RESUMEN
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.
Asunto(s)
Aminopeptidasas/metabolismo , Antígeno HLA-B51/metabolismo , Células Asesinas Naturales/enzimología , Antígenos de Histocompatibilidad Menor/metabolismo , Neoplasias/enzimología , Receptores KIR3DL1/metabolismo , Aminopeptidasas/antagonistas & inhibidores , Aminopeptidasas/genética , Antineoplásicos/farmacología , Degranulación de la Célula , Línea Celular , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Inhibidores Enzimáticos/farmacología , Antígeno HLA-B51/genética , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Antígenos de Histocompatibilidad Menor/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/inmunología , Receptores KIR3DL1/genética , Transducción de SeñalRESUMEN
Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA-B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA-peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.
Asunto(s)
Síndrome de Behçet/metabolismo , Antígeno HLA-B51/química , Péptidos/química , Alelos , Secuencia de Aminoácidos , Antígeno HLA-B51/metabolismo , Antígeno HLA-B52/metabolismo , Humanos , Simulación de Dinámica Molecular , Péptidos/metabolismo , Unión Proteica , Conformación Proteica , TermodinámicaRESUMEN
Behcet syndrome is an autoimmune multisystem disorder often affecting young adults and its pathological origin is unclear. Here we present a case report of a 24 year old male who presented with high grade fever with orogenital ulcers. On evaluation, diagnosis of Behcet syndrome was made based on clinical presentation, positive pathergy test and HLA B51.
Asunto(s)
Enfermedades Autoinmunes , Síndrome de Behçet/diagnóstico , Adulto , Fiebre/diagnóstico , Antígeno HLA-B51/metabolismo , Humanos , Masculino , Úlcera , Adulto JovenRESUMEN
The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.
Asunto(s)
Síndrome de Behçet/etiología , Antígeno HLA-B51/genética , Antígeno HLA-B51/inmunología , Alelos , Presentación de Antígeno/inmunología , Autoinmunidad/genética , Autoinmunidad/inmunología , Síndrome de Behçet/metabolismo , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Epítopos/química , Epítopos/inmunología , Predisposición Genética a la Enfermedad , Antígeno HLA-B51/química , Antígeno HLA-B51/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Microbiota , Péptidos/química , Péptidos/inmunología , Pliegue de Proteína , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
OBJECTIVE: Association of position 97 (P97) residue polymorphisms in human leucocyte antigen (HLA)-B, including HLA-B*27, with ankylosing spondylitis (AS) has recently been reported. We studied the effect of P97 variations on cell surface expression of the AS-associated HLA-B*27 and HLA-B*51, and the AS-protective HLA-B*7. METHODS: Flow cytometry was used to measure surface expression of HLA-B*27 in C1R/HeLa cells expressing HLA-B*27 (N97) and six mutants at P97 (N97T, N97S, N97V, N97R, N97W and N97D). Transporter associated with antigen processing-deficient T2, tapasin-deficient 220, ß2m-deficient HCT15 and endoplasmic reticulum aminopeptidase 1 or ß2m-clustered regularly interspaced short palindromic repeats/Cas9-knockout HeLa cells were used to provide evidence for specific protein interactions. Surface expression of HLA-B*7/HLA-B*51 P97 mutants was also studied. RESULTS: Mutation of HLA-B*27 P97 to the AS risk residue threonine increased cell surface free heavy chain (FHC) expression. Protective residues (serine or valine) and non-AS-associated residues (arginine or tryptophan) did not alter FHC expression. The N97D mutation reduced expression of conventional and FHC forms of HLA-B*27. Differences in FHC expression levels between HLA-B*27, HLA-B*27-N97T and HLA-B*27-N97D were dependent on the presence of functional ß2m. HLA-B*7, which has an AS-protective serine at P97, expressed lower levels of FHC than HLA-B*27 or HLA-B*51. Introduction of asparagine at P97 of both HLA-B*7 and HLA-B*51 increased FHC expression. CONCLUSIONS: The nature of P97 residue affects surface expression of HLA-B*27, B*7 and B*51, with AS-associated residues giving rise to higher FHC expression levels. The association of P97 amino acid polymorphisms with AS could be, at least in part, explained by its effect on HLA-B*27 FHC cell surface expression.
