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HLA-B*13:01 allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic polymorphisms in dapsone-induced severe cutaneous adverse reactions (SCAR). We investigated the association of HLA alleles and cytochrome P450 (CYP) alleles with dapsone-induced SCAR in Thai non-leprosy patients. A prospective cohort study, 16 Thai patients of dapsone-induced SCARs (5 SJS-TEN and 11 DRESS) and 9 Taiwanese patients of dapsone-induced SCARs (2 SJS-TEN and 7 DRESS), 40 dapsone-tolerant controls, and 470 general Thai population were enrolled. HLA class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). CYP2C9 , CYP2C19 , and CYP3A4 genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with HLA-B*13:01 and HLA-B*13:02 alleles by the molecular docking approach. Among all the HLA alleles, only HLA-B*13:01 allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67-198.21, p = 5.3447 × 10 -7 ), SJS-TEN (OR = 36.00, 95% CI = 3.19-405.89, p = 2.1657 × 10 -3 ), and DRESS (OR = 40.50, 95% CI = 6.38-257.03, p = 1.0784 × 10 -5 ) as compared to dapsone-tolerant controls. Also , HLA-B*13:01 allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67-149.52, p = 2.8068 × 10 -7 ) and Taiwanese (OR = 31.50, 95% CI = 4.80-206.56, p = 2.5519 × 10 -3 ). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the HLA-B*13:01 allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 ( CYP2C9 , CYP2C19 , and CYP3A4 ) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the HLA-B*13:01 allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TB declared a past collaboration with the author W-HC to the handling editor., (Copyright © 2021 Satapornpong, Pratoomwun, Rerknimitr, Klaewsongkram, Nakkam, Rungrotmongkol, Konyoung, Saksit, Mahakkanukrauh, Amornpinyo, Khunarkornsiri, Tempark, Wantavornprasert, Jinda, Koomdee, Jantararoungtong, Rerkpattanapipat, Wang, Naisbitt, Tassaneeyakul, Ariyachaipanich, Roonghiranwat, Pirmohamed, Chung and Sukasem.)

The coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by SARS-CoV-2. Since its first report in December 2019, COVID-19 has evolved into a global pandemic causing massive healthcare and socioeconomic challenges. HLA system is critical in mediating anti-viral immunity and recent studies have suggested preferential involvement of HLA-B in COVID-19 susceptibility. Here, by investigating the HLA-B genotypes in 190 unrelated Chinese patients with confirmed COVID-19, we identified a significant positive association between the B22 serotype and SARS-CoV-2 infection (p = 0.002, Bonferroni-corrected p = 0.032). Notably, the B22 serotype has been consistently linked to susceptibility to other viral infections. These data not only shed new insights into SARS-CoV-2 pathogenesis and vaccine development but also guide better infection prevention/control., (© 2020 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

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., Competing Interests: We have the following interests: Dr. Bertoli is an unpaid consultant for Brookwood Biomedical. There are no patents, products in development, or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., Competing Interests: The authors have declared no conflicting interests., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

A growing body of evidence links the analysis of the KIR genotype and the presence of their HLA-B and -C ligands to a wide repertoire of human diseases. We noticed that, using a panel of 184 Caucasoid donors, a limited number of HLA alleles were incorrectly supratyped by previously described pyrosequence-based assays. Here we describe a simple implementation of the reported methods that corrects all the discrepancies found with HLA-B and -C molecular typing and allows establishing a quick and high-throughput method for the determination of HLA-Bw4 I(80), Bw4T(80), Bw6 and HLA-C1 or -C2 supratype., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

HLA-B*44:203 shows one nucleotide difference to B*44:03:01 at codon 171 (TAC>CAC, Y171>H171)., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Human leukocyte antigen (HLA) class I molecules are critical components of the cell-mediated immune system that bind and present intracellular antigenic peptides to CD8(+) T cell receptors. To understand the interaction mechanism underlying human leukocyte antigen (HLA) class I specificity in detail, we studied the structural interaction characteristics of 16,393 nonameric peptides binding to 58 HLA-A and -B molecules. Our analysis showed for the first time that HLA-peptide intermolecular bonding patterns vary among different alleles and may be grouped in a superfamily dependent manner. Through the use of these HLA class I 'fingerprints', a high resolution HLA class I superfamily classification schema was developed. This classification is capable of separating HLA alleles into well resolved, non-overlapping clusters, which is consistent with known HLA superfamily definitions. Such structural interaction approach serves as an excellent alternative to the traditional methods of HLA superfamily definitions that use peptide binding motifs or receptor information, and will help identify appropriate antigens suitable for broad-based subunit vaccine design.

