RESUMO
One nucleotide substitution in codon 30 of HLA-DRB4*01:03:01:01 results in a novel allele, HLA-DRB4*01:179.
Assuntos
Alelos , Éxons , Cadeias HLA-DRB4 , Teste de Histocompatibilidade , Humanos , Sequência de Bases , Códon , Cadeias HLA-DRB4/genética , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
HLA-DRB4*01:182 differs from HLA-DRB4*01:03:01:01 by one nucleotide substitution in codon 172 in exon 3.
Assuntos
Alelos , Sequência de Bases , Éxons , Cadeias HLA-DRB4 , Teste de Histocompatibilidade , Análise de Sequência de DNA , Humanos , Teste de Histocompatibilidade/métodos , Análise de Sequência de DNA/métodos , Cadeias HLA-DRB4/genética , Códon , Alinhamento de SequênciaRESUMO
HLA-DRB4*01:01:12 differs from HLA-DRB4*01:01:01:01 by one nucleotide substitution in codon 175 in exon 3.
Assuntos
Alelos , Sequência de Bases , Éxons , Cadeias HLA-DRB4 , Teste de Histocompatibilidade , Análise de Sequência de DNA , Humanos , Teste de Histocompatibilidade/métodos , Análise de Sequência de DNA/métodos , Cadeias HLA-DRB4/genética , Códon , Alinhamento de SequênciaRESUMO
Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs.
Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cadeias HLA-DRB4 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Nivolumabe/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Estudos Retrospectivos , Biomarcadores , Imunoterapia/efeitos adversos , Antígenos HLARESUMO
HLA-DRB4*01:165N exhibits deletion of a nucleotide in exon 3, producing a premature stop codon.
Assuntos
Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequência de Bases , Cadeias HLA-DRB4/genética , AlelosRESUMO
The HLA-DRB4*01:162N allele differs from HLA-DRB4*01:03:01:01 allele by a single nucleotide in codon 131.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias HLA-DRB4/genética , Alelos , CódonRESUMO
One nucleotide substitution in codon 179 of HLA-DRB4*01:03:01:01 results in a novel allele HLA-DRB4*01:152.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Nucleotídeos , Alelos , Sequência de Bases , Códon , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB4/genética , Humanos , KuweitRESUMO
BACKGROUND/OBJECTIVES: Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients. METHODS: Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study. Forty-four patients with chronic pancreatitis (CP) and 254 healthy subjects served as control groups. DNA was isolated from blood samples and two-digit HLA typing was performed with sequence-specific primer (SSP-) PCR. HLA allele association strength to AIP was calculated as odds ratio. RESULTS: We uncovered a strong enrichment of HLA-DQB1 homozygosity in type 1 and type 2 AIP patients. Moreover, a significantly increased incidence of the HLA-DRB1∗16 and HLA-DQB1∗05 alleles and a concomitant lack of the HLA-DRB1∗13 allele was detected in AIP type 1 and type 2 patients. In contrast, the HLA-DQB1∗02 allele was underrepresented in the 'not otherwise specified' (NOS) AIP subtype. We detected no significant difference in the HLA-DRB3, HLA-DRB4 and HLA-DRB5 allele frequency in our cohort. CONCLUSIONS: Although AIP type 1 and type 2 are characterized by distinct histopathological characteristics, both subtypes are associated with the same HLA alleles, indicating that the disease might rely on similar immunogenic mechanisms. However, AIP NOS represented another subclass of AIP.
Assuntos
Pancreatite Autoimune , Alelos , Frequência do Gene , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB4/genética , Haplótipos , HumanosRESUMO
HLA-DRB4*01:151 differs from DRB4*01:01:01:01 by one nucleotide substitution in codon 178 in exon 3.