Asunto(s)
Antígenos de Superficie/genética , Antígeno HLA-B27/genética , Espondilitis Anquilosante/genética , Microglobulina beta-2/metabolismo , Transportadoras de Casetes de Unión a ATP/deficiencia , Transportadoras de Casetes de Unión a ATP/genética , Aminopeptidasas/deficiencia , Aminopeptidasas/genética , Antígenos de Superficie/metabolismo , Asparagina/genética , Citometría de Flujo , Antígeno HLA-B27/química , Antígeno HLA-B27/metabolismo , Antígeno HLA-B51/genética , Antígeno HLA-B51/metabolismo , Antígeno HLA-B7/genética , Antígeno HLA-B7/metabolismo , Células HeLa , Humanos , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Antígenos de Histocompatibilidad Menor/genética , Mutación , Serina/genética , Espondilitis Anquilosante/inmunología , Treonina/genética , Transfección , Valina/genética , Microglobulina beta-2/genéticaAsunto(s)
Encéfalo/diagnóstico por imagen , Síndrome de Sweet/líquido cefalorraquídeo , Síndrome de Sweet/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Antígeno HLA-B51/metabolismo , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Trastornos Migrañosos/líquido cefalorraquídeo , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/tratamiento farmacológico , Síndrome de Sweet/tratamiento farmacológicoRESUMEN
UNLABELLED: Antiviral CD8(+) T cells are a key component of the adaptive immune response against HCV, but their impact on viral control is influenced by preexisting viral variants in important target epitopes and the development of viral escape mutations. Immunodominant epitopes highly conserved across genotypes therefore are attractive for T cell based prophylactic vaccines. Here, we characterized the CD8(+) T cell response against the highly conserved HLA-B*51-restricted epitope IPFYGKAI1373-1380 located in the helicase domain of NS3 in people who inject drugs (PWID) exposed predominantly to HCV genotypes 1a and 3a. Despite this epitope being conserved in both genotypes, the corresponding CD8(+) T cell response was detected only in PWID infected with genotype 3a and HCV-RNA negative PWID, but not in PWID infected with genotype 1a. In genotype 3a, the detection of strong CD8(+) T cell responses was associated with epitope variants in the autologous virus consistent with immune escape. Analysis of viral sequences from multiple cohorts confirmed HLA-B*51-associated escape mutations inside the epitope in genotype 3a, but not in genotype 1a. Here, a distinct substitution in the N-terminal flanking region located 5 residues upstream of the epitope (S1368P; P = 0.00002) was selected in HLA-B*51-positive individuals. Functional assays revealed that the S1368P substitution impaired recognition of target cells presenting the endogenously processed epitope. The results highlight that, despite an epitope being highly conserved between two genotypes, there are major differences in the selected viral escape pathways and the corresponding T cell responses. IMPORTANCE: HCV is able to evolutionary adapt to CD8(+) T cell immune pressure in multiple ways. Beyond selection of mutations inside targeted epitopes, this study demonstrates that HCV inhibits epitope processing by modification of the epitope flanking region under T cell immune pressure. Selection of a substitution five amino acids upstream of the epitope underlines that efficient antigen presentation strongly depends on its larger sequence context and that blocking of the multistep process of antigen processing by mutation is exploited also by HCV. The pathways to mutational escape of HCV are to some extent predictable but are distinct in different genotypes. Importantly, the selected escape pathway of HCV may have consequences for the destiny of antigen-specific CD8(+) T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Hepacivirus/inmunología , Hepatitis C/inmunología , Evasión Inmune , Epítopos Inmunodominantes/inmunología , Mutación , Proteínas no Estructurales Virales/inmunología , Estudios de Cohortes , Genotipo , Antígeno HLA-B51/metabolismo , Hepacivirus/genética , Humanos , Epítopos Inmunodominantes/genética , Abuso de Sustancias por Vía Intravenosa/complicaciones , Proteínas no Estructurales Virales/genéticaRESUMEN
OBJECTIVE: To characterize the peptidome of the Behçet's disease-associated HLA-B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP-1)-mediated processing. METHODS: The endogenous B*51:01-bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP-1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well-established algorithms. ERAP-1 and ERAP-2 from 721.221 cells were characterized by genomic sequencing and Western blotting. RESULTS: The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C-terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP-1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01-peptide complexes. CONCLUSION: ERAP-1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP-1 resistant. This pattern provides a mechanism for the epistatic association of ERAP-1 and B*51:01 in Behçet's disease.