The new allele HLA-B*35:87 was generated by recombination between HLA-B*35:01 and B*08:01 in intron 2., (© 2011 John Wiley & Sons A/S.)

The novel B*51:63 is identical to B*51:01:01 with an exception of one base substitution at position 76 (A > C) of exon 3 resulting in codon #116 changed from TAC (Tyr) to TCC (Ser)., (© 2011 John Wiley & Sons A/S.)

The sequence of HLA-B*08:01:08 differs from other HLA-B*08:01 alleles by at least two synonymous nucleotide exchanges., (© 2011 John Wiley & Sons A/S.)

Major histocompatibility complex (MHC) class I and class II genes regulate the balance between appropriate aggressive responses and invading pathogens while minimizing the destruction of host tissue. Several studies have shown that in hemorrhagic fever with renal syndrome (HFRS) patients, the disease outcome is determined by a complex interaction between the virus and immunopathologic and human genetic factors. In Slovenia, the severity of the disease caused by Puumala virus (PUUV) is significantly lower than that of HFRS due to Dobrava virus (DOBV). We have determined 23 different HLA-B and 12 different HLA-DRB1 types in Slovenian HFRS patients. Comparison of HLA frequencies between healthy individuals and HFRS patients showed no strong association with the susceptibility for hantaviral infection. Significant associations were recognized when the patient group was separated according to the virus responsible for the infection. DOBV-infected patients have a significantly higher frequency of HLA-B*35 than PUUV-infected patients. For HLA class II genes, the biggest difference between the PUUV- and DOBV-infected groups of patients was in HLA-DRB1*13, where this phenotype was more frequent in PUUV-infected patients, especially in the severe form of the disease. HLA-B*07 could play a protective role in PUUV-caused HFRS in the Slovenian population. Our study shows diverse associations of HLA molecules with DOBV- and PUUV-induced HFRS, and therefore, we presume that different hantaviruses are presented differently through the same HLA molecules and that this might lead to either a more severe or a milder form of the disease. In line with this idea, we have noticed that HLA-B*35 might be a genetic risk factor for DOBV infection in the Slovenian population.

Generation of the HLA-B*15 group of alleles has been analyzed using exon 1, intron 1, exon 2, intron 2, and exon 3 sequences from human and nonhuman primates. Results indicated that the 230 alleles analyzed could be grouped into 5 different lineages of evolution coming from nonhuman primate MHC-B* alleles sharing characteristic nucleotide sequences. The major evolutionary mechanism of evolution in this group of alleles is the gene conversion event with the exchange of genomic sequences present in other HLA-B*alleles. This evolutionary event reflects the importance of the exchanges between different genomic regions of distinct HLA-A*, -B*, or -C* alleles and only 1 group of HLA-B* alleles (B*15 in the present paper). These data also correlated with the geographic distribution of the lineages postulated and with the corresponding serologic specificities (B62, -63, -71, -72, -75, -76, and -77). In conclusion, the high degree of polymorphism of 1 group of alleles has a specific and simple pathway of evolution, which could result in new insight into the study of immune system functionality, disease association studies, and anthropological studies., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

This study was purposed to investigate the nucleotide sequences of a novel HLA-B*15:124 allele and its molecular mechanism. The genomic DNA from whole blood was extracted by using commercial DNA extraction kit. The sequences of exon 2, 3 and 4 of HLA-B locus in the proband were amplified by PCR with group-specific primers, the PCR products were purified by enzymes digestion, then exon 2 to 4 of HLA-B locus for both orientations was sequenced. The results showed that 2 HLA-B alleles of proband were gained after amplification and sequencing of group-specific primers, among them one was a B*40:03, another was a novel allele. After BLAST analysis, the novel allele showed nucleotides different from HLA-B*15:52 in exon 3 at nucleotide position 427 A > T and 440 G > T which resulted in amino acid change from Thr to Ser at codon 143 and Trp to Leu at conon 147. It is concluded that a novel HLA-B allele has two different nucleotides. This HLA-B allele is identified and has been officially named B*15:124 by the WHO Nomenclature Committee.

