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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1397-1405, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798433

RESUMO

OBJECTIVE: To analyze the characteristics of allelic and haplotypic polymorphisms of human leukocyte antigens at HLA-A, -B, -C, DRB1 and DQB1 loci in Guangxi Zhuang population. METHODS: Polymerase chain reaction-sequence based typing (PCR-SBT) was used to detect. The five loci (HLA-A, -B, -C, -DRB1, -DQB1) in 350 unrelated Zhuang ethnic individual from Guangxi region. Allelic and haplotypic frequencies were calculated by using Arlequin software 3.5.2.2. Phylogeny tree were constructed by using MEGA software 6.0, and SPSS software was used for principal component analysis. RESULTS: Among the five loci in the population, only HLA-A and DRB1 loci were observed as departures from Hardy-Weinberg expectations. A total of 19 HLA-A, 42 HLA-B, 22 HLA-C, 25 HLA-DRB1 and 15 HLA-DQB1 alleles were found in 350 samples. The most highest frequent alleles were A*11: 01(28.57%), B*46: 01(14.00%), C*01: 02(18.43%), DRB1*16: 02 (15.71%)and DQB1*05: 02 (35.00%) . The most common five loci haplotype was A*33: 03-C*03: 02-B*58: 01-DRB1*03: 01-DQB1*02: 01(6.86%). The phylogenetic tree analysis showed that Guangxi Zhuang population had a relative close genetic relationship with southern Han Chinese populations. CONCLUSION: This reaserch found that the HLA-A, B, C, DRB1 and DQB1 loci are highly polymorphic in Guangxi Zhuang population.


Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Alelos , China , Frequência do Gene , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Filogenia
2.
Int J Immunogenet ; 47(4): 324-328, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32623831

RESUMO

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Predisposição Genética para Doença/genética , Teste de Histocompatibilidade , Pneumonia Viral/imunologia , Alelos , Infecções por Coronavirus/patologia , Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Transplante de Órgãos , Pandemias , Pneumonia Viral/patologia , Transplantados
3.
Phys Rev Lett ; 124(15): 158301, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32357052

RESUMO

A key question in the current diversity crisis is how diversity has been maintained throughout evolution and how to preserve it. Modern coexistence theories suggest that a high invasion rate of rare new types is directly related to diversity. We show that adding almost any mechanism of catastrophes to a stochastic birth, death, and mutation process with limited carrying capacity induces a novel phase transition characterized by a positive invasion rate but a low diversity. In this phase, new types emerge and grow rapidly, but the resulting growth of very large types decreases diversity. This model also resolves two major drawbacks of neutral evolution models: their failure to explain balancing selection without resorting to fitness differences and the unrealistic time required for the creation of the observed large types. We test this model on a classical case of genetic polymorphism: the HLA locus.


Assuntos
Biodiversidade , Modelos Teóricos , Dinâmica Populacional , Alelos , Evolução Biológica , Antígenos HLA-A/genética , Humanos , Polimorfismo Genético , Processos Estocásticos
4.
Klin Monbl Augenheilkd ; 237(4): 431-440, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32330990

RESUMO

PURPOSE: To establish the prevalence, morphological, and functional characteristics and evolution of advanced cases of birdshot retinochoroiditis (BRC). METHODS: A retrospective review of all BRC cases seen at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, with at least 3 years of follow-up since the onset of symptoms. The following parameters were evaluated: demographic characteristics, best-corrected visual acuity (BCVA), fundus photographs, fluorescein (FA) and indocyanine green (ICGA) angiography frames, and visual field evaluation from initial visit to last follow-up. RESULTS: Out of the 1920 patients with uveitis who were followed from 1995 until 2018, 32 (1.67%) were diagnosed with BRC; 20 of these 32 patients had sufficient data to be included. Three of these twenty patients (15.0%) had severe forms of the disease. Two patients had received insufficient treatment and one progressed despite attempted maximal therapy. The mean BCVA was 0.62 (± 0.42) at presentation, which was already at an advanced stage of the disease, and 0.51 (± 0.37) at last follow-up. The average visual field mean defect (VFMD) was 19.65 (± 4.71 dB) at presentation and 21.40 (± 2.45 dB) at last follow-up. Choroidal inflammatory activity monitored by ICGA decreased from 10.67 (± 9.18) at presentation to 6.67 (± 5.61) at last follow-up. FA revealed mild retinal vasculitis at 6.50 (± 4.76), which remained stable to 4.67 (± 3.20). EDI-OCT estimated choroidal thickness (EDI-OCT-CT) measurements were 246.36 (± 116.93 µm) at presentation and 231.30 (± 120.70 µm) at the last follow-up. CONCLUSIONS: In our setting, 15% of BRC cases had a severe course and suffered extensive irreversible chorioretinal damage, obviously due to insufficient treatment in two cases. This underlines the importance of correctly diagnosing BRC and initiating therapy as promptly as possible to avoid such outcomes in an otherwise possibly controllable disease.