Asunto(s)
Aminopeptidasas/genética , Síndrome de Behçet/metabolismo , Antígeno HLA-B51/metabolismo , Péptidos/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Aminopeptidasas/metabolismo , Línea Celular , Cromatografía de Afinidad , Genotipo , Humanos , Antígenos de Histocompatibilidad Menor , Polimorfismo de Nucleótido Simple , Espectrometría de Masas en TándemRESUMEN
Behçet's disease (BD) is an inflammatory disorder of unknown aetiology characterised by recurrent attacks affecting the mucocutaneous tissues, eyes, joints, blood vessels, brain and gastrointestinal tract. It is a multifactorial disease classified as a variable vessel vasculitis, and several environmental triggers may induce inflammatory episodes in genetically susceptible individuals. BD has several autoinflammatory features including recurrent self-limited clinical manifestations overlapping with monogenic autoinflammatory disorders, significant host predisposition and abnormally increased inflammatory response, with a robust innate component. Human leukocyte antigen (HLA)-B*51 is the strongest susceptibility factor described so far affecting the disease risk and typical phenotype. Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis. Although genomewide association studies revealed an increased risk associated with recessively inherited ERAP1 variations in HLA-B*51 positive patients, it is not clear yet whether certain peptide-HLA allele combinations result in an adaptive response by a self-antigen-directed cytotoxic response or an innate response by modulating an NK cell activity or causing an unfolded protein response. Understanding of major histocompatibility complex (MHC) Class I-driven inflammatory response is expected to provide insights for the development of better treatment and remission-induction options in BD as well as in ankylosing spondylitis (AS) and psoriasis.
Asunto(s)
Síndrome de Behçet/diagnóstico , Síndrome de Behçet/etiología , Síndrome de Behçet/tratamiento farmacológico , Susceptibilidad a Enfermedades , Antígeno HLA-B51/química , Antígeno HLA-B51/genética , Antígeno HLA-B51/inmunología , Antígeno HLA-B51/metabolismo , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/etiología , Humanos , Inflamación/etiología , Inflamación/metabolismoRESUMEN
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is associated with variable rates of disease progression, influenced by the quality of CD8 T-lymphocyte response, which is determined by human leukocyte antigen (HLA) I alleles. Some individuals progress slowly and maintain viral control, while at the opposite end of the spectrum some individuals endure a faster progression with rapid CD4 decline. We sought to determine the role of HLA-B allele frequency on rapid HIV disease progression. It was hypothesized that rapid progression is associated with the presence of high allele frequency of HLA-B35 and HLA-B homozygocity. METHODS: This retrospective cohort study was conducted in the Manitoba HIV Program, Health Sciences Centre, a tertiary care facility in Winnipeg, Manitoba, Canada. We defined a set of new criteria to describe a subset of individuals with the most rapid HIV disease progression, and collected demographic, clinical, laboratory (CD4 count, viral load) and HLA data on a subset of 20 individuals meeting these criteria. RESULTS: Among those individuals who display extreme rapid progression, an overrepresentation of Aboriginal ethnicities, high frequencies of HLA-B35 and significantly higher rates of HLA-B51, as well as a very high rate of homozygocity for HLA-B alleles, were observed. CONCLUSIONS: Individuals with the most rapid disease progression have higher rates of HLA-B homozygocity, HLA-B51 alleles and higher viral loads than those with normal progression rates. This group, at the extreme end of the spectrum of progression, should be targeted for early treatment.
