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PubMed2002

Description of six new HLA-B alleles in the 5C CREG including a B*58 intron two sequence.

Five of the six novel HLA-B alleles described in this report contain polymorphic motifs previously reported in HLA-B alleles, suggesting an origin resultant from a gene conversion mechanism. The sixth allele, B*35012, contains a polymorphism previously unreported in HLA-B molecules. In addition to previously reported polymorphisms, B*5806 carries a previously unreported intronic substitution in a sequencing primer annealing site.

Alleles↗
PubMed2001

Human leukocyte antigen class II allele frequencies and haplotype association in Iranian normal population.

The polymorphism of the HLA class II genes DRB1, DQA1, and DQB1 was investigated in 100 unrelated Iranian individuals from Fars province in Southern Iran, using the restriction fragment length polymorphism (RFLP) method. Subtyping of DRB1*04, *15, and *16 alleles was performed using PCR amplification with sequence specific primes (PCR-SSP). The allele and the haplotype frequencies were calculated. The most common DRB1 alleles were DRB1*11, DRB1*15, and DRB1*04 with a frequency of 25.0%, 14.5%, and 10.5%, respectively. In contrast, the allelic frequency of DRB1*12 and DRB1*08 was very low (1.5% for each). In the DR15 group DRB1*1501 was the most prevalent variant (6.0%). Concerning DR4, the most common alleles were DRB1*0405 and DRB1*0402 (3.5% for each). Interestingly, DRB1*0402 was associated with DQB1*0302 and DRB1*0405 was associated with DQB1*0302 and DQB1*02, the latter being a rare DRB1/DQB1 haplotype in Caucasian individuals. The most frequent DQB1 alleles were DQB1*0301 (31.0%), and DQB1*05 (22.0%). The most frequent DQA1 variants were DQA1*0501 (39.0%) and DQA1*0102 (14.5%). The most common haplotype was DRB1*11-DQB1*0301-DQA1*0501 (25.0%) followed by DRB1*0301-DQB1*02-DQA1*0501 (10%) and DRB1*0701- DQB1*02-DQA1*0201 (6.5%). Data presented in this study suggest that the Iranian population shares some HLA components with populations resident in eastern and southern European countries.

Alleles↗
PubMed2004

Variation of HLA class II genes in the Nganasan and Ket, two aboriginal Siberian populations.

Allelic frequencies at the three most polymorphic loci of the HLA class II region (DRB1, DQA1 and DQB1) were determined in the Nganasan and Ket, the remnants of the two most ancient groups in the Lower Yenisey River/Taimyr Peninsula region in northern Siberia. By single-stranded conformational polymorphism typing, verified by sequencing, 19 HLA-DRB1-DQA1-DQB1 haplotypes and 15 HLA-DRB1, seven DQA1 and 11 DQB1 alleles were found. The most frequent alleles were DRB1*1301 (23.5%), DQA1*0103 (29.4%), *0501/03/05 (29.4%), and DQB1*0301/09 (32.4%) in the Ket, and DRB1*0901 (25%), DQA1*0301 (39.6%), and DQB1*0301/09 (37.5%) in the Nganasan. The distribution patterns and comprehensive phylogenic analysis based on the haplotype frequencies of 17 Siberian populations suggest that the founders of both the Ket and the Nganasan came from Palaeolithic populations in the Altai-Sayan Upland.

Alleles↗
PubMed1985

Further antigenic determinants on HLA-A molecules.

Monoclonal antibodies detect a new polymorphic antigenic determinant shared by HLA-A2, 3, 28, 29, 30, 31 and w33. This was demonstrated by population and family studies, including an HLA-A,B recombinant family, and by lysostrip experiments. Competition experiments, measuring the binding of 125I labelled MoAbs to B lymphoblastoid cell lines coated with anti-HLA conventional alloantisera and MoAbs showed that this new epitope is spatially distant from other known epitopes of A3 molecules and from monomorphic and polymorphic determinants of A2 molecules detected by monoclonal antibodies. On the other hand, anti-HLA-A2 polyclonal alloantisera are able to inhibit binding.

Antibodies, Monoclonal↗
PubMed1995

Importance of HLA-DRB1 and DQA1 genes and of the amino acid polymorphisms in the functional domain of DR beta 1 chain in multiple sclerosis.

The association of some HLA class II alleles with multiple sclerosis (MS) has been amply documented. In the present study the role of HLA class II haplotypes and genotypes and of polymorphic amino acids at the DR beta 1 locus, located in the antigen binding groove and the CD4 binding domain of the DR beta 1 chain, were studied in 78 unrelated Caucasian chronic progressive MS (CP MS) patients and 204 controls. The results confirmed the positive association of the DRB1*1501 allele and through linkage also of the DRB1*1501-DQA1*0102 haplotype with MS. In addition, the results showed that the DRB1*1501/DRB1*0400 or DR beta 1Ala71+ His13+ genotype conferred the highest relative risk for MS (RR = 9.14). Alleles encoding for DR beta 1Phe47+, DR beta 1Asp70+ and DR beta 1Thr140+, DQ alpha 1Phe25+, DQ alpha 1Leu69+ residues were protective and the highest protection (RR = 0.24) was provided by the DR beta 1(Phe47+)-DQ alpha 1Phe25+ and DR beta 1(Ser13+)-DQ alpha 1Phe25+ haplotypes. Our results suggest that both DQ and DR alpha beta heterodimers might contribute to the increased or decreased risk to develop MS by the shape of their antigen-binding groove.