Background: Previous studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups., Methodology/principal Findings: High-resolution HLA typing for the Uyghur ethnic minority group using polymerase chain reaction-sequence-based-typing method was first reported. HLA-A, -B and -DRB1 allelic distributions were determined in 104 unrelated healthy Uyghur individuals and haplotypic frequencies and linkage disequilibrium parameters for HLA loci were estimated using the maximum-likelihood method. A total of 35 HLA-A, 51 HLA-B and 33 HLA-DRB1 alleles were identified at the four-digit level in the population. High frequency alleles were HLA-A*1101 (13.46%), A*0201 (12.50%), A*0301 (10.10%); HLA-B*5101(8.17%), B*3501(6.73%), B*5001 (6.25%); HLA-DRB1*0701 (16.35%), DRB1*1501 (8.65%) and DRB1*0301 (7.69%). The two-locus haplotypes at the highest frequency were HLA-A*3001-B*1302 (2.88%), A*2402-B*5101 (2.86%); HLA-B*5001-DRB1*0701 (4.14%) and B*0702-DRB1*1501 (3.37%). The three-locus haplotype at the highest frequency was HLA-A*3001-B*1302-DRB1*0701(2.40%). Significantly high linkage disequilibrium was observed in six two-locus haplotypes, with their corresponding relative linkage disequilibrium parameters equal to 1. Neighbor-joining phylogenetic tree between the Uyghur group and other previously reported populations was constructed on the basis of standard genetic distances among the populations calculated using the four-digit sequence-level allelic frequencies at HLA-A, HLA-B and HLA-DRB1 loci. The phylogenetic analyses reveal that the Uyghur group belongs to the northwestern Chinese populations and is most closely related to the Xibe group, and then to Kirgiz, Hui, Mongolian and Northern Han., Conclusions/significance: The present findings could be useful to elucidate the genetic background of the population and to provide valuable data for HLA matching in clinical bone marrow transplantation, HLA-linked disease-association studies, population genetics, human identification and paternity tests in forensic sciences.

Human leukocyte antigen (HLA)-A, -B, and -DRB1 alleles were typed in 46,915 healthy Taiwanese volunteers recruited for Tzu Chi Taiwan Marrow Donor Registry (TCTMDR). The volunteers were separated into Taiwanese and Taiwanese aborigines. In this study, a total of 51 A, 121 B, and 53 DRB1 alleles were found in the Taiwanese group, and 17 A, 32 B, and 23 DRB1 alleles were identified in the Taiwanese aborigines. Some commonly shared alleles appeared more frequently in one group than in the other. The two haplotypes, among the 20 most frequently observed haplotypes in each group, shared in common by both groups were A*3303-B*5801-DRB1*0301 and A*0207-B*4601-DRB1* 0901. However, both haplotype frequencies in each group were extremely different, indicating the existence of genetic diversity between the two groups. In addition, principal component analysis and clustering results based on high-resolution HLA-A, -B, and -DRB1 alleles indicated that the Taiwanese group was closest to Southern Chinese and reiterated HLA diversity between the Taiwanese and the Taiwanese aborigines. We believe that our findings in this study may provide useful information in search for HLA-matched donors for patients., (Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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.

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.

Human leukocyte antigen (HLA)-B*15 encompasses an increasing number of subtypes of more than 150. Frequency studies and a strong genetic association between HLA subtypes and susceptibility to drug hypersensitivity have been reported in different ethnic populations. To identify HLA-B*15 subtypes in Burmese using sequence-based typing (SBT) method, we selected 65 HLA-B*15-positive samples from 170 unrelated healthy Burmese who were genotyped HLA-B* by polymerase chain reaction with the sequence-specific primer method. The frequency of HLA-B*15 in Burmese was found to be 38.2%. By the SBT method, results showed 10 alleles of HLA-B*15 subtypes. Four common alleles, B*1502 (45.2%), B*1532 (16.4%), B*1525 (12.3%), and B*1501 (8.2%), were found in 82.1% of HLA-B*15-positive Burmese. Whereas the B*1501 was the highest in the Caucasians, Koreans, and Japanese, the highest frequency of HLA-B*15 alleles in Burmese was B*1502 (45.2%) that is similar to the frequency found in northeastern Thais and Vietnamese. This study is the first report of HLA-B*15 subtypes in Burmese. These results will provide the basic data in the further study in transplantations, genetic association with diseases, and drug hypersensitivity.