Asunto(s)
Infecciones por VIH/genética , Infecciones por VIH/inmunología , Antígenos HLA-B/genética , Antígeno HLA-B51/metabolismo , Homocigoto , Recuento de Linfocito CD4 , Progresión de la Enfermedad , Frecuencia de los Genes , Infecciones por VIH/etnología , Infecciones por VIH/virología , Antígeno HLA-B35 , Antígeno HLA-B51/genética , Humanos , Manitoba/etnología , Estudios Retrospectivos , Carga ViralRESUMEN
The aim of this study was to investigate the subclasses and the immunophenotypic profile of peripheral mononuclear cells in patients with Behçet's disease (BD) and to assess associations between the expression of HLA-B51 antigen and that of other cell markers. Thirty healthy volunteer blood donors and forty patients with BD were enrolled into this study. Phenotyping was performed using two color flow cytometry. HLA-B51 typing was performed using the complement dependent microlymphocytotoxicity assay. Unlike controls, patients with BD presented a modified immunophenotypic profile of lymphocytes. Compared to those in the remission phase, patients with active BD showed an increased mean of MFI ratio of CD56 on CD16+CD56+ cells (32.47 ± 14.26 versus 23.87 ± 10.3; p = 0.032), increased absolute numbers of CD4(-)CD8(bright) and CD4(+)CD8(+) cells (657.1 ± 463.6 cells/µL versus 319.24 ± 116.4 cells/µL; p = 0.017 and 40.77 ± 36.41 cells/µL versus 10.77 ± 9.78 cells/µL; p < 0.0001, respectively) and an elevated mean of MFI ratio of CD19 on B cells (252.3 ± 56.7 versus 205.67 ± 32.3; p = 0.021). However, expression of HLA-B51 was not associated with any specific immunophenotypic profile. In conclusion, abnormal immunophenotypic profile of peripheral lymphocytes was found in patients with BD, especially in active phase, reflecting an immune dysregulation. Moreover, HLA-B51 expression was not found to be related to the expression of other cell markers.
Asunto(s)
Síndrome de Behçet/inmunología , Síndrome de Behçet/metabolismo , Antígeno HLA-B51/inmunología , Antígeno HLA-B51/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Fenotipo , Adolescente , Adulto , Antígenos de Superficie/metabolismo , Síndrome de Behçet/diagnóstico , Estudios de Casos y Controles , Niño , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
CD8(+) CTL responses directed toward the HLA-B*51:01-restricted HIV-RT128-135 epitope TAFTIPSI (TI8) are associated with long-term nonprogression to AIDS. Clonotypic analysis of responses to B51-TI8 revealed a public clonotype using TRAV17/TRBV7-3 TCR genes in six out of seven HLA-B*51:01(+) patients. Structural analysis of a TRAV17/TRBV7-3 TCR in complex with HLA-B51-TI8, to our knowledge the first human TCR complexed with an 8-mer peptide, explained this bias, as the unique combination of residues encoded by these genes was central to the interaction. The relatively featureless peptide-MHC (pMHC) was mainly recognized by the TCR CDR1 and CDR2 loops in an MHC-centric manner. A highly conserved residue Arg(97) in the CDR3α loop played a major role in recognition of peptide and MHC to form a stabilizing ball-and-socket interaction with the MHC and peptide, contributing to the selection of the public TCR clonotype. Surface plasmon resonance equilibrium binding analysis showed the low affinity of this public TCR is in accordance with the only other 8-mer interaction studied to date (murine 2C TCR-H-2K(b)-dEV8). Like pMHC class II complexes, 8-mer peptides do not protrude out the MHC class I binding groove like those of longer peptides. The accumulated evidence suggests that weak affinity might be a common characteristic of TCR binding to featureless pMHC landscapes.