Assuntos
Coriorretinite , Angiofluoresceinografia , Antígenos HLA-A , Humanos , Prevalência , Estudos Retrospectivos , Suíça , Tomografia de Coerência Óptica
6.
Transfusion ; 60(5): 1004-1014, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32167176

RESUMO

BACKGROUND: Most chimeric antigen receptor T (CAR-T) cells and other adoptive T-cell therapies (ACTs) are currently manufactured by ex vivo expansion of patient lymphocytes in culture media supplemented with human plasma from group AB donors. As lymphocytes do not express A or B antigens, the isoagglutinins of non-AB plasmas are unlikely to cause deleterious effects on lymphocytes in culture. STUDY DESIGN AND METHODS: Seeding cultures with peripheral blood mononuclear cell (PBMNC) concentrates from group A1 donors and using a CAR-T culture protocol, parallel cultures were performed, each with unique donor plasmas as media supplements (including group O plasmas with high-titer anti-A and group AB plasmas as control). An additional variable, a 3% group A1 red blood cell (RBC) spike, was added to simulate a RBC-contaminated PBMNC collection. Cultures were monitored by cell count, viability, flow cytometric phenotype, gene expression analysis, and supernatant chemokine analysis. RESULTS: There was no difference in lymphocyte expansion or phenotype when cultured with AB plasma or O plasma with high-titer anti-A. Compared to controls, the presence of contaminating RBCs in lymphocyte culture led to poor lymphocyte expansion and a less desirable phenotype-irrespective of the isoagglutinin titer of the plasma supplement used. CONCLUSIONS: This study suggests that ABO incompatible plasma may be used as a media supplement when culturing cell types that do not express ABO antigens-such as lymphocytes for CAR-T or other ACT. The presence of contaminating RBCs in culture was disadvantageous independent of isoagglutinin titer.


Assuntos
Sistema ABO de Grupos Sanguíneos/sangue , Meios de Cultura/química , Imunoterapia Adotiva , Plasma/fisiologia , Cultura Primária de Células/métodos , Linfócitos T/citologia , Células Cultivadas , Citometria de Fluxo , Antígenos HLA-A/sangue , Antígenos HLA-A/imunologia , Humanos , Imunoterapia Adotiva/métodos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/transplante , Ativação Linfocitária , Plasma/química , Cultura Primária de Células/normas , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Linfócitos T/transplante , Doadores de Tecidos
7.
Cancer Immunol Immunother ; 69(8): 1651-1662, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32219501

RESUMO

BACKGROUND: This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. METHODS: HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients' cohort; in total, 11 patients were enrolled for the recommended dose. RESULTS: Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. CONCLUSIONS: This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.


Assuntos
Carboximetilcelulose Sódica/análogos & derivados , Neoplasias Gastrointestinais/terapia , Glipicanas/imunologia , Antígenos HLA-A/imunologia , Antígenos HLA-G/administração & dosagem , Proteínas de Choque Térmico HSP70/imunologia , Fragmentos de Peptídeos/administração & dosagem , Poli I-C/administração & dosagem , Polilisina/análogos & derivados , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboximetilcelulose Sódica/administração & dosagem , Estudos de Coortes , Feminino , Seguimentos , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Glipicanas/metabolismo , Antígenos HLA-A/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Polilisina/administração & dosagem , Prognóstico , Taxa de Sobrevida
8.
Immunogenetics ; 72(3): 143-153, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31970435