Background: The HLA system is known to be the most polymorphic genetic system in human, and HLA allele and haplotype distribution varies widely among different ethnic groups. This study was performed to examine the frequencies of HLA alleles and haplotypes in Koreans., Methods: We examined HLA-A, -B, and -DR alleles at the serologic level in 1,500 cord blood units obtained from Koreans using the PCR-sequence specific oligonucleotide (SSO) method. Allele and haplotype frequencies were estimated by the maximum likelihood method using the computer program developed for the 11th International Histocompatibility Workshop., Results: HLA alleles found in Koreans were 12 in A, 31 in B, and 13 in DR loci. Most frequent alleles with frequencies > or =10% in each locus in decreasing order of frequency were: A2, A24, A33, A11; B62; DR4, DR15, DR9, and DR13. Two-locus haplotypes with frequencies > or =0.1% were 104 A-B and 115 B-DR haplotypes, among which those with frequencies > or =1.0% showing significant positive linkage disequilibrium (P< or =0.001) were 21 A-B and 20 B-DR haplotypes. A total of 169 A-B-DR haplotypes with frequencies > or =0.1% were identified. The results were similar to those of a previous study in 1,600 Koreans, although some differences were noted in the distribution of some less frequent alleles or haplotypes with frequencies < or =0.5%., Conclusions: We provided the allele and haplotype frequencies of HLA-A, -B, and -DR in cord blood units of Korean ethnicity defined by a DNA typing method, which can be used as basic data on Koreans for organ transplantation and disease association studies.

An unknown HLA-B allele which was similar to HLA-B*270401 was detected by FLOW-SSOPCR-SSP and heterozygous sequence-based typing (SBT) in Chinese Han individual. Its anomalous patterns suggested the possible presence of new allele. Amplifying exon 2-5(include intron 2-4) of the HLA-B*27 allele separately by using allele-specific primers and sequencing in both directions. Identifying the difference between the novel B*27 allele and B*270401. The sequence of novel B*27 from exon 2 to partial exon 5 is 1 815 bp. There are 10 nt changes from B*270401 in exon 3-4, at nt634where A-->C(codon130 AGC-->CGC, 130 S-->R); nt670 where A-->T (codon142 ACC-->TCC, 142 T-->S); nt683 where G-->T (codon146 TGG-->TTG, 146 W-->L); nt698 where A-->T (codon151 GAG-->GTG, 151 E-->V); nt774 where G-->C (codon176 GAG-->GAC, 176 E-->D); nt776 where C-->A (codon177 ACG-->AAG, 177 T-->K); nt781 where C-->G (codon179 CAG-->GAG, 179Q-->E); nt789 where G-->T (codon181 GCG-->GCT) resulting no coding change; nt1438 where C-->T (codon206 GGC-->GGT) resulting no coding change; nt1449 where G-->C (codon210 GGG-->GCG, 210G-->A). In IMGT/HLA database, only three alleles (B*270502/2706/2732) have sequences of introns. The same sequence in intron 2 showed homology between the novel HLA-B*27 allele and B*2706, but their homology could not be supported in intron 3-4. Comparing the sequence of the novel B*27 allele in intron 3 and 4 with B*27 group, it showed there are three mutations at nt106 C-->G, nt179 G-->A, nt536 G-->A and one deletion at nt168 in intron 3 and one mutations at nt82 T-->C in intron 4, but the sequence of the novel B*27 allele in intron 3 and 4 was all the same to B*070201. The sequence was submitted to Gen-Bank and the accession number was DQ915176. The allele has been confirmed as an extension of B*2736 by the WHO Nomenclature committee in November 2006.

Objective: To identify a novel HLA allele in Chinese population., Methods: A new HLA-B allele was initially detected by an usual PCR-SSP and PCR-SSOP in routine typing HLA allele. Sequence-based typing (SBT) was used to identify and analysis the difference between the new allele and HLA-B 4409 allele., Results: The HLA-B exon 3 nucleotide sequence of the novel allele was different from all other known alleles. The allele had 3 nucleotides replaced of the closest matching B 4409 allele at nt538(G>C), nt539(A>T) and nt540 (C>G) in exon 3, resulting in an amino acid change from D(GAC) to L(CTG) at codon 180., Conclusion: A novel HLA allele was confirmed by the SBT and it was officially designated as HLA-B 4446 by WHO Nomenclature Committee for Factors of the HLA System in September,2005.