Asunto(s)
Epítopos/inmunología , Transcriptasa Inversa del VIH/inmunología , Antígeno HLA-B51/inmunología , Linfocitos T/inmunología , Alelos , Secuencia de Aminoácidos , Presentación de Antígeno/inmunología , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/inmunología , Regiones Determinantes de Complementariedad/metabolismo , Epítopos/química , Epítopos/metabolismo , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Antígeno HLA-B51/genética , Antígeno HLA-B51/metabolismo , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/química , Péptidos/inmunología , Péptidos/metabolismo , Unión Proteica/inmunología , Estructura Terciaria de Proteína , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: A lot of work has been done to study the association between human leukocyte antigen (HLA) and papillary thyroid carcinoma (PTC) in various populations. But the results of the currently available studies are not consistent. The aim of this study was to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 with PTC in the Chinese Han population of the coastal areas of Shandong Province with respect to age and sex. METHODS: A total of 154 patients diagnosed with PTC were analyzed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles by using a polymerase chain reaction sequence-based typing (PCR-SBT) method. Two hundred unrelated healthy individuals were typed as controls. RESULTS: Compared with the controls, the HLA-B*51:01 (8.8% vs. 4.5%, p=0.029, OR 2.039 [CI 1.101-3.775]) and HLA-C*07:06 (2.6% vs. 0.5%, p=0.024, OR 5.307 [CI 1.119-25.171]) allele frequencies were higher in the PTC patients, while the HLA-C*07:01 (1.3% vs. 6.0%, p=0.001, OR 0.206 [CI 0.071-0.601]) allele frequency was lower in the PTC patients that did not persist after Bonferroni correction for multiple tests. This showed no statistically significant correlation of the HLA-A, -DRB1, and -DQB1 alleles and PTC. The incidence of PTC was more frequent in females between 30 and 60 years old. There were no significant differences in the age and sex distributions between the total and the HLA-B*51:01 positive PTC patients. CONCLUSIONS: The HLA associations in this Chinese Han population differ markedly from studies done in Europeans and Caucasians. The results reveal that HLA-B*51:01 is more likely to be a susceptible allele for PTC in addition to age and sex in the coastal areas of Shandong Province.
Asunto(s)
Carcinoma/genética , Predisposición Genética a la Enfermedad , Antígenos HLA-B/genética , Antígeno HLA-B51/genética , Antígenos HLA-C/genética , Polimorfismo Genético , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico , Carcinoma/metabolismo , Carcinoma Papilar , China , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Antígenos HLA-B/metabolismo , Antígeno HLA-B51/metabolismo , Antígenos HLA-C/metabolismo , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismo , Adulto JovenRESUMEN
AIM: To comparatively study the clinical manifestations, sexual and HLA-B51 associations in patients with Behçet's disease (BD) in two ethnic groups. SUBJECTS AND METHODS: The authors examined 143 patients with the valid diagnosis of BED who were divided into 2 groups: 1) 85 patients, the dwellers of Dagestan (a multiethnic cohort), 63 men and 22 women (mean age 29 +/- 7.4 years); 2) 58 Russian men and women (mean age 33 +/- 11.7 years). RESULTS: Two major criteria for BD, such as aphthous stomatitis and external genital ulcers, were found with the same frequency. Panuveitis and angiitis of the retina were diagnosed more frequently in the Dagestani population with BD than in the Russians. Out of the minor criteria for BD, the incidence of lower limb deep venous thrombosis was 23% for the Dagestanis versus 3% for the Russians. Arterial thromboses and pulmonary artery aneurysms became causes of death in 4 in 5 men aged 19-23 years from their Dagestani ancestry. HLA B51 (B marker) was found in the dwellers of Dagestan: in 70% of the men and 40% of the women who had BD. CONCLUSION: BD runs a more severe course in male patients and is characterized by severe eye diseases and the systematic pattern of the process at young age. Gender-specific and genetic aspects call for further comparative investigations on large ethnic patient cohorts of other ancestries.
