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HLA-A
Selected AbstractsImmune modulation of HLA-G dimer in maternal-fetal interfaceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Kimiko Kuroki Abstract HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including ,2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of ,2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that ,2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: http://dx.doi.org/10.1002/eji.200737089 [source] IL-15-induced human DC efficiently prime melanoma-specific naive CD8+ T cells to differentiate into CTLEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Peter Dubsky Abstract Monocytes differentiate into dendritic cells (DC) in response to GM-CSF combined with other cytokines including IL-4 and IL-15. Here, we show that IL15-DC are efficient in priming naive CD8+ T cells to differentiate into melanoma antigen-specific cytotoxic T,lymphocytes (CTL). While both melanoma peptide-pulsed IL15-DC and IL4-DC expand high-precursor frequency MART-1-specific CD8+ T cells after two stimulations in vitro, IL15-DC require much lower peptide concentration for priming. IL15-DC are more efficient in expanding gp100-specific CD8+ T cells and can expand CD8+ T cells specific for Tyrosinase and MAGE-3. CTL primed by IL15-DC are superior in their function as demonstrated by (i),higher IFN-, secretion, (ii),higher expression of Granzyme,B and Perforin, and (iii),higher killing of allogeneic melanoma cell lines, most particularly the HLA-A*0201+ Sk-Mel-24 melanoma cells that are resistant to killing by CD8+ T cells primed with IL4-DC. Supernatants of the sonicated cells demonstrate unique expression of IL-1, IL-8 and IL-15. Therefore, membrane-bound IL-15 might contribute to enhanced priming by IL15-DC. Thus, IL-15 induces myeloid DC that are efficient in priming and maturation of melanoma antigen-specific CTL. [source] Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class,I invariant regionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007Linda Wooldridge Abstract CD8+ cytotoxic T,lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class,I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the ,2,domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by,,50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 ,,chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens. [source] Crystal structure of HLA-A*2402 complexed with a telomerase peptideEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2006David Abstract HLA-A*2402 is the most commonly expressed HLA allele in oriental populations. It is also widely expressed in the Caucasian population, making it one of, if not the most abundant HLA,I types. In order to study its structure in terms of overall fold and peptide presentation, a soluble form of this HLA,I (,1, ,2, ,3 and ,2m domains) has been expressed, refolded and crystallized in complex with a cancer-related telomerase peptide (VYGFVRACL), and its structure has been solved to 2.8,Å resolution. The overall structure of HLA-A*2402 is virtually identical to other reported peptide-HLA,I structures. However, there are distinct features observable from this structure at the HLA,I peptide binding pockets. The size and depth of pocket,B makes it highly suitable for binding to large aromatic side chains, which explains the high prevalence of tyrosine at peptide position,2. Also, for HLA binding at peptide position,5, there is an additional anchor point, which allows the proximal amino acids to protrude out, providing a prominent feature for TCR interaction. Finally, pocket,F allows the anchor residue at position,9 to be bound unusually deeply within the HLA structure. [source] Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class,Ia and HLA-E expression: impact on target susceptibility to NK cell subsetsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003Manuel Llano Abstract We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class,Ia surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI,8866 B,lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-ER, HLA-EG) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone,A. US6 down-regulated expression of all class,I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class,Ia molecules but preserved HLA-E; this rendered US11+ cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A+KIR2DL2, effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class,Ia molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2+ targets became sensitive to KIR2DL2+ cells but remained resistant to CD94/NKG2A+CD85j+ NK clones. The differential effects of US proteins on HLA class,Ia