HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms.

Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.

Transposon-mediated death of an ancestral A-23-like allele: evolution of TCR-positioning motifs in the HLA-A lineage.

HLA-A alleles are characterized by tandem arginine and histidine/arginine motifs (i.e., R65 and H151R motifs) present on the α1- and α2-helix, respectively. In crystallographic structures, α/ß T-cell receptors (TCR) contact both motifs and appear to be geometrically positioned for alloreactivity. Herein, bioinformatics of "dual-motif" MHC A-like alleles were investigated across phylogeny. While A-like alleles with the R65 motif are widespread, the H151R motif has segregated out of most species. Surprisingly, an uncharacterized orf in tarsiers (Loc-103275158) encodes R151 within a truncated A-23-like gene, which is in frame with short footprints of Tc5 and Tigger transposons (TE); the extant tarsier A-23 allele is totally missing exon-3 and part of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele. Since the only other (non-human) dual-motif A-like alleles are in gorilla, chimpanzee, and the Florida manatee, we speculate that dual-motif A alleles first emerged in the Afrotherian lineage and reappeared during the evolution of higher primates.

Different patterns of A*80:01:01:01 allele generation based on exon or intron sequences.

Generation of the HLA-A*80:01:01:01 allele has been analysed using its complete sequence. Direct comparison of the sequences and phylogenetic trees using the human leukocyte antigen (HLA)-A representative alleles and the major histocompatibility complex (MHC)-A sequences of non-human primates has been made. Results based on exon sequences confirm previously published, but considering only the sequences of the introns, two distinct regions can be differentiated. The first one comprises from the 5' untranslated region region to the first part of intron 3 sequence (shared with A2 family), and the second one includes the sequence from the end of intron 3 to intron 7 (shared with A1/A3/A11/A36/A30 family). Each of them clusters with Gorilla and Chimpanzee MHC-A sequences, respectively, suggesting an origin coming from a common ancestor to Gorilla and Chimpanzee.

A novel allele, HLA-A*66:14, identified in a Brazilian volunteer bone marrow donor.

The new allele might have arisen from HLA-A*66:01 through a point mutation at codon 182.1 (ACG→GCG) resulting in a non-conservative change from threonine to alanine.

Sequence-based typing confirmed a new HLA-A allele, A*31:53, in a liver recipient patient.

In this report, we present the full-length coding sequence of A*31:53, a novel allele with a single-nucleotide difference in exon 3 with respect to A*31:01:02.

Role of human leukocyte antigen class I alleles in progressive multifocal leukoencephalopathy.

Because human leukocyte antigen (HLA) associations with various infectious diseases have recently been reported, we examined the role of HLA class I alleles in the development of progressive multifocal leukoencephalopathy (PML) or its outcome in 152 patients, including 123 Caucasians and 29 African Americans. Compared to a human immunodeficiency virus positive (HIV+) control population, we observed decreased frequency of HLA-A3 (P = 0.03) in the Caucasian PML group, whereas B18 (P = 0.02), was more frequent. No such difference was found among African American PML patients. We then sought to characterize differences in HLA between PML progressors, whose survival doesn't exceed 1 year, and survivors. Caucasian survivors were less likely to harbor A68 (P = 0.01), whereas African American survivors less frequently displayed Cw4 (P = .01). However, none of these differences reached statistical significance after Bonferroni correction for multiple testing. Further investigations are needed to assess the role of genetics in the incidence of PML or its outcome. Physicians may exercise caution in the use of immunomodulatory medications in patients whose genetic background is associated with an increased risk of PML.

[Cloning and sequencing HLA-A and -B genomic DNA and analyzing polymorphism in regulatory regions in Chinese Han individuals].

In the present study, a high-resolute method for cloning and sequencing genomic full-length HLA-A and -B using 20 Chinese Han individuals was established. We detected 10 HLA-A allele sequences 4.2 kb in length and 6 HLA-B allele sequences 3.7 kb in length, and the sequences included all exons, all introns, 5'promoter, and 3'UTR of the two genes. All sixteen sequences have been submitted to GenBank and IMGT/HLA database. A*1153 is a novel allele, and the introns of B*151101 are firstly reported here. The 5'promoter and 3'UTR sequences of 5 HLA-A alleles and 2 HLA-B alleles are also firstly disclosed, and all other alleles have extended the genomic full length sequences released in IMGT/HLA database. The polymorphic structures of upper 5'promoter and downstream 3'UTR, which were uncovered in IMGT/HLA database, are firstly depicted in Chinese Han individuals. Twenty-six single nucleotide polymorphisms (SNPs) and one 3 bp-insertion/deletion (Indel) were located in the upper 5'promoter and 14 SNPs were located in the 3'UTR of HLA-A. In addition, five SNPs and one 1 bp-indel were located in the upper 5'promoter and 5 SNPs were located in the 3'UTR of HLA-B. Through analyzing the phylogenetic trees of 5'promoter, exons and 3'UTR of the two genes, we found that the evolution history of regulatory regions and exons is different between the two genes. The regulatory regions are tightly linked with exons in most of HLA-A alleles excluding A*24020101. On the contrary, recombinant events may occur frequently between regulatory regions and exons in most HLA-B alleles.