RESUMO

Specificity analyses of peptide binding to human leukocyte antigen (HLA)-A molecules have been hampered due to a lack of proper monoclonal antibodies (mAbs) for certain allomorphs, such as the prevalent HLA-A1 for Caucasians and HLA-A11 for Asians. We developed a mAb that recognizes a conformational epitope common to most HLA-A allomorphs. The mAb, named A-1, does not discriminate peptides by amino acid sequences, making it suitable for measuring peptide binding. A stabilization assay using TAP-deficient cell lines and A-1 was developed to investigate the specificity of peptide binding to HLA-A molecules. Regarding the evolution of HLA-A genes, the A-1 epitope has been conserved among most HLA-A allomorphs but was lost when the HLA-A gene diversified into the HLA-A*32, HLA-A*31, and HLA-A*33 lineages together with HLA-A*29 after bifurcating from the HLA-A*25 and HLA-A*26 branchs. The establishment of A-1 is expected to help researchers investigate the peptide repertoire and develop computational tools to identify cognate peptides. Since no HLA-A locus-specific mAb has been available, A-1 will also be useful for analyzing the locus-specific regulation of the HLA gene expression.


Assuntos
Anticorpos Monoclonais/metabolismo , Antígenos HLA-A/imunologia , Antígeno HLA-A1/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Antígenos HLA-A/química , Antígeno HLA-A1/química , Humanos , Modelos Moleculares , Peptídeos/imunologia , Ligação Proteica/imunologia , Conformação Proteica
9.
Nat Commun ; 10(1): 5579, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811120

RESUMO

Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8+ T cells to mount robust responses. We elucidate the HLA-A*68:01+CD8+ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP145+CD8+ T cell responses. Dissecting A68/NP145+CD8+ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP145+CD8+ memory T cells with clonally expanded TCRαßs, while low-responders display A68/NP145+CD8+ T cells with predominantly naïve phenotypes and non-expanded TCRαßs. Single-cell index sorting and TCRαß analyses link expansion of A68/NP145+CD8+ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8+ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8+ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos HLA-A/imunologia , Antígenos HLA-A/metabolismo , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Apresentação do Antígeno , Antígenos Virais/química , Linhagem Celular , Proteção Cruzada , Reações Cruzadas/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-A/química , Antígenos HLA-A/genética , Humanos , Memória Imunológica/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Modelos Moleculares , Nucleoproteínas/química , Orthomyxoviridae/genética , Orthomyxoviridae/imunologia , Fragmentos de Peptídeos/química , Fenótipo , Conformação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Proteínas do Core Viral/genética
10.
BMC Med Genomics ; 12(Suppl 8): 175, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31856847

RESUMO

BACKGROUND: Hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol consumption are predominant causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying how differently these causes are implicated in HCC development are not fully understood. Therefore, we investigated differential alternative splicing (AS) regulation among HCC patients with these risk factors. METHODS: We conducted a genome-wide survey of AS events associated with HCCs among HBV (n = 95), HCV (n = 47), or alcohol (n = 76) using RNA-sequencing data obtained from The Cancer Genome Atlas. RESULTS: In three group comparisons of HBV vs. HCV, HBV vs. alcohol, and HCV vs. alcohol for RNA seq (ΔPSI> 0.05, FDR < 0.05), 133, 93, and 29 differential AS events (143 genes) were identified, respectively. Of 143 AS genes, eight and one gene were alternatively spliced specific to HBV and HCV, respectively. Through functional analysis over the canonical pathways and gene ontologies, we identified significantly enriched pathways in 143 AS genes including immune system, mRNA splicing-major pathway, and nonsense-mediated decay, which may be important to carcinogenesis in HCC risk factors. Among eight genes with HBV-specific splicing events, HLA-A, HLA-C, and IP6K2 exhibited more differential expression of AS events (ΔPSI> 0.1). Intron retention of HLA-A was observed more frequently in HBV-associated HCC than HCV- or alcohol-associated HCC, and intron retention of HLA-C showed vice versa. Exon 3 (based on ENST00000432678) of IP6K2 was less skipped in HBV-associated in HCC compared to HCV- or alcohol-associated HCC. CONCLUSION: AS may play an important role in regulating transcription differences implicated in HBV-, HCV-, and alcohol-related HCC development.