HLA-A and HLA-B genes were typed by DNA sequencing in a mestizo population from Guadalajara, Jalisco, Mexico. Thirty-seven HLA-A and 51 HLA-B alleles were observed in 103 samples. The common typical Amerindian alleles (>5%) and haplotypes (>or=2.0%) found were A*02010101, *24020101, *310102, B*350101, and *4002, and A*310102-B*4002, A*240201-B*350101, and the typical European alleles were A*010101, *29010101, B*1402, B*180101, and A*020101-B*1402, A*020101-B*510101, and A*3002-B*180101. This reflects the blending of the two main parental populations of mestizos: Amerindian and Iberian. Mexicans were found to be relatively closer to the Portuguese than to Spaniards. This proximity may indicate a larger Portuguese influence in Mexicans than previously considered. Present data contribute to the understanding of the genetic structure in Mexico.

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/.

A novel HLA-B allele, B*3549, was identified in a bone marrow transplantation candidate. B*3549 differs from B*3525 by two nucleotides at exon 2, position 142 (T to G) and 165 (G to C). The difference at position 142 resulted in an amino acid difference (serine to alanine). However, the difference at position 165 did not cause any amino acid change. This novel allele was found on a haplotype with A*3101, B*3549, Cw*0401, DRB1*0407, and DQB1*0302.

We report here four novel HLA-B alleles, B*1590, B*1591, B*2726, and B*4705, identified from an East African population during sequence-based HLA-B typing. The novel alleles were confirmed by sequencing two separate polymerase chain reaction products, and by molecular cloning and sequencing multiple clones. B*1590 is identical to B*1510 at exon 2 and exon 3, except for a difference (GCCGTC) at codon 158. Sequence differences at codon 152 (GAGGTG) and codon 167 (TGGTCG) differentiate B*1591 from B*1503 at exon 3. B*2726 is identical to B*2708 at exon 2 and exon 3, except for a difference (AAGCAG) at codon 70. B*4705 was identified in three Kenyan women. The allele is identical to B*47010101/02 at exon 2 and exon 3, except for differences at codon 97 (AGGAAT) and codon 99 (TTTTAT). These new alleles have been named by the WHO Nomenclature Committee. Identification of these novel HLA-B alleles reflects the genetic diversity of this East African population.

Objective: To evaluate the accuracy of PCR with sequence-specific primers (PCR-SSP) for HLA-I genotyping and analyze the causes of the errors occurring in the genotyping., Methods: DNA samples and were obtained from 34 clinical patients, and serological typing with monoclonal antibody (mAb) and HLA-A and, B antigen genotyping with PCR-SSP were performed., Results: HLA-A and, B alleles were successfully typed in 34 clinical samples by mAb and PCR-SSP. No false positive or false negative results were found, and the erroneous and missed diagnosis rates were obviously higher in serological detection, being 23.5% for HLA-A and 26.5% for HLA-B. Error or confusion was more likely to occur in the antigens of A2 and A68, A32 and A33, B5, B60 and B61., Conclusions: DNA typing for HLA-I class (A, B antigens) by PCR-SSP has high resolution, high specificity, and good reproducibility, which is more suitable for clinical application than serological typing. PCR-SSP may accurately detect the alleles that are easily missed or mistaken in serological typing.

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.

Two theories about MHC allele generation have been put forward: (1) point mutation diversification and/or (2) gene conversion events. A model supporting the existence of both of these mechanisms is shown in this paper; the possible evolution of the HLA-B*570101 and HLA-B*5801 alleles (which belong to the HLA-B17 serology group) is studied. The hypothesis favoured is that gene conversion events have originated these alleles, because intron sequences are also analysed. Evolution by point mutation should only be accepted if flanking introns have also been sequenced.

In this brief communication we report the characterization of two new HLA-B variants officially named HLA-B*0817 and HLA-B*1311. The HLA-B*0817 allele was identified in a Caucasoid male candidate for renal transplantation in the North Italy Transplant program. The nucleotidic sequence of exons 2, 3 and 4 of this novel allele is identical to that of HLA-B*0804 except for three point mutations in exon 2: from A to G at position 259, from C to G at position 261 and from G to A at position 302. These mutations are responsible for two aminoacidic substitutions [Asn (r) Glu, codon 63, and Ser (r) Asn, codon 77]. HLA-B*1311 was found in a volunteer donor belonging to National Marrow Donor Program(R). This new variant is identical to that of HLA-B*1301 except for three nucleotide substitutions at positions 353, 355 and 369 leading to two aminoacidic variations from Ile to Thr at codon 94 and from Ile to Leu at codon 95 and a silent mutation at codon 99.

