RESUMO
The novel HLA-B*18:243 allele, first described in a potential bone marrow donor from Brazil.
Assuntos
Antígeno HLA-B18 , Humanos , Alelos , Brasil , Éxons , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade/métodos , Antígeno HLA-B18/genética , Antígeno HLA-B18/imunologia , Análise de Sequência de DNA/métodos , Doadores de TecidosRESUMO
BACKGROUND: Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness. METHODS: MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (nâ =â 166) and controls (nâ =â 149). A replication cohort of patients with dengue (nâ =â 222) was used to confirm specific MICB associations with disease. RESULTS: MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR],â 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR,â 0.41; 95% CI, .21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR,â 0.43; 95% CI, .22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI, .14-.60). CONCLUSIONS: Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.
Assuntos
Povo Asiático/genética , Genes MHC Classe I/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Dengue Grave/genética , Adolescente , Alelos , Criança , Pré-Escolar , Antígeno HLA-B18/genética , Antígeno HLA-B40/genética , Antígeno HLA-B44/genética , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Fatores de Proteção , Tailândia/etnologiaRESUMO
HLA-B*18:147 differs from HLA-B*18:01:01:01 by one nucleotide substitution.
Assuntos
Bancos de Sangue , Sangue Fetal , Antígeno HLA-B18/genética , Mutação Puntual , Colômbia , HumanosRESUMO
Liver fibrosis is accelerated in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected compared with HCV monoinfected patients, due to multiple cofactors. Recently, HLA-B18 haplotype has been associated with short-term liver disease progression in this population. Our aim was to assess the influence of HLA-B18 on the fibrosis process in HIV/HCV coinfected individuals, untreated for HCV, during a long-term follow-up. All consecutive HIV/HCV co-infectedcoinfected patients followed in our center, with positive HCV-RNA and available human leukocyte antigen (HLA) haplotypes (determined by sequence-specific oligonucleotide primed polymerase chain reaction and simple sequence repeats polymerase chain reaction using Luminex Technology) were included. Liver fibrosis progression was assessed by means of fibrosis-4 index for liver fibrosis (FIB-4) and AST to platelet ratio index. The association between FIB-4 score over time and laboratory and clinical parameters, including HLA, was evaluated by univariate and multivariate multilevel generalized linear models. A total of 29 out of 148 screened patients were excluded because of spontaneous HCV clearance (27% were HLA-B18+). Among the remaining 119 individuals (82% males; median age at first visit = 30 years [interquartile range, IQR, 26-35]; median follow-up = 21.5 years [IQR, 15-25]), 26% were HLA-B18+. No baseline differences were evidenced between HLA-B18+ and B18- patients. Fibrosis progression was significantly faster in HLA-B18+ than in HLA-B18- patients ( P < 0.001) (Figure 1). At univariate analysis, age ( P < 0.001), HLA-B18 haplotype ( P = 0.02) and HIV-RNA viral load overtime ( P < 0.001) were associated with liver disease progression. At multivariate analysis, only age ( P < 0.001) remained independently associated with liver fibrosis progression. Our data suggest a possible association between HLA-B18 and an accelerated liver fibrosis in HIV/HCV coinfected with a long-term follow-up.
Assuntos
Progressão da Doença , Infecções por HIV/complicações , Antígeno HLA-B18/genética , Hepatite C Crônica/complicações , Cirrose Hepática/genética , Adulto , Coinfecção/genética , Feminino , Humanos , Masculino , Estudos Retrospectivos , Carga Viral , Adulto JovemRESUMO
OBJECTIVE: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A*24, -B*18, and -B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS: Unlike HLA-B*18 or -B*39, HLA-A*24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8+ relatives with IA-2 or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not -B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS: HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and -B*18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.
Assuntos
Autoanticorpos/sangue , Autoimunidade/genética , Diabetes Mellitus Tipo 1/patologia , Antígeno HLA-A24/genética , Antígeno HLA-B18/genética , Antígenos HLA-DQ/genética , Ilhotas Pancreáticas/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Anticorpos Anti-Insulina/sangue , Masculino , Sistema de Registros , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (Pâ=â3.5â×â10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's Râ=â0.75; Pâ=â7.6â×â10) and in unlinked HIV/HLA data from 43 countries (Spearman's Râ=â0.34, Pâ=â0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.