and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance. [source] The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patientsEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2007C. Smestad The human leucocyte antigen (HLA) class II haplotype DRB1*15,DQB1*06 (DR15,DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal,Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort. [source] Intrinsic genetic instability of normal human lymphocytes and its implication for loss of heterozygosityGENES, CHROMOSOMES AND CANCER, Issue 4 2001Arnolda G. de Nooij-van Dalen A combination of flow cytometry and microsatellite analysis was used to investigate loss of expression of HLA-A and/or HLA-B alleles and concurrent LOH at polymorphic chromosome 6 loci both in freshly isolated lymphocytes (in vivo mutations) and in lymphocytes cultured ex vivo. The fraction of in vivo mutants that showed LOH at 6p appeared to vary from 0%,49% for various donors. During culturing ex vivo, HLA-A, cells arose at a high rate and showed simultaneous loss of expression at the linked HLA-B locus. Up to 90% of the ex vivo arisen HLA-A2, cell population showed LOH of multiple 6p markers, and 50% had lost heterozygosity at 6q. This ex vivo spectrum resembles that found in HLA-A2 mutants obtained from lymphoblastoid cells. The HLA-A2 mutants present in vivo may reflect only a small fraction of the mutants that can be detected ex vivo. In normal lymphocytes, in vivo only mitotic recombination appears to be sustained, indicating the importance of this mechanism for tumor initiation in normal cells. Although mutations resulting in LOH at both chromosome 6 arms were shown to result in nonviable cells in normal lymphocytes, they have been shown to result in viable mutants in lymphoblastoid cells. We hypothesize that these types of mutations also occur in vivo but only survive in cells that already harbor a mutated genetic background. In light of the high rate at which these types of mutations occur, they may contribute to cancer progression. © 2001 Wiley-Liss, Inc. [source] Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single sourceHEPATOLOGY, Issue 1 2004Susan M. McKiernan The role of cytotoxic T lymphocyte responses, restricted by human leukocyte antigen (HLA) class I alleles, is recognized as highly significant in the successful clearance of hepatitis C virus (HCV). The frequency of class I alleles in females inoculated with HCV genotype 1b from a single source was examined for an association with outcome. Class I typing was performed using polymerase chain reaction sequence-specific primers in 227 female subjects: 141 had chronic infection and 86 had viral clearance. Statistical analysis included ,2 testing and multiple logistic regression analysis. A*03, B*27, and Cw*01 occurred more frequently in those with viral clearance (39.5%, 14%, and 9.3%, respectively) compared with those with chronic infection (19.1%, 2.1%, and 1.4%, respectively; P , .005). B*08 occurred more often in those with chronic infection compared with viral clearance (39.7% vs. 19.8%; P = .002). In combination with previously reported class II allele associations, over 75% that successfully eliminate HCV carry either A*03, DRB1*0101, or *0401, compared with only 37% of those with chronic infection (P < .0001). The haplotypes A*03-B*07-DRB1*15-DQB1*0602 and A*02-B*27-Cw*01-DRB1*0101-DQB1*0501 are associated with viral clearance (P = .004 and .01, respectively). By multiple logistic regression analysis, the alleles A*03, B*27, DRB1*0101, *0401, and *15 are associated with viral clearance, and B*27 has the strongest association (odds ratio [OR] 7.99). The haplotype A*01-B*08-Cw*07-DRB1*03011-DQB1*0201 is associated with chronic infection (P = .002), being independent for DQB1*0201 (OR 0.27). In conclusion, certain class I alleles are associated with outcome in this homogenous cohort. More significantly, either HLA-A*03, -DRB1*0101, or -*0401 are carried by an overwhelming majority of those subjects who successfully clear HCV. (HEPATOLOGY 2004;40:108,114.) [source] Species-specific evolution of MHC class I genes in the higher primatesIMMUNOLOGICAL REVIEWS, Issue 1 2001Erin J. Adams Summary: Humans express three highly polymorphic ,classical' (HLA-A,B and C) and three conserved ,non-classical' (HLA-E, F and G) MHC class I genes. Their comparison with the MHC class I genes of apes and monkeys reveals the differential extent to which MHC class I genes have been preserved during primate evolution. African apes have orthologues of all six human genes, and although allelic lineages of the A and C loci are shared, these species share none of the human alleles. In Asian apes, several MHC class I genes show significant differences from