HLA genes constitute a highly polymorphic multigene system. In the present study, HLA-B oligonucleotide chips were manufactured by using a set of sequence-specific oligonucleotide probes derived from polymorphic regions in exon 2 and exon 3 of HLA-B gene spotted by microarrayer onto the aldehyde modified glass slides. In addition, the sequenced HLA-B gene clones used as standard samples were amplified from exon 2 and exon 3 by PCR. Together with the correct hybridization and wash conditions, the PCR products were bound with the array probes on the chip, and the hybridization patterns were transformed to HLA-B genotypes. The results showed that the genotypes of standard samples by the HLA-B oligonucleotide chips were completely identical with the sequenced clones. In conclusion, the oligonucleotide chip method presented here for HLA-B genotyping is a rapid, accurate, sensitive and attractive high throughput biochemical way.

We report herein the identification of a new HLA-B*51 allele in a Spanish Caucasoid organ donor. The novel allele, designated B*5130, differs from B*51011 by one nucleotide change at position 787 (A to G) in exon 4, leading to an amino acid change from Arg (AGA) to Gly (GGA) at codon 239 in the alpha3 domain. This substitution is present in most classical and nonclassical HLA class I loci (A, C, E, and G) but not in any of the HLA-B alleles reported so far, except for B*7301. Although the frequency of the new variant seems to be low, its existence makes mandatory the analysis of exon 4 before assigning a B*5101 type.

No convincing association exists between HLA type and breast cancer development but certain HLA types have been suggested to be associated with poor risk disease. Here, the HLA type (class I and II) for 141 breast cancer patients was compared to a control population of 100 individuals and to the prognostic indicators for the patients. No association was found between HLA type and breast cancer development. Consideration of individual HLA/prognostic factor relationships previously reported confirmed that HLA-B7 was over-represented in premenopausal oestrogen-receptor (ER)-positive, grade 3 tumours (p = 0.04) and that HLA-A1 correlated positively with Nottingham Prognostic Index (p < 0.05) and with ER-negative disease (p < 0.05). These findings suggest that some previously identified associations between HLA type I and particular prognostic factors may be real, if weak but appear to conflict with the only other sizeable study investigating HLA type II in breast cancer (which negatively correlated HLA-DR 11 with early onset disease).

Little is known of the role of classical HLA-A and -B class I alleles in determining resistance, susceptibility, or the severity of acute viral infections. Appropriate paradigms for immunogenetic studies of acute viral infections are dengue fever (DF) and dengue hemorrhagic fever (DHF). Both primary and secondary infections with dengue virus (DEN) serotypes 1, 2, 3 or 4, can result in either clinically less severe DF or the more severe DHF. In secondary exposures, a memory response is induced in immunologically primed individuals, which can both clear the infecting dengue virus and contribute to its pathology. In a case-control study of 263 ethnic Thai patients infected with either DEN-1, -2, -3 or -4, we detected HLA class I associations with secondary infections, but not in immunologically naive patients with primary infections. HLA-A*0203 was associated with the less severe DF, regardless of the secondary infecting virus serotype. By contrast, HLA-A*0207 was associated with susceptibility to the more severe DHF in patients with secondary DEN-1 and DEN-2 infections only. Conversely, HLA-B*51 was associated with the development of DHF in patients with secondary infections, and HLA-B*52 was associated with DF in patients with secondary DEN-1 and DEN-2 infections. Moreover, HLA-B44, B62, B76 and B77 also appeared to be protective against developing clinical disease after secondary dengue virus infection. These results confirm that classical HLA class I alleles are associated with the clinical outcome of exposure to dengue virus, in previously exposed and immunologically primed individuals.

Serological mistypings of HLA-A and HLA-B in 27 cases were analyzed. The results showed that for HLA-A and HLA-B typing, the rates of incorrect antigen assignments were significantly higher than rates of antigen misses (P < 0.05), but there was no significant difference between HLA-A and HLA-B typings. The frequencies of miss-assigned HLA-A and HLA-B specificities were A1 (66.7%), A3 (50.0%), A11 (13.5%), A9 (11.8%), A19 (7.1%), and B16 (50.0%), B48 (43.9%), B15 (16.7%), B40 (11.1%), B13 (10.0%) and B17 (9.1%). In conclusion, the serologic and DNA-based typing techniques should be reciprocally complementary in HLA-A and HLA-B typing.

