RESUMO
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
The novel HLA-B*18:37:03 allele, first described in a potential bone marrow donor from Brazil.
Assuntos
Alelos , Éxons , Humanos , Sequência de Bases , Transplante de Medula Óssea , Brasil , Teste de Histocompatibilidade , Antígeno HLA-B18/genética , Antígeno HLA-B18/imunologia , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
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: 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
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
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
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
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
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
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.