the human genes, a trend which continues with the Old World monkeys, and even more so in the New World monkeys, where E and F are the only human gene orthologues. The C locus is confined to humans and apes. Multiple A -related and B -related loci have been identified in apes and Old World monkeys showing that duplication of these loci has been a common event during primate evolution. Certain of the daughter loci exhibit low polymorphism, suggesting they have adopted a non-classical function. The differing rates at which MHC class I genes have evolved during primate evolution likely reflects their differing functions in the immune response. [source] The shared tumor associated antigen cyclin-A2 is recognized by high-avidity T-cellsINTERNATIONAL JOURNAL OF CANCER, Issue 10 2009Eisei Kondo Abstract Cyclin-A2, a key cell cycle regulator, has been shown to be overexpressed in various types of malignancies with little expression in normal tissue. Such tumor-associated genes potentially are useful targets for cancer immunotherapy. However, high-avidity cyclin-specific T cells are considered to be thymically deleted. We identified at least one nonameric HLA-A*0201 binding cyclin-A2 epitope by a reverse immunology approach. Using a highly efficient T-cell expansion system that is based on CD40-activated B (CD40-B) cells as sole antigen-presenting cells we successfully generated cyclin-A2 specific CTL from HLA-A*0201+ donors. Interestingly, high-avidity cyclin-A2 specific CTL lines, which recognized peptide-pulsed and antigen expressing target cells, were indeed generated by stimulation with CD40-B cells when pulsed with low concentrations of peptide, whereas CD40-B cells pulsed at saturating concentrations could only induce low-avidity CTL, which recognized peptide-pulsed target cells only. One high-avidity CTL line was subcloned and CTL clones, whose peptide concentration required for half-maximal lysis were less than 1 nM, could lyse cyclin-A2 expressing tumor cells. Taken together, cyclin A2 is an attractive candidate for immune intervention in a significant number of cancer patients and high-avidity T cells can be readily generated using CD40-B cells as antigen-presenting cells. © 2009 UICC [source] B and CTL responses to the ALK protein in patients with ALK-positive ALCLINTERNATIONAL JOURNAL OF CANCER, Issue 3 2006Kamel Ait-Tahar Abstract Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) has a good prognosis compared to ALK-negative ALCL, possibly as a result of the immune recognition of the ALK proteins. The aim of our study was to investigate the presence of both a B and cytotoxic T cell (CTL) response to ALK in ALK-positive ALCL. We confirmed the presence of an antibody response to ALK in all 9 ALK-positive ALCL patients investigated. An ELISpot assay was used to detect a ,-interferon (IFN) T cell response after short term culture of mononuclear blood cells with 2 ALK-derived HLA-A*0201 restricted peptides: ALKa and ALKb. A significant ,-IFN response was identified in all 7 HLA-A*0201-positive ALK-positive ALCL patients but not in ALK-negative ALCL patients (n = 2) or normal subjects (n = 6). CTL lines (>95% CD8-positive) raised from 2 ALK-positive ALCL patients lysed ALK-positive ALCL derived cell lines in a MHC-Class I restricted manner. This is the first report of both a B cell and CTL response to ALK in patients with ALK-positive ALCL. This response persisted during long-term remission. The use of modified vaccinia virus Ankara (MVA) to express ALK is also described. Our findings are of potential prognostic value and open up therapeutic options for those ALK-positive patients who do not respond to conventional treatment. © 2005 Wiley-Liss, Inc. [source] Melanoma patients respond to a new HLA-A*01-presented antigenic ligand derived from a multi-epitope region of melanoma antigen TRP-2INTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Annette Paschen Abstract Tyrosinase-related protein-2 (TRP-2) is a known target antigen of spontaneous cytotoxic T cell responses in melanoma patients. Its frequent expression in metastatic tumors suggests that it might be an ideal candidate antigen for T cell-based immunotherapy. To provide knowledge about TRP-2-derived T cell epitopes useful for immunotherapy we applied a "reverse immunology strategy" based on repeated in vitro peptide stimulation of peripheral blood lymphocytes (PBL) from normal donors with predicted HLA-A*01 ligands. This led to the identification of TRP-2181,190 as the first HLA-A*01-presented TRP-2-derived epitope. T-cell lines specific for peptide TRP-2181,190 could be established from PBL of 50% of the normal HLA-A*01+ donors tested. Such T cells responded specifically to