Duration of frequent or severe respiratory tract infection in adults before diagnosis of IgG subclass deficiency.

Many adults with IgG subclass deficiency (IgGSD) experience long intervals of frequent/severe respiratory tract infection before IgGSD diagnosis, but reasons for delays in IgGSD diagnoses are incompletely understood. We performed a retrospective study of 300 white adults (ages ≥18 y) with IgGSD including frequency analyses of age at IgGSD diagnosis, duration of frequent/severe respiratory tract infection before IgGSD diagnosis, and age at onset of frequent/severe infection (calculated). We performed multivariable regressions on age at diagnosis, infection duration, and age at infection onset using these variables, as appropriate: sex; age at diagnosis; diabetes; autoimmune condition(s); atopy; allergy; corticosteroid use; body mass index; serum immunoglobulin isotype levels; blood lymphocyte subsets; three IgGSD-associated human leukocyte antigen-A and -B haplotypes; and referring physician specialties. Mean age at diagnosis was 50 ± 12 (standard deviation) y (median 50 y (range 19-79)). There were 247 women (82.3%). Mean infection duration at IgGSD diagnosis was 12 ± 13 y (median 7 y (range 1-66)). Mean age at infection onset was 38 ± 16 y (median 38 y (range 4, 76)). Age at infection onset was ≥18 y in 95.7% of subjects. Regressions on age at diagnosis and infection duration revealed no significant associations. Regression on age at infection onset revealed one positive association: age at diagnosis (p <0.0001). We conclude that the median duration of frequent/severe respiratory tract infection in adults before IgGSD diagnosis was 7 y. Older adults may be diagnosed to have IgGSD after longer intervals of infection than younger adults. Duration of frequent/severe respiratory tract infection before IgGSD diagnosis was not significantly associated with routine clinical and laboratory variables, including referring physician specialties.

[The analysis of the hepatitis C virus infection course and efficacy of treatment dependence on HLA A antigens in children and youth]. / Analiza zwiazku przebiegu zakazenia wirusem zapalenia watroby typu C oraz skutecznosci leczenia dzieci i mlodziezy z antygenami HLA A.

UNLABELLED: The hepatitis C virus (HCV) infection course and efficacy of treatment may be depended on HLA antigens. The aim of the study is attempt to define dependence between the course of HCV infection and efficacy its treatment and HLA A antigens in children and youth. PATIENTS AND METHODS: To the study included 61 patients (51 after treatment for HCV infection and 10 not treated). The average age was 13.77 years (range 5-18 years). Patients were divided to subgroups in depend on effect of the treatment: virusological and biochemical response. Antigens HLA A were molecularly typed on the low resolution method. To statistical analysis we applied the chi-square test. RESULTS: We demonstrated no statistical significant dependences between HCV infection course and efficacy of its treatment children and youth HLA A antigens. However we observed following tendencies: antigens HLA A *01 and HLA A *02 can be related to unprofitable course of infection and unsuccessful antiviral therapy; HLA A *03 can be favorable prognostic factor for HCV infection course and response to treatment; HLA A *24 can be related to mild course of infection and profitable response to treatment; HLA A *11 can be favorable prognostic factor for course of infection; HLA A *30 can be profitable for efficacy of treatment and HLA A *25 can be disadvantage for it. Probably study performed with larger group of patients could gain dependencies statistical significant. CONCLUSIONS: It is possible that course if HCV infection and efficacy of antiviral treatment are depended on HLA A antigens.

HLA allele and haplotype diversity in the Croatian population: State of the art.

The aim of this report was to compare our data with data presented in the European Federation for Immunogenetics (EFI) catalogue (version 1.0) and to evaluate whether or not current (CUR) HLA alleles found in the Croatian population fall into the same categories of common (COM) or well-documented (WD) HLA alleles as those listed in the EFI catalogue. Among 237 HLA-A, -B, -DRB1 alleles observed in the Croatian population so far, 181 alleles were observed ≥3 times. According to our criteria, 36 alleles at HLA-A locus, 71 alleles at HLA-B locus and 51 alleles at HLA-DRB1 locus were characterised as CUR in Croatia (COM or WD in EFI catalogue), while 23 local HLA alleles are not listed at all among COM or WD alleles in EFI catalogue.

