos
Linfócitos B/metabolismo , Genes MHC da Classe II , Centro Germinativo/citologia , Animais , Feminino , Centro Germinativo/fisiologia , Imunidade Humoral , Camundongos Endogâmicos C57BL
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