Assuntos
Cadeias HLA-DRB4 , Alelos , Códon , Éxons/genética , Cadeias HLA-DRB4/genética , Humanos , Análise de Sequência de DNARESUMO
BACKGROUND: Vitiligo is a multifactorial depigmentation condition, which is due to skin melanocyte destruction. Increased expression of HLA class II genes in patients with pre-lesions of Vitiligo suggests a crucial role for the participation of immune response in Vitiligo development. Recent studies progressively focused on HLA-DRB1 and DQB1 genes. In this study, we have evaluated the association and role of HLA-DRB4*01:01, -DRB1*07:01, and -DQB1*03:03:2 genes in different clinical subtypes of Vitiligo in the Iranian population. METHODS: First, Genomic DNA from peripheral blood of 125 unrelated Vitiligo patients and 100 unrelated healthy controls were extracted through the salting-out method. Then, HLA class II genotyping was performed using the sequence-specific primer PCR method. Finally, the clinical relevance of the testing for these genotypes was evaluated by applying the PcPPV (prevalence-corrected positive predictive value) formula. RESULTS: Our results indicated the positive associations of DRB4*01:01 and DRB1*07:01 allelic genes with early-onset Vitiligo (p = 0.024 and 0.022, respectively). DRB4*01:01 also showed strong protection against late-onset Vitiligo (p = 0.0016, RR = 0.360). Moreover, our data revealed that the DRB1*07:01 increases the susceptibility to Sporadic Vitiligo (p = 0.030, RR = 1.702). Furthermore, our findings proposed that elevated vulnerability of Vitiligo patients due to DRB4*01:01 and DRB1*07:01 alleles maybe is correlated with the presence of amino acid Arginine at position 71 at pocket 4 on the antigen-binding site of the HLA-DRB1 receptor. CONCLUSION: Our findings on different subtypes of Vitiligo suggest that, despite a more apparent autoimmune involvement, a non-autoimmune nature for the etiology of Vitiligo should also be considered.
Assuntos
Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB4/genética , Vitiligo/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Irã (Geográfico) , MasculinoRESUMO
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%-12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02-1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05-1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.
Assuntos
Cadeias HLA-DRB3/imunologia , Cadeias HLA-DRB4/imunologia , Cadeias HLA-DRB5/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Seleção do Doador , Alemanha , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Teste de Histocompatibilidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
Allele frequencies and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 have been rarely reported in South Koreans using unambiguous, phase-resolved next generation DNA sequencing. In this study, HLA typing of 11 loci in 173 healthy South Koreans were performed using next generation DNA sequencing with long-range PCR, TruSight® HLA v2 kit, Illumina MiSeqDx platform system, and Assign™ for TruSight™ HLA software. Haplotype frequencies were calculated using the PyPop software. Direct counting methods were used to investigate the association with DRB1 for samples with only one copy of a particular secondary DRB locus. We compared these allele types with the ambiguous allele combinations of the IPD-IMGT/HLA database. We identified 20, 40, 26, 31, 19, 16, 4, and 16 alleles of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1, respectively. The number of HLA-DRB3/4/5 alleles was 4, 5, and 3, respectively. The haplotype frequencies of most common haplotypes were as follows: A*33:03:01-B*44:03:01-C*14:03-DRB1*13:02:01-DQB1*06:04:01-DPB1*04:01:01 (2.89%), A*33:03:01-B*44:03:01-C*14:03 (4.91%), DRB1*08:03:02-DQA1*01:03:01-DQB1*06:01:01-DPA1*02:02:02-DPB1*05:01:01 (5.41%), DRB1*04:05:01-DRB4*01:03:01 (12.72%), DQA1*01:03:01-DQB1*06:01:01 (13.01%), and DPA1*02:02:02-DPB1*05:01:01 (30.83%). In samples with only one copy of a specific secondary DRB locus, we examined its association with DRB1. We, thus, resolved 10 allele ambiguities in HLA-B, -C (each exon 2+3), -DRB1, -DQB1, -DQA1, and -DPB1 (each exon 2) of the IPD-IMGT/HLA database. Korean population was geographically close to Japanese and Han Chinese populations in the genetic distances by multidimensional scaling (MDS) plots. The information obtained by HLA typing of the 11 extended loci by next generation sequencing may be useful for more exact diagnostic tests on various transplantations and the genetic population relationship studies in South Koreans.