autologous dendritic cells transduced virally with TRP-2, as well as to HLA-A*01+, TRP-2+ melanoma cells, although tumor cells had to be pretreated with IFN-, to become susceptible to T cell recognition. Interestingly, short-term in vitro peptide stimulation of PBL from HLA-A*01+ melanoma patients showed the presence of TRP-2181,190 -reactive CD8+ T cells in some donors, suggesting their in vivo sensitization. Because TRP-2181,190 overlaps with the known HLA-A*0201-presented epitope TRP-2180,188, an 11mer peptide encompassing both epitopes might be of specific value for vaccination of a broad population of melanoma patients. © 2005 Wiley-Liss, Inc. [source] E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class IINTERNATIONAL JOURNAL OF CANCER, Issue 2 2005G. Hossein Ashrafi Abstract Papillomaviruses have evolved mechanisms that result in escape from host immune surveillance. The E5 protein is expressed early in papillomavirus infection in the deep layers of the infected epithelium. It is localized to the Golgi apparatus (GA) and endoplasmic reticulum. The E5 protein of bovine papillomavirus (BPV) impairs the synthesis and stability of major histocompatibility (MHC) class I complexes and prevents their transport to the cell surface due to retention in the GA. Here we show that human papillomavirus type 16 (HPV-16) E5 also causes the retention of MHC (HLA) class I complexes in the GA and impedes their transport to the cell surface, which is rescued by treatment with interferon. Unlike BPV E5, HPV-16 E5 does not affect the synthesis of HLA class I heavy chains or the expression of the transporter associated with antigen processing TAP. These results show that downregulation of surface MHC class I molecules is common to both BPV and HPV E5 proteins. Moreover, we determined that HPV-16 E5 downregulates surface expression of HLA-A and HLA-B, which present viral peptides to MHC class I-restricted cytotoxic T lymphocytes (CTLs), but not the natural killer (NK) cell inhibitory ligands HLA-C and HLA-E. Selective downregulation of cell surface HLA class I molecules may allow the virus to establish infection by avoiding immune clearance of virus-infected cells by both CTLs and NK cells. [source] Genetic susceptibility to nasopharyngeal carcinoma within the HLA-A locus in TaiwaneseINTERNATIONAL JOURNAL OF CANCER, Issue 6 2003Cheng-Chan Lu Abstract NPC is an epithelial tumor that is highly prevalent among the southern Chinese. Numerous studies have indicated that specific HLA haplotypes and genes within the HLA complex are associated with NPC. As a first effort to localize the gene responsible for susceptibility, the HLA-A, -B, and -A2 subtypes were examined for their association to NPC. Consistent with previous reports, frequencies of HLA-A2 [OR = 2.50, pc = 0.020 (study population); OR = 3.73, pc = 0.0030 (,40 years old)] were significantly higher in patients with NPC than in healthy controls. Two-locus analysis indicated that A2+B46+ individuals are at greater risk for NPC than A2,B46, individuals in both the population studied and the ,40-year-old group. This, however, may be due to the close linkage of these 2 genes. Moreover, A2+B38+ individuals were at higher risk than A2,B38, individuals in both the population studied and the ,40-year-old group; A2 and B38 are not genetically linked. These findings suggest that B38 or B46 alone cannot confer a high risk of NPC but that, in conjunction with A2, B38 or B46 positivity greatly increases risk. None of 5 A2 subtypes identified from studied populations was significantly associated with NPC. Microsatellite marker D6S211, located 97 kb telomeric to HLA-A, was analyzed for its association with NPC. Allele 4 of D6S211 was significantly associated with NPC (OR = 3.97, pc = 0.0042). These results strongly support the hypothesis that genes associated with susceptibility to NPC in the HLA region are within the HLA-A locus. © 2002 Wiley-Liss, Inc. [source] Analysis of high-resolution HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles and haplotypes in 718 Chinese marrow donors based on donor,recipient confirmatory typingsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5 2009A.