Asunto(s)
Síndrome de Behçet/epidemiología , Oftalmopatías/epidemiología , Antígeno HLA-B51/metabolismo , Estomatitis Aftosa/epidemiología , Adulto , Síndrome de Behçet/etnología , Síndrome de Behçet/fisiopatología , Daguestán/epidemiología , Oftalmopatías/etnología , Oftalmopatías/etiología , Femenino , Humanos , Incidencia , Masculino , Federación de Rusia/epidemiología , Índice de Severidad de la Enfermedad , Factores Sexuales , Estomatitis Aftosa/etnología , Estomatitis Aftosa/etiología , Úlcera/epidemiología , Úlcera/etnología , Úlcera/etiología , Adulto JovenRESUMEN
Pol283-8-specific, HLA-B*51:01-restricted, cytotoxic T cells (CTLs) play a critical role in the long-term control of HIV-1 infection. However, these CTLs select for the reverse transcriptase (RT) I135X escape mutation, which may be accumulating in circulating HIV-1 sequences. We investigated the selection of the I135X mutation by CTLs specific for the same epitope but restricted by HLA-B*52:01. We found that Pol283-8-specific, HLA-B*52:01-restricted CTLs were elicited predominantly in chronically HIV-1-infected individuals. These CTLs had a strong ability to suppress the replication of wild-type HIV-1, though this ability was weaker than that of HLA-B*51:01-restricted CTLs. The crystal structure of the HLA-B*52:01-Pol283-8 peptide complex provided clear evidence that HLA-B*52:01 presents the peptide similarly to HLA-B*51:01, ensuring the cross-presentation of this epitope by both alleles. Population level analyses revealed a strong association of HLA-B*51:01 with the I135T mutant and a relatively weaker association of HLA-B*52:01 with several I135X mutants in both Japanese and predominantly Caucasian cohorts. An in vitro viral suppression assay revealed that the HLA-B*52:01-restricted CTLs failed to suppress the replication of the I135X mutant viruses, indicating the selection of these mutants by the CTLs. These results suggest that the different pattern of I135X mutant selection may have resulted from the difference between these two CTLs in the ability to suppress HIV-1 replication.
Asunto(s)
Epítopos de Linfocito T/inmunología , VIH-1/inmunología , VIH-1/patogenicidad , Evasión Inmune , Selección Genética , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Pueblo Asiatico , Epítopos de Linfocito T/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/genética , Antígeno HLA-B51/inmunología , Antígeno HLA-B51/metabolismo , Antígeno HLA-B52/inmunología , Antígeno HLA-B52/metabolismo , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Missense , Unión Proteica , Población BlancaRESUMEN
OBJECTIVE: To fully define cytotoxic T-lymphocyte (CTL) escape variants of an HLA-B*51-restricted integrase epitope in early HIV-1 infection. DESIGN: Ninety-four longitudinally sampled acute/early HIV-1 subtype B-infected participants were assessed to determine HLA-B*51-restricted LPPVVAKEI (LI9) escape variants. METHODS: LI9 was sequenced at baseline and subsequent time points. Interferon-γ (IFNγ) ELISpot assays were performed using serial log dilutions of variant LI9 peptides to determine the cellular response and functional avidity. RESULTS: There is a significant association between HLA-B*51 expression and an evolving LI9 sequence from baseline to year 1 (P < 0.0001). We detected that the V32I and P30X polymorphisms emerged within HLA-B*51 participants over time. Reversion of the P30S polymorphism was observed by year 1 in one HLA-B*51 participant. LPPIIAKEI and LPSIVAKEI had significantly lower functional avidity compared with LPPVVAKEI and so may be less well recognized by LI9-specific CTLs; a positive IFNγ response to IPSVVAKEI was rarely seen. Functional avidity to wild-type LI9 inversely correlated with viral load (R = 0.448, P = 0.0485). CONCLUSION: Our results provide support for the role of HLA-B*51-restricted CTLs and functional avidity in the control of early HIV-1 infection.