Nucleic acid-based methods for allele identification have revealed more than 470 polymorphic variants at the HLA-B locus. Screening of potential bone marrow donors with sequence specific primer polymerase chain reactions and sequence specific oligonucleotide probe hybridization assays revealed apparent variants within the B*58, *44, *15, and *48 allele groups. DNA sequencing of cloned DNA identified the new alleles B*5804, B*4418, and B*1558 within these groups and observed new sequence information for the previously reported allele B*4805. These findings further extend our knowledge of the substantial genetic variation present at the HLA-B locus within human populations.

As part of the American Society for Histocompatibility and Immunogenetics coordinated studies among minority populations, human leukocyte antigen (HLA) alleles were defined for 460 volunteer Yup'ik Eskimos from the Yukon Kuskokwim delta region of southwestern Alaska. The study group included 252 adults with no other first-degree relatives and 48 informative nuclear families. Full Yupik ancestry through both maternal and paternal grandparents was claimed by 81.1% of participants. HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles were determined by SBT, SSOP, reverse SSOP, and/or RSCA according to the protocols of five participating laboratories. Polymorphism was limited with 3-6 alleles comprising > 80% of the alleles observed at each locus. Homozygosity was high, particularly at the HLA-A and -DQB1 loci, with 36.6% and 44% of individuals having a single allele defined at these respective loci. HLA-A, -B, and -DRB1 alleles were in Hardy-Weinberg equilibrium, whereas HLA-Cw and -DQB1 alleles gave significant deviation (p = 0.002; 0.005). Significant linkage disequilibrium (p < or = 0.00001) was observed in all pairwise evaluations. A new Cw*0806 allele was observed in high linkage disequilibrium with B*4801(Delta = 0.099; Delta(rel) = 1.0). Three extended haplotypes were found to have frequencies > 5%, the most prevalent being A*2402; B*4801; DRB1*0401; DQB1*0301 (0.0933). Comparison of available class I data indicate that the Yup'ik share several common alleles with other Native American populations, including: A*2402, *0206, *6801; B*1501, *2705, *3501, *4002, *4801, *5101; and Cw*0202, *0304, *0401. Comparisons of class II data also confirm a close relationship of the Yup'ik to two other Eskimo populations, Siberian and East Greenland Eskimos. DRB1*0401 and *1101, which occur in high frequency among these Eskimo populations, but not in other Native Americans, were also prevalent among the Yup'ik, with respective frequencies of 0.232 and 0.107.

Objective: To study the relationship between the susceptibility to two subtypes of Guillain-Barre syndrome(GBS) AIDP and AMAN and the frequency of HLA-class I and II alleles as well as to approach the characteristics of AIDP and AMAN patients in immune genetics., Methods: A case control research was done on 31 AIDP and 33 AMAN and 132 health individuals. DNA was extracted from peripheral blood leucocytes by improved fast salting out. HLA genes were typed with DNA-based technology and PCR-sequence specific primers (PCR-SSP) method., Results: HLA-A33 frequency of HLA-class I, and DR16 and DQ5 frequencies of HLA-class II showed a significant increase in AIDP group as compared with the control. Relative risk (RR) was 6.13, 8.28 and 3.47 respectively. Corrected probability (Pc) was 0.011, 0.014 and 0.025(P < 0.05). HLA-B15,B35 frequency of HLA-class I showed a significant increase in patients with AMAN as compared with the controls,RR was 4.09 and 7.08 respectively, Pc was 0.015 and 0.000 8 respectively., Conclusions: HLA-A33, DR15 and DQ5 may have association with susceptibility to AIDP; HLA-B15, B35 may have association with susceptibility to AMAN. HLA-class II genes were not found to have any association with AMAN.

HLAMatchmaker is a computer algorithm that assesses human leukocyte antigen (HLA) compatibility at the structural level by intralocus and interlocus comparisons of polymorphic amino acid triplets in antibody-accessible sequences of HLA class I molecules. This program permits the identification of mismatched HLA antigens that share all of their polymorphic triplets with the patient's HLA antigens and, therefore, could be considered fully compatible. The validity of this algorithm has been verified by analyzing the antibody specificity patterns of 127 well-characterized sera (panel reactive antibody [PRA] > 80%) that had been screened by direct complement-dependent and/or anti-human globulin augmented lymphocytotoxicity testing with large HLA-typed cell panels. A 2 x 2 table-based Chi-square analysis program was applied to determine positive and negative correlations between serum reactivity and the presence HLA triplets assigned from the HLA types in the cell panel. The results indicate that high PRA patients do not produce antibodies to shared triplets on mismatched HLA antigens. Moreover, this serum analysis has permitted the identification of triplets with different degrees of immunogenicity as indicated by the frequencies of positive and negative correlations of serum reactivity with the HLA-typed cell panel. Mismatching for triplets with low immunogenicity provides further opportunities for identifying donors with acceptable HLA mismatches for highly sensitized patients.