-L. Hei Summary High-resolution human leucocyte antigen (HLA)-A, -B, -Cw, -DRB1, and -DQB1 alleles and haplotype frequencies were analysed from 718 Chinese healthy donors selected from the Chinese Marrow Donor Program registry based on HLA donor,recipient confirmatory typings. A total of 28 HLA-A, 61 HLA-B, 30 HLA-Cw, 40 HLA-DRB1 and 18 HLA-DQB1 alleles were identified, and HLA-A*1101, A*2402, A*0201, B*4001, Cw*0702, Cw*0102, Cw*0304, DRB1*0901, DRB1*1501, DQB1*0301, DQB1*0303 and DQB1*0601 were found with frequencies higher than 10% in this study population. Multiple-locus haplotype analysis by the maximum-likelihood method revealed 45 A,B, 38 Cw,B, 47 B,DRB1, 29 DRB1,DQB1, 24 A,B,DRB1, 38 A,Cw,B, 23 A,Cw,B,DRB1, 33 Cw,B,DRB1,DQB1 and 22 A,Cw,B,DRB1,DQB1 haplotypes with frequencies >0.5%. The most common two-, three-, four- and five-locus haplotypes in this population were: A*0207,B*4601 (7.34%), Cw*0102,B*4601 (8.71%), B*1302,DRB1*0701 (6.19%), DRB1*0901,DQB1*0303 (14.27%), A*3001,B*1302,DRB1*0701 (5.36%), A*0207,Cw*0102,B*4601 (7.06%), A*3001,Cw*0602,B*1302,DRB1*0701 (5.36%), Cw*0602,B*1302,DRB1*0701,DQB1*0202 (6.12%) and A*3001,Cw*0602,B*1302,DRB1*0701,DQB1*0202 (5.29%). Presentation of the high-resolution alleles and haplotypes data at HLA-A, -B, -Cw, -DRB1 and -DQB1 loci will be useful for HLA matching in transplantation as well as for other medical and anthropological applications in the Chinese population. [source] HLA haplotypes in recurrent aphthous stomatitis: a mode of inheritance?INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2008E. Albanidou-Farmaki Summary The aim of this study was to investigate the genetic association between recurrent aphthous stomatitis (RAS) and human leucocyte antigen (HLA) class I and II alleles and HLA haplotypes. Families selected had at least one child suffering from recurrent aphthous stomatitis in addition to one or both of the parents. HLA-A, -B and -DR alleles were typed in 29 families, 27 nuclear and two extended (121 subjects). HLA haplotypes of all family members with RAS were compared with those who were RAS negative. Although major histocompatibility complex class I and II gene analysis failed to demonstrate any significant association between RAS and HLA antigens, the study of HLA haplotypes revealed a significant association between HLA haplotypes and susceptibility to RAS. The results indicate that susceptibility to RAS segregates in families in association with HLA haplotypes. [source] Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: a cohort of 95 SARS-recovered individuals in a population of Guangdong, southern ChinaINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2008P. Xiong Summary Severe acute respiratory syndrome (SARS), caused by infection with a novel coronavirus (SARS-CoV), was the first major novel infectious disease at the beginning of the 21st century, with China especially affected. SARS was characterized by high infectivity, morbidity and mortality, and the confined pattern of the disease spreading among the countries of South-East and East Asia suggested the existence of susceptible factor(s) in these populations. Studies in the populations of Hong Kong and Taiwan showed an association of human leucocyte antigen (HLA) polymorphisms with the development and/or severity of SARS, respectively. The aim of the present study was to define the genotypic patterns of HLA-A, -B and -DRB1 loci in SARS patients and a co-resident population of Guangdong province, southern China, where the first SARS case was reported. The samples comprised 95 cases of recovered SARS patients and 403 unrelated healthy controls. HLA -A, -B and -DRB1 alleles were genotyped using polymerase chain reaction with sequence-specific primers. The severity of the disease was assessed according to the history of lung infiltration, usage of assisted ventilation and occurrence of lymphocytopenia. Although the allelic frequencies of A23, A34, B60, DRB1*12 in the SARS group were slightly higher, and A33, -B58 and -B61 were lower than in the controls, no statistical significance was found when the Pc value was considered. Similarly, no association of HLA alleles with the severity of the disease was detected. Thus, variations in the major histocompatibility complex are unlikely to have contributed significantly to either the susceptibility or the severity of SARS in the population of Guangdong. [source] Determination of HLA-A, -B and -DRB1 haplotypes based on allelic homozygosity data in selected bone marrow donors of the Taiwanese marrow donor registryINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5 2007K. L. Yang Summary From 120 unrelated Taiwanese marrow stem cell donors with allelic homozygosities at human leucocyte antigen (HLA)-A, -B and -DRB1 loci, we determined 85 distinguishable haplotypes. Using the predetermined haplotype data, we deduced 418 haplotypes from 1903 unrelated individual stem cell donors selected for HLA confirmatory test. Eighteen of the 20 (90%) most frequently observed haplotypes determined in Asian Americans using computer prediction were found in this study. In comparison with haplotypes determined by maximum likelihood algorithm in Korean population, 18 of the 29 (62.07%) Korean haplotypes