Assuntos
Processamento Alternativo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Feminino , Genômica , Antígenos HLA-A/genética , Antígenos HLA-C/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , RNA-Seq , Fatores de Risco
11.
J Assist Reprod Genet ; 36(12): 2515-2523, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31758512

RESUMO

PURPOSE: To investigate the validity, accuracy, and clinical outcomes of Karyomapping in preimplantation genetic testing (PGT) for ß-thalassemia combined with human leukocyte antigen (HLA) matching. METHODS: A total of 128 cycles from January 2014 to December 2017 were identified, and 1205 embryos were biopsied. The case group included 88 cycles using Karyomapping for PGT-HLA, compared with 40 cycles using polymerase chain reaction-short tandem repeat (PCR-STR) as the control group. RESULTS: There were significant differences in the HLA matching rate (21.34 vs. 14.37%), the matched transferable embryo rate (9.79 vs. 14.07%), the clinical pregnancy rate (65.08 vs. 41.86%), and the spontaneous miscarriage rate (2.44 vs. 22.22%) between the case and control groups. In the case group, nearly 1/3 (33.37%) of the embryos showed aneuploidy. According to the results of single nucleotide polymorphism (SNP) haplotype analysis, the recombination rates of HBB (hemoglobin subunit beta) and HLA were 11.46% and 5.61% respectively. HLA gene recombination was mostly distributed between HLA-A and HLA-B and the downstream region of HLA-DQB1. In addition, STR analysis could be considered in the case of copy-neutral loss of heterozygosity (LOH) in the region where the HLA gene is located. CONCLUSION: Karyomapping contributes to accurate selection of matched embryos, along with aneuploidy screening. However, STRs assist identification in cases of LOH in the target region.


Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cariotipagem/métodos , Diagnóstico Pré-Implantação , Talassemia beta/diagnóstico , Adulto , Biópsia , Transferência Embrionária , Feminino , Cadeias beta de HLA-DQ/genética , Subunidades de Hemoglobina/genética , Humanos , Perda de Heterozigosidade/genética , Gravidez , Taxa de Gravidez , Talassemia beta/genética , Talassemia beta/patologia
12.
BMC Med Genomics ; 12(1): 147, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660973

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, especially in East Asia. Even with the progress in therapy, 5-year survival rates remain unsatisfied. Chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) has been epidemiologically associated with HCC and is the major etiology in the East Asian population. The detailed mechanism, especially the changes of DNA methylation and gene expression between the two types of virus-related HCC, and their contributions to the HCC development, metastasis, and recurrence remain largely unknown. METHODS: In this integrated analysis, we characterized genome-scale profiles of HBV and HCV infected HCC by comparing their gene expression pattern, methylation profiles, and copy number variations from the publicly accessible data of The Cancer Genome Atlas Program (TCGA). RESULTS: The HLA-A, STAT1, and OAS2 genes were highly enriched and up-regulated discovered in the HCV-infected HCC. Hypomethylation but not copy number variations might be the major factor for the up-regulation of these immune-related genes in HCV-infected HCC. CONCLUSIONS: The results indicated the different epigenetic changes of HBV/HCV related hepatocarcinogenesis. The top up-regulated genes in HCV group were significantly clustered in the immune-related and defense response pathways. These findings will help us to understand the pathogenesis of HBV/HCV associated hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/genética , Hepatite B Crônica/genética , Hepatite C Crônica/genética , Neoplasias Hepáticas/genética , 2',5'-Oligoadenilato Sintetase/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Metilação de DNA , Expressão Gênica , Antígenos HLA-A/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT1/genética , Regulação para Cima
13.
Ann Rheum Dis ; 78(12): 1616-1620, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31471298

RESUMO

OBJECTIVE: Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients. METHODS: ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative). RESULTS: V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG. CONCLUSION: Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/genética , Artrite Reumatoide/genética , Previsões , Antígenos HLA-A/genética , Imunoglobulina G/imunologia , Alelos , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Cromatografia Líquida de Alta Pressão , Progressão da Doença , Epitopos/genética , Epitopos/imunologia , Seguimentos , Glicosilação , Antígenos HLA-A/imunologia , Humanos
14.
PLoS Pathog ; 15(9): e1008040, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527904

RESUMO

To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with ß2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome.


Assuntos
Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Antígenos HLA-B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Virais/metabolismo , Apresentação do Antígeno , Linhagem Celular , Citomegalovirus/genética , Degradação Associada com o Retículo Endoplasmático/imunologia , Antígenos HLA-A/metabolismo , Antígenos HLA-B/química , Células HeLa , Humanos , Evasão da Resposta Imune , Ligantes , Modelos Imunológicos , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas Virais/química , Proteínas Virais/genética
15.
Hum Immunol ; 80(11): 906-907, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31558331

RESUMO

A total of 194 Southeast Asia Chinese from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, the HLA-B, HLA-DRB1 and HLA-DQB1 were in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from HWEP in HLA-A (p < 0.05) and HLA-C (p < 0.01) loci. This genotype data was available in Allele Frequencies Network Database (AFND) Dos Santos et al. (2016).