Assuntos
Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias alfa de HLA-DP/genética , Cadeias beta de HLA-DP/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB3/genética , Cadeias HLA-DRB4/genética , Cadeias HLA-DRB5/genética , Haplótipos , Povo Asiático/genética , Frequência do Gene/genética , Loci Gênicos/genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , República da CoreiaRESUMO
Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers' presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters' binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.
Assuntos
Antígenos HLA-DP/metabolismo , Antígenos HLA-DQ/metabolismo , Cadeias HLA-DRB1/metabolismo , Cadeias HLA-DRB4/metabolismo , Gravidez/imunologia , Adulto , Apresentação de Antígeno , Epitopos/imunologia , Epitopos/metabolismo , Feminino , Teste de Histocompatibilidade , Humanos , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Isoantígenos/metabolismo , Masculino , Peptídeos/imunologia , Peptídeos/metabolismoRESUMO
One nucleotide substitution in codon 39 of HLA-DRB4*01:01:01:01 results in a novel allele, HLA-DRB4*01:44.
Assuntos
Cadeias HLA-DRB4 , Alelos , Sequência de Bases , Códon , Cadeias HLA-DRB4/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNARESUMO
Full-length sequencing of HLA-DRB4*01:14 showed the same splice site mutation as in HLA-DRB4*01:03:01:02N.
Assuntos
Antígenos HLA-DR , Alelos , Antígenos HLA-DR/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB4/genética , Humanos , Mutação , Sítios de Splice de RNARESUMO
The development of peptide-MHC class II multimers has provided a novel approach in studying antigen-specific CD4+ T-cells and extended the knowledge of these T cells in various disease settings, including infectious diseases, autoimmune diseases, cancer, and allergies. This chapter discusses the various applications of the peptide-MHC class II multimer technologies, specifically their uses in the evaluation of antigen-specific CD4+ T-cells ex vivo, and their uses in epitope identification.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Epitopos , Biologia Molecular/métodos , Peptídeos/metabolismo , Multimerização Proteica , Antígenos/metabolismo , Mapeamento de Epitopos , Citometria de Fluxo , Cadeias HLA-DRB4/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Coloração e RotulagemRESUMO
Next-generation targeted sequencing of HLA-DRB1 and HLA-DRB3, -DRB4, and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity as a result of high polymorphisms and extended linkage disequilibrium among the DR loci, we applied a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease-associated DR sequences and identifies 11 residues of DRB1, sequences of which retain all significant associations observed by DR genes. Furthermore, all 11 residues locate under/adjoining the peptide-binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. The 15 residues of DRB345, located respectively in the ß49-55 homodimerization patch and on the face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds that DRB1 residues significantly associated with ZnT8A and DRB345 residues with GADA. The strongest association is between four residues (ß14, ß25, ß71, and ß73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15, P = 10-18), and another sequence, ERKG, confers a protective association (odds ratio 0.59, P = 10-11), despite a difference of only one amino acid. Because motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.
Assuntos
Diabetes Mellitus Tipo 1/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB3/genética , Cadeias HLA-DRB4/genética , Cadeias HLA-DRB5/genética , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , SuéciaRESUMO
The association between the DRB4*01:03:01:02N null allele and the HLA-DRB1*07~DQB1*03:03 haplotype has often been reported. Nevertheless, more unusual associations have also been found in other countries, such as its association with HLA-DRB1*04. HLA class I and II antigen typing is currently performed using DNA-based methods, making it more difficult to identify null alleles than if serological methods were used. Furthermore, the DRB3/4/5 loci are not usually studied. However, the identification of non-expressed HLA alleles is of great importance for transplantation so it is necessary to identify HLA antigen associations with null alleles and report these findings. In this paper, we describe the association of DRB4*01:03:01:02N null allele with DRB1*04 for the first time in Spain.