with a frequency over 0.5% were also among the haplotypes determined in this investigation. Randomized family studies confirmed that over 50% of the haplotypes observed in the families were among the haplotypes deduced based on allelic homozygosity, suggesting that proportionally additional haplotypes can be determined as the number of donors being studied is increased. Haplotypes carrying low incidence allele characteristics of Taiwanese were also observed in this study. This established haplotype information will be beneficial for patients searching for stem cell donors in our registry domestically and internationally. [source] A novel HLA-A2 variant, A*9203, identified by sequence-based typingINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2007C.-C. Chu Summary HLA-A*9203, found in Taiwan using sequence-based typing method, was identical to HLA-A*0207 in exon 3 but differed in exon 2 by five nucleotide substitutions at positions 240,282 corresponding to three amino acid changes at codons 62, 66 and 70. Since this substitution motif is also seen in A*11 and A*03, it is likely that a gene conversion event from A*11 or A*03 to a A*0207 backbone may have been the process used in generating HLA-A*9203. [source] Molecular diversity of HLA-A*19 group of alleles in south Indian populationINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2006V. Vettriselvi Summary To determine the genetic diversity of the human leucocyte antigen (HLA)-A*19 group of alleles in the south Indian Tamil population, we studied 100 random healthy unrelated individuals. The frequency of HLA-A*19 was 37% with A*33 (45.9%), A*32 (29.7%), A*31 (16.2%), A*30 (5.4%), A*29 (2.7%) and A*74 (0%). The frequency distribution of the HLA-A*19 alleles was distinct and revealed marked similarities and variations with other populations [source] Recognition of HLA-A*0248 in a Chinese donorINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2003K. L. Yang Summary HLA-A*0248, a rare allele originally found in an individual of Filipino background, was detected in a Chinese donor. We confirmed the novel sequence and analysed its serological reaction pattern. The exon 2 sequence of A*0248 was apparently generated in a gene conversion event with an A2 gene, receiving a sequence segment comprising codons 56 to 74 from an A*24 donor gene. Serological typing showed a clear-cut A2 reaction pattern, indicating that the three amino acid positions 62, 65 and 74, are probably not a critical part of the A2 epitope. Our typing experience also demonstrated that different typing technologies often complement each other in fine HLA typing. [source] HLA class I polymorphism in a Moroccan population from CasablancaINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2002F. Choukri Summary We have studied the distribution of HLA-A and -B alleles and haplotypes by sequence-specific primer amplification in a sample of 100 unrelated healthy individuals belonging to both Berber and Arabic-speaking groups from the region of Casablanca in Morocco. Among the 17 HLA-A and 23 HLA-B alleles observed, the most frequent were HLA-A2 (21%), -A1 (11%), -A3 (10%), -B44 (11.4%), -B50 (9.9%), -B5(8.5%) and -B35 (6.5%). Six two-locus haplotypes were observed with a frequency above 5%: A2-B50 (9.6%), A23-B44 (7.4%), A2-B15 (6.4%), A68-B39 (5.3%), A1-B51 (5.3%) and A68-B44 (4.3%). Our data confirm that, on the basis of genetic distances, the majority of present-day North Africans from Morocco are closely related to Berbers and also to Iberians. They cluster apart from Middle-Eastern Mediterranean populations, and show greater genetic distances to Eastern and other Mediterranean populations. This study will serve as a reference for further anthropological studies, as well as studies of HLA and disease associations. [source] Further characterization of MHC haplotypes demonstrates conservation telomeric of HLA-A: update of the 4AOH and 10IHW cell panelsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5-6 2000S. K. Cattley Cell panels have been used extensively in studies of polymorphism and disease associations within the major histocompatibility complex (MHC), but the results from these panels require continuous updates with the increasing availability of novel data. We present here an updated table of the typings of the 10IHW and 4AOH panels. Local data included are HFE, HERV-K(C4) and six microsatellites telomeric of HLA-A. Typings for class I, MICA (PERB11.1), MICB (PERB11.2), XA, XB, LMP2 and 10 microsatellites reported by others have also been consolidated in this table. The tabulation shows that the length of conservation in the human MHC is even more extensive than previously thought. Human MHC ancestral haplotypes are inherited as a conserved region of genomic sequence spanning some 6,8 megabases from the HLA class II region and beyond the HLA class I region up to and including the HFE gene. Numerous examples of historical recombinations were also observed. [source] Large-scale molecular dynamics simulations of HLA-A*0201 complexed with a tumor-specific antigenic peptide: Can the ,3 and ,2m domains be neglected?