Assuntos
Antirretrovirais/farmacologia , Farmacorresistência Viral , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Evasão da Resposta Imune , Mutação de Sentido Incorreto , Profilaxia Pré-Exposição , Saúde Global , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , HIV-1/genética , Antígeno HLA-B18/genética , Humanos , Polimorfismo Genético , Rilpivirina/farmacologiaRESUMO
Full-length sequences of HLA-B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing in Chinese donors.
Assuntos
Alelos , Éxons , Antígeno HLA-B14/genética , Antígeno HLA-B18/genética , Antígeno HLA-B7/genética , Polimorfismo Genético , Povo Asiático , Sequência de Bases , Clonagem Molecular , Códon/química , Expressão Gênica , Antígeno HLA-B14/imunologia , Antígeno HLA-B18/imunologia , Antígeno HLA-B7/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Íntrons , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
HLA-B*18:119 differs from HLA-B*18:01:01 at nucleotide 28 C>T in exon 4 changing histidine to tyrosine.
Assuntos
Alelos , Éxons , Antígeno HLA-B18/genética , Polimorfismo de Nucleotídeo Único , Transplantados , Substituição de Aminoácidos , Sequência de Bases , Códon/química , Expressão Gênica , Genótipo , Antígeno HLA-B18/imunologia , Teste de Histocompatibilidade , Humanos , Transplante de Rim , Reação em Cadeia da Polimerase , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/cirurgia , Alinhamento de Sequência , Análise de Sequência de DNA , População BrancaRESUMO
Our aim was to analyze the influence of HLA-B haplotypes on liver fibrosis progression in HIV/hepatitis C virus (HCV) co-infected patients. Retrospective longitudinal study including HIV/HCV, non-cirrhotic and HCV treatment-naïve patients. The main outcome variable was liver fibrosis progression of at least one stage. One hundred and four patients constituted the study population (F0-F1: 62 (59.6%); F2: 22 (21.2%); F3: 20 (19.2%)). During a median follow-up of 54.5 months (IQR: 26.2-77), 45 patients (43.3%) showed an increase in the stage of liver fibrosis (time to event: 29 (IQR: 14-49.5) months). HLA-B18pos patients more frequently had a higher and faster fibrosis progression rate (73.3%; 24 (IQR: 8-29) months) than HLA-B18neg patients (38.2%; 34.5 (IQR: 14.7-51.2) months). This association was also observed in the development of F3-F4 fibrosis among F0-F2 patients (HLA-B18pos: 69.2%; 18 (6.5-37) months vs HLA-B18neg: 28.2%; 37 (IQR: 19-52) months). These results could impact the timing of HCV therapy in F0-F2 patients.
Assuntos
Infecções por HIV/tratamento farmacológico , Antígeno HLA-B18/genética , Hepatite C/tratamento farmacológico , Cirrose Hepática/imunologia , Adulto , Coinfecção , Progressão da Doença , Feminino , Genótipo , Infecções por HIV/complicações , Infecções por HIV/genética , Infecções por HIV/virologia , Hepatite C/complicações , Hepatite C/genética , Hepatite C/virologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Falha de Tratamento , Carga ViralAssuntos
Infecções por HIV/tratamento farmacológico , Antígeno HLA-B18/genética , Hepatite C/tratamento farmacológico , Cirrose Hepática/genética , Coinfecção , Progressão da Doença , Genótipo , Infecções por HIV/complicações , Infecções por HIV/genética , Hepatite C/complicações , Hepatite C/genética , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Fatores de Risco , Análise de Sobrevida , Falha de TratamentoRESUMO
A total of 3 novel human leukocyte antigen-B (HLA-B) alleles were detected by next generation sequencing and confirmed by monoallelic sequencing.
Assuntos
Alelos , Éxons , Antígenos HLA/genética , Antígeno HLA-B18/genética , Antígeno HLA-B8/genética , Polimorfismo de Nucleotídeo Único , Substituição de Aminoácidos , Expressão Gênica , Genótipo , Antígenos HLA/imunologia , Antígeno HLA-B18/imunologia , Antígeno HLA-B8/imunologia , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , TransplantadosRESUMO
The HLA-B*18:122 allele showed four nucleotide differences from HLA-B*18:01:01:01.