This report presents the serological equivalents of 123 HLA-A, 272 HLA-B and 155 HLA-DRB1 alleles. The equivalents cover over 64% of the presently identified HLA-A, -B and -DRB1 alleles. The dictionary is an update of the one published in 1999 (<1>Schreuder et al., 1999, Tissue Antigens, 54, 409) and also includes equivalents for HLA-C, DRB3, DRB4, DRB5 and DQB1 alleles. The data summarize information obtained by the WHO Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP) and individual laboratories. In addition, a listing is provided of alleles that are expressed as antigens with serological reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programmes where HLA typings from donors and from recipients on waiting lists represent mixtures of serological and molecular typings. The tables with HLA equivalents and a questionnaire for submission of serological reaction patterns for poorly identified allelic products will also be available on the WMDA web page: www.worldmarrow.org

In comparison to South America, native North Americans tend to be less diverse in their repertoire of HLA class I alleles. Based upon this observation, we hypothesized that the Yupik Eskimo would exhibit a limited number of previously identified class I HLA alleles. To test this hypothesis, sequence-based typing was performed at the HLA-A, -B and -C loci for 99 Central Yupik individuals from southwestern Alaska. Two new class I alleles, A*2423 and Cw*0806, were identified. While A*2423 was observed in only one sample, Cw*0806 was present in 26 of the 99 individuals and all of the Cw*0806 samples contained B*4801. Allele Cw*0806 differs from Cw*0803 by a single nucleotide substitution such that Cw*0803 may be the progenitor of Cw*0806. Allele Cw*0803 was originally characterized as unique to South America, but detection of Cw*0803 in the Yupik indicates that Cw*0803 was a founding allele of the Americas. The presence of new alleles and previously unrecognized founding alleles in the Yupik population show that natives of North America are more diverse than previously envisioned.

Major histocompatibility complex class I chain-related gene (MICA) is a recently discovered polymorphic gene in the HLA region expressed mainly by certain epithelial cells, keratinocytes, endothelial cells, fibroblasts, and monocytes. MICA is structurally quite different from the HLA class I genes and is potentially associated with some diseases and with immune response to transplants. Some DNA-based typing techniques have previously been described for MICA including sequence-based typing (SBT) and analysis of single strand conformational polymorphisms (SSCP). In the present experiments we have developed a strategy that allows identification of all 54 MICA alleles described so far, using group-specific polymerase chain reactions (PCR) and sequence-specific oligonucleotide probes (SSOP). To analyze for the polymorphisms in exons 2, 3, and 4 an initial screening with group-specific primers, based on polymorphism at position 69 of exon 2, and at position 615-616 of exon 4, was used to determine four major groups of alleles. Then group-specific PCR amplifications were performed and the amplified DNA was hybridized with the corresponding panels of SSOP. An additional amplification was performed with locus-specific primers and hybridized with a set of SSOP to identify and/or confirm the presence of some of the alleles. Unequivocal MICA typing was achieved for 97 of 103 individuals. Of 54 previously described alleles, only 14 were observed in this population. One unexpected hybridization pattern was observed, and molecular cloning and sequencing confirmed it to be a novel sequence, which was given the local designation MICA-055D. The gene frequencies among 103 unrelated North American Caucasian donors were determined and the linkage disequilibrium between MICA and HLA-B was analyzed.

The application of reference strand conformation analysis (RSCA) to HLA-A typing using the ABI PRISM 310 capillary based genetic analyzer has recently been described. This study outlines the development and validation of capillary RSCA for HLA-B typing. Mobility values for 93 HLA-B alleles were defined following electrophoresis of known controls through the system. Three fluorescently labelled references, labelled with three different dyes can be electrophoresed simultaneously. The technique was validated by comparing results from 296 cord blood donors with those obtained using reverse SSO. Following capillary RSCA 14.5% of samples required confirmatory typing, compared with a repeat rate of 5.1% following reverse SSO. In samples where no other typing was necessary there was 100% correlation between the two methods. Capillary RSCA for HLA-B typing is quick, easy to implement, and with the introduction of new FLRs and gel matrices has the potential to evolve into a high resolution typing method.