Assuntos
Grupo com Ancestrais do Continente Asiático , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Alelos , Ásia Sudeste , Frequência do Gene , Genética Populacional , Haplótipos , Teste de Histocompatibilidade , Humanos , Malásia
16.
An Bras Dermatol ; 94(3): 287-292, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365656

RESUMO

BACKGROUND: Renal transplant recipients are submitted to immunosuppression to avoid graft rejection, which makes them susceptible to various conditions. Furthermore, these individuals present malignant tumors more frequently than the general population, including nonmelanoma skin cancer. The individual genetic basis that acts in the pathogenesis of cutaneous cancer may present a protection or susceptibility factor for disease development. One of these factors is the HLA complex. OBJECTIVE: To investigate HLA alleles association to the occurrence of nonmelanoma skin cancer in renal transplant recipients from São Paulo State. METHODS: A total of 213 patients (93 renal transplant recipients with nonmelanoma skin cancer and 120 renal transplant recipients without nonmelanoma skin cancer) were evaluated by retrospective and cross-sectional study. Epidemiological, clinical and HLA typing data were found in databases. HLA class I (A, B) and class II (DR) alleles were compared to establish their association with nonmelanoma skin cancer. RESULTS: Comparing renal transplant recipients with and without nonmelanoma skin cancer, the HLA-B*13 allele was associated with higher risk of developing nonmelanoma skin cancer while B*45 and B*50 alleles were associated with protection. STUDY LIMITATIONS: The HLA A, B and DR alleles identification for the kidney transplantation routine is done by low and medium resolution techniques that do not allow discrimination of specific alleles. CONCLUSION: The involvement of HLA alleles in nonmelanoma skin cancer in renal transplant recipients was confirmed in this study. Renal transplant recipients with HLA-B*13 showed higher risk for developing a skin cancer (OR= 7.29) and should be monitored for a long period of time after transplantation.


Assuntos
Antígenos HLA/genética , Transplante de Rim/efeitos adversos , Neoplasias Cutâneas/genética , Adulto , Idoso , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Predisposição Genética para Doença/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etiologia , Transplantados
17.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408937

RESUMO

Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas WT1/imunologia , Tumor de Wilms/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Antígenos HLA-A/imunologia , Humanos , Neoplasias Renais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Antígenos de Linfócitos T/imunologia , Tumor de Wilms/imunologia
18.
Microbiol Immunol ; 63(8): 316-327, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31254409

RESUMO

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major cause of morbidity and mortality worldwide. In the host's immune response system, T cells play a critical role in mediating protection against Mtb infection, but the role of CD8+ T cells is still controversial. We evaluated the phenotypical characterization and cytotoxic ability of CD8+ T cells by flow cytometry-based assay. Cytokine levels in serum were measured by multiplex cytokine assay. Our data show that cells from TB patients have an increased percentage of peripheral blood CD8+ αß+ T (p = 0.02) and CD56+ CD8+ T (p = 0.02) and a decreased frequency of NKG2D+ CD8+ T (p = 0.02) compared with healthy donors. Unlike CD8+ T cells from healthy donors, CD8+ T cells from TB patients exhibit greater cytotoxicity, mediated by HLA class I molecules, on autologous monocytes in the presence of mycobacterial antigens (p = 0.005). Finally, TB patients have a proinflammatory profile characterized by serum high level of TNF-α (p = 0.02) and IL-8 (p = 0.0001), but, interestingly, IL-4 (p = 0.002) was also increased compared with healthy donors. Our data show evidence regarding the highly cytotoxic status of CD8+ T cells in Mtb infection. These cytotoxic cells restricted to HLA-A, B, and C could be used to optimize strategies for designing new TB vaccines or for identifying markers of disease progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxinas/toxicidade , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Adolescente , Adulto , Antígenos de Bactérias/imunologia , Citocinas/sangue , Feminino , Citometria de Fluxo , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Humanos , Interleucina-4/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Vacinas contra a Tuberculose/imunologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
19.
PLoS One ; 14(5): e0216940, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112572