HLA-A*30:01 and HLA-A*33:03 are the protective alleles while HLA-A*01:01 serves as the susceptible gene for cervical cancer patients in Xinjiang, China.

OBJECTIVE: This study aims to investigate the distribution of HLA-A genes and identify alleles related to cervical cancer. MATERIALS AND METHODS: A total of 252 cervical cancer patients (56 Han ethnic and 196 Uyghur ethnic) and 213 controls (103 Han ethnic and 110 Uyghur ethnic) were recruited in this study. HLA-A alleles were examined by polymerase chain reaction with sequence-specific primers. The frequencies of different HLA-A alleles were compared between the two ethnic groups as well as patients and controls. The correlation of HLA-A frequencies with various clinical characteristics and short-term treatment efficacy was analyzed. RESULTS: (1) Significantly higher frequencies of HLA-A*03:01 and HLA-A*03:02 and lower frequencies of HLA-A*11:01, HLA-A*24:02, and HLA-A*30:01 were observed in the Uyghur control groups than in Han control groups (P ≤ 0.05). (2) The frequency of HLA-A*01:01 in patients was significantly higher than controls. In contrast, the frequencies of HLA-A*30:01 and HLA-A*33:03 were lower in patients (P ≤ 0.05). (3) The frequency of HLA-A*30:01 in Han patients was lower than Han control group (P ≤ 0.05). However, there was no statistically significant in the frequency of HLA-A between Uyghur patients and controls (P > 0.05). (4) There was no significant association between HLA-A alleles and HPV16 or squamous cell carcinoma antigen levels (P > 0.05). (5) The frequency of HLA-A*30:01 allele in complete response + partial response group was higher than stable disease + progressive disease group (P ≤ 0.05). CONCLUSIONS: People from two ethnic groups displayed different HLA-A gene distribution. HLA-A*30:01 and HLA-A*33:03 alleles are the protective factors to cervical cancer patients from Xinjiang while HLA-A*01:01 serves as the susceptible gene.

Immunological characterization of respiratory syncytial virus N protein epitopes recognized by human cytotoxic T lymphocytes.

Virus-specific cytotoxic T lymphocytes (CTLs) are crucial for the control of respiratory syncytial virus (RSV) infection. This study has identified CTL epitopes of the RSV N protein in healthy subjects. We screened the primary structure of the N protein for HLA-A 0201-binding amino acid consensus motifs, identifying three peptides designated as N-RSV1, N-RSV2, and N-RSV3. These peptides were used to generate CTL lines by stimulating human HLA-A 02.01 peripheral blood mononuclear cells (PBMCs) in vitro. These CTL lines were then characterized by performing CTL chromium release assays and IFN-gamma secretion detection by intracellular cytokine staining. N-RSV1 and N-RSV3 peptides elicited the strongest cytolytic activity against RSV-infected cells and they could be useful epitopes for the analysis of CTL responses to RSV and for understanding immune-induced disease pathogenesis.

PEPVAC: a web server for multi-epitope vaccine development based on the prediction of supertypic MHC ligands.

Prediction of peptide binding to major histocompatibility complex (MHC) molecules is a basis for anticipating T-cell epitopes, as well as epitope discovery-driven vaccine development. In the human, MHC molecules are known as human leukocyte antigens (HLAs) and are extremely polymorphic. HLA polymorphism is the basis of differential peptide binding, until now limiting the practical use of current epitope-prediction tools for vaccine development. Here, we describe a web server, PEPVAC (Promiscuous EPitope-based VACcine), optimized for the formulation of multi-epitope vaccines with broad population coverage. This optimization is accomplished through the prediction of peptides that bind to several HLA molecules with similar peptide-binding specificity (supertypes). Specifically, we offer the possibility of identifying promiscuous peptide binders to five distinct HLA class I supertypes (A2, A3, B7, A24 and B15). We estimated the phenotypic population frequency of these supertypes to be 95%, regardless of ethnicity. Targeting these supertypes for promiscuous peptide-binding predictions results in a limited number of potential epitopes without compromising the population coverage required for practical vaccine design considerations. PEPVAC can also identify conserved MHC ligands, as well as those with a C-terminus resulting from proteasomal cleavage. The combination of these features with the prediction of promiscuous HLA class I ligands further limits the number of potential epitopes. The PEPVAC server is hosted by the Dana-Farber Cancer Institute at the site http://immunax.dfci.harvard.edu/PEPVAC/.

High-resolution HLA-A, -B and -DRB1 allele and haplotype frequencies in 7823 Han marrow donors of Liaoning province, China.