Assuntos
Alelos , Éxons , Antígeno HLA-B18/genética , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Substituição de Aminoácidos , Sequência de Bases , Transplante de Medula Óssea , Códon/química , Expressão Gênica , Genoma Humano , Antígeno HLA-B18/imunologia , Teste de Histocompatibilidade , Humanos , Íntrons , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
Characterization of four new human leukocyte antigen (HLA) class I alleles, A*32:01:23, B*18:01:24, B*18:72:02 and C*12:166.
Assuntos
Alelos , Éxons , Antígenos HLA-A/genética , Antígeno HLA-B18/genética , Antígenos HLA-C/genética , Mutação Puntual , Doadores de Tecidos , Sequência de Bases , Clonagem Molecular , Expressão Gênica , Genótipo , Antígenos HLA-A/imunologia , Antígeno HLA-B18/imunologia , Antígenos HLA-C/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Alinhamento de Sequência , Análise de Sequência de DNA , EspanhaRESUMO
BACKGROUND: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. METHODS AND FINDINGS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. CONCLUSIONS: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.
Assuntos
Expressão Gênica/imunologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Receptores KIR/imunologia , Adulto , Idade de Início , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B18/genética , Antígeno HLA-B18/imunologia , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Antígeno HLA-DR3/genética , Antígeno HLA-DR3/imunologia , Haplótipos , Hepatite Autoimune/genética , Hepatite Autoimune/patologia , Humanos , Células Matadoras Naturais/patologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Receptores KIR/genética , Receptores KIR2DL3/genética , Receptores KIR2DL3/imunologia , Receptores KIR3DL1/genética , Receptores KIR3DL1/imunologiaRESUMO
Limited reports are available on association of HLA-B with HIV infection from India, a home to the third largest population of HIV infected people in the world. This emphasizes the need to have more information specifically the genetic constitution of HIV serodiscordant couples (DCs), where one spouse is seropositive (HSP) while the other remains seronegative (HSN) even after repeated exposure. Hence, aim of this study was to document association of HLA-B with HIV infection in DCs living in Mumbai, India. A cohort was designed to enroll DCs attending the ICTC/Shakti Clinic of KEM Hospital, Mumbai. A group of unexposed volunteers were also enrolled as healthy controls (HC). HLA-B alleles were typed using sequence-specific oligonucleotide probes. Allele frequency comparison was done using 2×2 contingency tables. Results were considered significant, when p<0.05 with two-tailed Fisher's exact test. At HLA-B locus, the frequencies of HLA-B*40;-B*35;-B*07;-B*15;-B*51;-B*44;-B*52;-B*37 and -B*57 were found in decreasing order in the population. Frequency of HLA-B*35 allele was significantly higher (HSP vs HSN; p<0.02 and HSP vs HC; p<0.04) in HSP. HLA-B*40 (HSN vs HSP; p<0.01 and HC vs HSP; p<0.01) and HLA-B*18 (HSN vs HSP; p<0.02) were significantly associated with HSN. Both HSN and HC had similar HLA-B*35 and -B*40 allele frequency. HLA-B*57 allele was observed in 15 individuals (3.69%). However, HLA-B*57:01 which is known to be associated with adverse reactions against Abacavir was observed in 7 of them. HLA-B*39 was observed exclusively in HSP. Our observation in DCs confirmed the association of HLA-B*35 with susceptibility while HLA-B*40 (specifically *B40:06), -B*18 with protection. These identified alleles can be used as possible marker associated with HIV transmission. In India, HLA screening is not carried out before initiation of HIV treatment. However, the presence of HLA-B*57:01 in the population emphasizes the importance of such screening to predict/avoid Abacavir hypersensitivity.