RESUMO

Many adults with IgG subclass deficiency (IgGSD) experience long intervals of frequent/severe respiratory tract infection before IgGSD diagnosis, but reasons for delays in IgGSD diagnoses are incompletely understood. We performed a retrospective study of 300 white adults (ages ≥18 y) with IgGSD including frequency analyses of age at IgGSD diagnosis, duration of frequent/severe respiratory tract infection before IgGSD diagnosis, and age at onset of frequent/severe infection (calculated). We performed multivariable regressions on age at diagnosis, infection duration, and age at infection onset using these variables, as appropriate: sex; age at diagnosis; diabetes; autoimmune condition(s); atopy; allergy; corticosteroid use; body mass index; serum immunoglobulin isotype levels; blood lymphocyte subsets; three IgGSD-associated human leukocyte antigen-A and -B haplotypes; and referring physician specialties. Mean age at diagnosis was 50 ± 12 (standard deviation) y (median 50 y (range 19-79)). There were 247 women (82.3%). Mean infection duration at IgGSD diagnosis was 12 ± 13 y (median 7 y (range 1-66)). Mean age at infection onset was 38 ± 16 y (median 38 y (range 4, 76)). Age at infection onset was ≥18 y in 95.7% of subjects. Regressions on age at diagnosis and infection duration revealed no significant associations. Regression on age at infection onset revealed one positive association: age at diagnosis (p <0.0001). We conclude that the median duration of frequent/severe respiratory tract infection in adults before IgGSD diagnosis was 7 y. Older adults may be diagnosed to have IgGSD after longer intervals of infection than younger adults. Duration of frequent/severe respiratory tract infection before IgGSD diagnosis was not significantly associated with routine clinical and laboratory variables, including referring physician specialties.


Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Deficiência de IgG/diagnóstico , Isotipos de Imunoglobulinas/classificação , Infecções Respiratórias/diagnóstico , Adulto , Fatores Etários , Idade de Início , Idoso , Índice de Massa Corporal , Feminino , Expressão Gênica , Antígenos HLA-A/classificação , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/classificação , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Haplótipos , Humanos , Deficiência de IgG/sangue , Deficiência de IgG/imunologia , Deficiência de IgG/fisiopatologia , Isotipos de Imunoglobulinas/sangue , Subpopulações de Linfócitos/classificação , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/sangue , Infecções Respiratórias/imunologia , Infecções Respiratórias/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo
20.
J Acquir Immune Defic Syndr ; 81(5): 508-515, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31107301

RESUMO

BACKGROUND: HIV's capacity to escape immune recognition by human leukocyte antigen (HLA) is a core component of HIV pathogenesis. A better understanding of the distribution of HLA class I in HIV-infected patients would improve our knowledge of pathogenesis in relation to the host HLA type and could better improve therapeutic strategies against HIV. MATERIALS AND METHODS: Three hundred one to 325 transmission pairs and 469-496 clusters were identified for analysis among Swiss HIV Cohort Study (SHCS) participants using HIV pol sequences from the drug resistance database. HLA class I data were compiled at 3 specificity levels: 4-digit, 2-digit alleles, and HLA-B supertype. The analysis tabulated HLA-I homogeneity as 2 measures: the proportion of transmission pairs, which are HLA concordant, and the average percentage of allele matches within all clusters. These measures were compared with the mean value across randomizations with randomly assorted individuals. RESULTS: We repeated the analysis for different HLA classification levels and separately for HLA-A, -B, and -C. Subanalyses by the risk group were performed for HLA-B. HLA-B showed significantly greater homogeneity in the transmission chains (2-digit clusters: 0.291 vs. 0.251, P value = 0.009; supertype clusters: 0.659 vs. 0.611, P value = 0.002; supertype pairs: 0.655 vs. 0.608, P value = 0.014). Risk group restriction caused the effect to disappear for men-who-have-sex-with-men but not for other risk groups. We also examined if protective HLA alleles B27 and B57 were under- or overrepresented in the transmission chains, although this yielded no significant pattern. CONCLUSIONS: The HLA-B alleles of patients within HIV-1 transmission chains segregate in homogenous clusters/pairs, potentially indicating preferential transmission among HLA-B concordant individuals.


Assuntos
Predisposição Genética para Doença , Infecções por HIV/genética , Infecções por HIV/transmissão , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Humanos , Suíça/epidemiologia
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