BACKGROUND: The human leukocyte antigen (HLA) system is the most polymorphic gene cluster in humans. High-resolution donor-recipient matching for HLA genes improves patient survival after unrelated hematopoietic stem cell transplantation. MATERIALS AND METHODS: In this study, we analyzed the high-resolution allele and haplotype frequencies at the HLA-A, -B and -DRB1 loci in the Liaoning Han population and analyzed its relationships with other populations. RESULTS: The 3 most frequent alleles at the HLA-A, -B and -DRB1 loci were A*24:02, A*02:01:01G, A*11:01; B*13:02, B*46:01, B*40:01:01G; DRB1*09:01, DRB1*15:01 and DRB1*07:01, respectively. The most frequent 2-locus haplotypes were A*30:01-B*13:02 and B*13:02-DRB1*07:01. A*30:01-B*13:02-DRB1*07:01 was determined to be the predominant 3-locus haplotype. Hot maps and multiple correspondence analyses based on the frequencies of HLA specificities, which allow statistical visualization of dependent and independent relationships among variables, indicate that the Liaoning Han population is closely related to Northern populations of China and shows relative close relationships with Asian populations. CONCLUSION: These data will provide an outline of the HLA characteristics of healthy individuals in our region and help bone marrow transplantation patients find suitable HLA-matched donors.

HLA class I variation in Iranian Lur and Kurd populations: high haplotype and allotype diversity with an abundance of KIR ligands.

HLA-A, -B and -C alleles of 285 individuals, representing three Iranian Lur populations and one Iranian Kurd population were sequenced completely, yielding human leukocyte antigen (HLA) class I genotypes at high resolution and filling four fields of the official HLA nomenclature. Each population has 87-99 alleles, evenly distributed between the three HLA class I genes, 145 alleles being identified in total. These alleles were already known, named and deposited in the HLA database. The alleles form 316 different HLA A-B-C haplotypes, with each population having between 80 and 112 haplotypes. The four Iranian populations form a related group that is distinguished from other populations, including other Iranians. All four KIR ligands - the A3/11, Bw4, C1 and C2 epitopes - are well represented, particularly Bw4, which is carried by three high-frequency allotypes: HLA-A*24:02, HLA-A*32:01 and HLA-B*51:01. In the Lur and Kurd populations, between 82% and 94% of individuals have the Bw4 epitope, the ligand for KIR3DL1. HLA-B*51:01 is likely of Neandertal origin and associated with Behcet's disease, also known as the Silk Road disease. The Lordegan Lur have the highest frequency of HLA-B*51:01 in the world. This allele is present on 46 Lur and Kurd haplotypes. Present at lower frequency is HLA-B*51:08, which is also associated with Behcet's disease. In the four Iranian populations, 31 haplotypes encode both Bw4(+) HLA-A and Bw4(+) HLA-B, a dual combination of Bw4 epitopes that is relatively rare in other populations, worldwide. This study both demonstrates and emphasizes the value of studying HLA class I polymorphism at highest resolution in anthropologically well-defined populations.

HLA-A, -B, -C, and -DRB1 genotyping of 1000 Northern Irish individuals from Belfast, Northern Ireland in the United Kingdom.

One thousand individuals from Belfast, Northern Ireland were genotyped at the HLA-A, -B, -C and -DRB1 loci using sequence-specific oligonucleotide probe methods. HLA-A locus genotypes display a minor Hardy-Weinberg (HW) deviation (p=0.0375); HLA-B, -C and -DRB1 genotypes are consistent with expected HW proportions. These genotype data are available in the Allele Frequencies Net Database under identifier AFND 1243.

HLA and longevity or aging among Shanghai Chinese.

Twenty-two centenarians and one hundred and seventy-nine nonagenarians (mean age 93 +/- 1.04 years) in the Shanghai Region of China were phenotyped for alleles of A (13 types), B (21 types) and C (6 types) loci of the human leukocyte antigen (HLA). The frequencies of HLA antigens were compared with 211 healthy adults whose ages ranged from 20 to 50 years. It was observed that A9 was highly associated with longevity (frequency in the longevity group is 38%, the control group 24%, P = 0.002). A30 showed marked inverse correlation (frequency in the longevity group is 8%, the control group 17%, P = 0.008). Cw3, Cw6 and Cw7 were also inversely correlated (P = 0.02, 0.04 and 0.02, respectively). Thus, it is likely that A9 may contribute to longevity while A30, Cw3, Cw6 and Cw7 may be associated with aging. The average superoxide dismutase (SOD) contents of erythrocytes in 48 cases with the HLA-A9 (without A30) antigen in the longevity group and in 13 cases with the HLA-A30 (without A9) antigen in the control group were 555 +/- 96 and 593 +/- 58 micrograms/gHb, respectively (t = 1.375, P > 0.05).