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2004Shunzhou Wan Abstract Large-scale massively parallel molecular dynamics (MD) simulations of the human class I major histocompatibility complex (MHC) protein HLA-A*0201 bound to a decameric tumor-specific antigenic peptide GVYDGREHTV were performed using a scalable MD code on high-performance computing platforms. Such computational capabilities put us in reach of simulations of various scales and complexities. The supercomputing resources available for this study allow us to compare directly differences in the behavior of very large molecular models; in this case, the entire extracellular portion of the peptide,MHC complex vs. the isolated peptide binding domain. Comparison of the results from the partial and the whole system simulations indicates that the peptide is less tightly bound in the partial system than in the whole system. From a detailed study of conformations, solvent-accessible surface area, the nature of the water network structure, and the binding energies, we conclude that, when considering the conformation of the ,1,,2 domain, the ,3 and ,2m domains cannot be neglected. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1803,1813, 2004 [source] Identification of a dengue virus-specific HLA-A*0201-restricted CD8+ T cell epitopeJOURNAL OF MEDICAL VIROLOGY, Issue 4 2010Jinsheng Wen Abstract In this study, a combination of epitope-prediction programs and in vitro assays was used to identify dengue virus (DENV)-specific CD8+ T cell epitopes. Peripheral blood mononuclear cells (PBMCs) isolated from patients who recovered from dengue fever were stimulated with candidate epitope peptides derived from DENV, which were predicted by using SYFPEITHI and RANKpep epitope-prediction programs. The IFN-, ELISpot results and the results of intracellular staining of IFN-, showed that peptides NS4b_40 (TLYAVATTI), E_256 (QEGAMHTAL), NS3_205 (LPAIVREAI), NS5_210 (SRNSTHEMY), and NS3_207 (AIVREAIKR) could induce the recall response of CD8+ T cells. Furthermore, the results of the MHC,peptide complex stabilization assay revealed that peptide NS4b_40 (TLYAVATTI) has a high affinity for HLA-A*0201 molecules. The IFN-, ELISpot results and staining of intracellular IFN-, confirmed that this peptide could induce high-level CD8+ T cell response in HLA-A*0201 positive PBMCs. Peptide NS4b_40 (TLYAVATTI) was identified as a novel DENV-specific HLA-A*0201-restricted CD8+ T cell epitope. J. Med. Virol. 82:642,648, 2010. © 2010 Wiley-Liss, Inc. [source] Evaluation of host genetic and viral factors as surrogate markers for HTLV-1-associated myelopathy/tropical spastic paraparesis in Peruvian HTLV-1-infected patientsJOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Michael Talledo Abstract Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a complication that affects up to 5% of HTLV-1-infected individuals. Several host genetic and viral factors have been associated with the risk of HAM/TSP. The aim of this study was to evaluate the performance of a prognostic model for HAM/TSP developed in Japan in a Peruvian population of 71 HAM/TSP patients and 94 asymptomatic carriers (ACs). This model included age, proviral load (PVL), the presence of HLA-A*02 and HLA-Cw*08 alleles, SDF-1 +801, and TNF -, ,863 polymorphisms, and viral subgroup. We describe frequencies for the four host genetic markers and demonstrate the presence of the HTLV-1 tax B subgroup in Peru. Using cross-validation, we show that the predictive ability of the prognostic model, as characterized by the area under the receiver-operating characteristic curve (AUC), does not differ from a model containing PVL only (both AUC,=,0.74). We found some suggestive evidence of a protective effect of the HLA-A*02 allele but failed to replicate the associations with the other three genetic markers and with viral subgroup. A logistic model containing PVL, age, gender, and HLA-A*02 provided the best predictive ability in the Peruvian cohort (AUC,=,0.79). J. Med. Virol. 