Assuntos
Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Soropositividade para HIV/imunologia , HIV-1/imunologia , Antígenos HLA-B/imunologia , Alelos , Estudos de Coortes , Feminino , Frequência do Gene , Infecções por HIV/genética , Infecções por HIV/virologia , Soronegatividade para HIV/genética , Soropositividade para HIV/genética , Soropositividade para HIV/virologia , HIV-1/fisiologia , Antígenos HLA-B/genética , Antígeno HLA-B18/genética , Antígeno HLA-B18/imunologia , Antígeno HLA-B35/genética , Antígeno HLA-B35/imunologia , Antígeno HLA-B40/genética , Antígeno HLA-B40/imunologia , Teste de Histocompatibilidade/métodos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Índia , Masculino , CônjugesRESUMO
Class I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA-B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno HLA-B18/imunologia , Antígeno HLA-B44/imunologia , Fragmentos de Peptídeos/imunologia , Sítios de Ligação de Anticorpos , Células Cultivadas , Epitopos de Linfócito T/imunologia , Antígeno HLA-B18/genética , Antígeno HLA-B44/genética , Humanos , Leucócitos Mononucleares/imunologia , Polimorfismo de Nucleotídeo Único , Estrutura Terciária de Proteína , Transativadores/imunologiaRESUMO
BACKGROUND: Rilpivirine is listed as an alternative key drug in current antiretroviral therapy (ART) guidelines. E138G/A/K in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are rilpivirine resistance-associated mutations and can be identified in a few ART-naive patients, although at low frequency. The 138th position in HIV-1 RT is located in one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted cytotoxic T lymphocytes (CTLs). CTL-mediated immune pressure selects escape mutations within the CTL epitope. Here we tested whether E138G/A/K could be selected by HLA-B*18-restricted CTLs. METHODS: The amino acid variation at the 138th position was compared between ART-naive HIV-1-infected patients with and without HLA-B*18. The optimal epitope containing the 138th position was determined and the impact of E138G/A/K on CTL response was analyzed by epitope-specific CTLs. The effect of E138G/A/K on drug susceptibility was determined by constructing recombinant HIV-1 variants. RESULTS: The prevalence of E138G/A/K was 21% and 0.37% in 19 and 1088 patients with and without HLA-B*18, respectively (odds ratio, 72.3; P = 4.9 × 10(-25)). The CTL response was completely abolished by the substitution of E138G/A/K in the epitope peptide. E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, respectively. CONCLUSIONS: E138G/A/K can be selected by HLA-B*18-restricted CTLs and confer significant rilpivirine resistance. We recommend drug resistance testing before the introduction of rilpivirine-based ART in HLA-B*18-positive patients.
Assuntos
Fármacos Anti-HIV/farmacologia , Epitopos de Linfócito T/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Nitrilas/farmacologia , Pirimidinas/farmacologia , Farmacorresistência Viral/genética , Transcriptase Reversa do HIV/genética , HIV-1/genética , HIV-1/imunologia , Antígeno HLA-B18/genética , Antígeno HLA-B18/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Modelos Moleculares , Mutação , Rilpivirina , Linfócitos T Citotóxicos/imunologiaRESUMO
AIMS/HYPOTHESIS: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. METHODS: A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. RESULTS: Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk. CONCLUSIONS/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.
Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Antígeno HLA-A24/genética , Antígeno HLA-B18/genética , Antígeno HLA-B39/genética , Antígenos HLA-DQ/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Medição de Risco , Adulto JovemRESUMO
NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8(+) T cell epitope, NY-ESO-1(88-96) (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1(157-165) epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1(88-96) is much more efficiently cross-presented from the soluble form, than NY-ESO-1(157-165). On the other hand, NY-ESO-1(157-165) is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A(26-35); whereas NY-ESO-1(88-96) was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1(88-96) is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18(+) melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1(88-96) from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8(+) T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Epitopos/imunologia , Antígeno HLA-B18/imunologia , Western Blotting , Linhagem Celular Tumoral , Humanos , Melanoma/imunologia , Melanoma/patologiaRESUMO
OBJECTIVES: In Morocco, the patients affected by ankylosing spondylitis (AS) presents a high frequency of coxitis. Our study reports, for the first time, the polymorphism of Human Leukocyte Antigen (HLA) class I and class II molecules in the Moroccan patients. METHODS: Forty-six patients diagnosed with an AS and coxitis were compared to a group of 183 healthy controls matched by age, sex and ethnic origin. The HLA typing was performed using microlymphocytotoxicity for the class I (-A, -B) and PCR-SSP for the class II (-DR, -DQ). RESULTS: We found a significant increase of the HLA-B27 antigen frequency (P<0.0001, RR=20.9) in AS patients (29.3%) compared to the controls (3.2%) and a significant decrease in the frequency of HLA-B12 and HLA-B18 antigens. Examination of HLA class II distribution shows a significant increase of the HLA-DRB1*11 allele frequency in patients (P<0.0001). Concerning HLA-DQB1* alleles, no significant difference between patients and controls was appreciable. CONCLUSIONS: The HLA-B27 antigen is involved in the predisposition to the AS with coxitis in the Moroccan population. However, the low frequency observed in our population suggests the existence of other genetic and/or environmental factors. Other HLA genes seem to confer a predisposing effect (DRB*11) or a protective effect (B12 and B18) against the disease.