82:460,466, 2010. © 2010 Wiley-Liss, Inc. [source] A peptide derived from hepatitis C virus (HCV) core protein inducing cellular responses in patients with HCV with various HLA class IA alleles,JOURNAL OF MEDICAL VIROLOGY, Issue 7 2009Yamei Niu Abstract C35-44 peptide is a well known HLA-A2-restricted CTL epitope originating from hepatitis C virus (HCV) core protein. It was reported that the majority of HCV positive patients had significant levels of serum IgG specific to this peptide. This study addressed whether C35-44 peptide could induce CTL activity restricted to various HLA class IA alleles or could not. This peptide demonstrated binding activity to HLA-A*2402, -A*2601, -A*3101, and -A*3303 molecules, but not to HLA-A*1101 by means of stabilization assay. This peptide also induced CTL activity restricted to each of them, except HLA-A11+ peripheral blood mononuclear cells from HCV 1b+ patients by means of 51Cr-release assay. With regard to HLA-A2 subtypes, this peptide demonstrated binding activity to HLA-A*0201 and -A*0206, but not to -A*0207 molecules. Furthermore, this peptide induced CTL activity from both the patients and healthy donors with all the HLA class IA molecules mentioned above by means of interferon-, production assay. These results may provide new insights for the development of a novel peptide vaccine against HCV compatible with various HLA class IA types. J. Med. Virol. 81:1232,1240, 2009. © 2009 Wiley-Liss, Inc. [source] HLA typing in Taiwanese patients with oral submucous fibrosisJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2004Hsin-Ming Chen Background:, A significant association of certain human leukocyte antigens (HLA) and haplotypic pairs with oral submucous fibrosis (OSF) has been reported. However, controversial result of no HLA association with OSF has also been reported. In this study, the phenotype and haplotype frequencies of HLA-A, -B, -C, -DRB1, and -DQB1 in 135 Taiwanese OSF patients were calculated and compared with those in 540 healthy control Taiwanese. Methods:, The analysis of HLA-A, -B, and -C antigens, and of HLA-DRB1 and -DQB1 alleles in OSF patients and healthy control subjects, was performed by serologic typing and DNA typing using polymerase chain reaction with sequence-specific primers (PCR-SSP), respectively. Results:, We found that the phenotype frequency of HLA-B76 (3.0%) in OSF patients was significantly greater than that (0%) in healthy control subjects (corrected P (Pc) = 0.000). In addition, the haplotype frequencies of HLA-B48/Cw7 (3.0%), -B51/Cw7 (6.7%), and -B62/Cw7 (8.2%) in OSF patients were significantly greater than the corresponding haplotype frequencies (0, 0.7, and 1.9%, respectively) in healthy control subjects (Pc = 0.000). The relative risk (RR) values of haplotypes B51/Cw7 (9.57) and B62/Cw7 (4.7) were greater than the RR values of phenotypes B51 (1.81), B62 (2.31), and Cw7 (1.91) in OSF patients. In addition, the etiologic fraction (EF) value of haplotype B51/Cw7 (0.63) was higher than the EF values of phenotypes B51 (0.2) and Cw7 (0.59). Conclusions:, We conclude that some Taiwanese areca quid (AQ) chewers with particular HLA phenotypes and haplotypes are prone to have OSF. In addition, some particular HLA haplotypes may play more important roles than the individual HLA phenotypes for the genetic susceptibility to OSF. However, the significantly increased HLA phenotype B76 and three of the common HLA haplotypes detected are present in only about 20% of incident cases of OSF. [source] Human leukocyte antigen and adult living-donor liver transplantation outcomes: An analysis of the organ procurement and transplantation network database,LIVER TRANSPLANTATION, Issue 10 2007S. Simona Jakab Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease. Liver Transpl 13:1405,1413, 2007. © 2007 AASLD. [source] Relationship of polymorphisms located in tumor necrosis factor region and HLA loci among CroatiansAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2009Katarina Stingl Polymorphism of TNFa, TNFb, and TNFd microsatellites, linkage disequilibrium (LD) within TNF region as well as relationship of TNF microsatellites with alleles at HLA-A, - B, and - DRB1 loci was investigated on a sample of 160 Croatians, previously typed for HLA-A, - B, and - DRB1 loci. Analysis of the relationship of TNF alleles and HLA specificities revealed that very strong associations exist between TNFa2, TNFb3, and TNFd2 alleles and HLA-A*01, -B*08, and -DRB1*03 specificities, therefore placing them in the 8.1 ancestral haplotype. Similar findings were observed for TNFa11, TNFb4, and TNFd4 alleles and HLA specificities, which are a part of the 7.1 ancestral haplotype. Finally, multiple associations with significant P- values were also observed between TNFa10, TNFb4, and TNFd4 microsatellite alleles and HLA-A*02, -B*18, -DRB1*11 specificities which form the 18.3 ancestral hapolotype. Am. J. Hum. Biol. 2009. © 2008 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||