Adult↗
PubMed1988

HLA-DR typing using restriction fragment length polymorphism (RFLP) with one enzyme and two probes.

A panel of 43 homozygous and 36 heterozygous highly selected cells, representing the most common DR-specificities, were investigated with the DNA hybridization technique. By using a single restriction enzyme, TaqI, and two probes, DR beta and DQ alpha, it was possible to construct assignment criteria giving a reasonable definition of DR1, 3, 4, 5, 7 + w9, w8, w10 and w11. The criteria sometimes require that certain bands must not be present. Therefore, in certain genotypic combinations, the presence or absence of the particular specificity on one haplotype cannot be decided. This is a problem only for DR2 and DRw6, which for this reason cannot be assigned in about 1/3 to 1/4 of the cases. The association between RFLP assignment and serological assignment is not absolute, the correlation coefficients ranking from 0.62 to 1.0. In the case of false negative RFLP assignment, this may be due to genetic heterogeneity, as in the case of a DR2 individual who proved to be Dw12 and not Dw2 associated. It is often stated that interpretation of the RFLP pattern is particularly difficult in random or heterozygous individuals compared to proven homozygotes. This is not the case in the present study, where in fact correlation coefficients between RFLP and serologically determined DR specificities were higher in the heterozygotes (range 0.79-1.00).

DNA↗
PubMed1999

HLA and schizophrenia: refutation of reported associations with A9 (A23/A24), DR4, and DQbeta1*0602.

The aim of this study was to test previous hypotheses of association between schizophrenia and human leukocyte antigen (HLA) specificities A9 (A23/24), DR4, and allele DQbeta1*0602. Using sequence-specific oligonucleotide probes, 256 familial schizophrenic patients and 261 unrelated controls were genotyped at polymorphisms for HLA-A, DRbeta1, and DQbeta1 loci. No significant (p < 0.05) differences in the allele frequencies between schizophrenics and controls were found, either when examining the sample as a whole or when subdivided by clinical subtype or gender. The present data do not support association between these HLA specificities and schizophrenia, and our review of previous studies suggests that reported associations may well be false positive results.

Case-Control Studies↗
PubMed1988

CD3 pathway of T-cell activation. II. Role of HLA-class I molecules in early events.

The role of distinct regions of HLA class I molecules in regulating T-cell activation via the CD3-antigen receptor complex was investigated. Monoclonal antibodies (MoAbs) which recognize monomorphic and polymorphic epitopes on HLA Class I molecules were shown to inhibit T-cell proliferation to OKT3. These MoAbs have differential effects on the synthesis of interleukin-2 (IL-2) and IL-2 receptor expression. Cell cycle analysis demonstrated that these MoAbs function both in inhibiting cell cycle entry (G0-G1 shift) and in blocking cell cycle progression (G1-S shift) of activated T cells. Furthermore, these MoAbs have regulatory effects on the alternate pathway of T-cell activation via the CD2 molecule, T-cell activation induced by PHA, and activation induced by the phorbol ester PMA in conjunction with the calcium ionophore Ionomycin. Thus these MoAbs have different effects depending upon the pathway of T-cell activation. The results indicate that HLA class I molecules are selectively involved in the sequence of intracellular events leading to T-cell activation and proliferation.

Antibodies, Monoclonal↗
PubMed2005

Pathogen-driven selection and worldwide HLA class I diversity.

The human leukocyte antigen (HLA; known as MHC in other vertebrates) plays a central role in the recognition and presentation of antigens to the immune system and represents the most polymorphic gene cluster in the human genome [1]. Pathogen-driven balancing selection (PDBS) has been previously hypothesized to explain the remarkable polymorphism in the HLA complex, but there is, as yet, no direct support for this hypothesis [2 and 3]. A straightforward prediction coming out of the PDBS hypothesis is that populations from areas with high pathogen diversity should have increased HLA diversity in relation to their average genomic diversity. We tested this prediction by using HLA class I genetic diversity from 61 human populations. Our results show that human colonization history explains a substantial proportion of HLA genetic diversity worldwide. However, between-population variation at the HLA class I genes is also positively correlated with local pathogen richness (notably for the HLA B gene), thus providing support for the PDBS hypothesis. The proportion of variations explained by pathogen richness is higher for the HLA B gene than for the HLA A and HLA C genes. This is in good agreement with both previous immunological and genetic data suggesting that HLA B could be under a higher selective pressure from pathogens.

Communicable Diseases↗
PubMed1980

[Frequency and gametic association of HLA antigens in a population living in Parma (author's transl)].

The HLA antigens are currently investigated in many diseases and are very useful in medico-legal tests for exclusion of paternity. However, because of the high polymorphism of the HLA system, for a correct interpretation of the results, it is essential to know the HLA antigens distribution in normal populations used as control. Up to now there are few studies about the HLA system in different regions of Italy and for this reason the Authors have studied the phenotypic, genic frequency and the gametic association of HLA A and B antigens in a population living in the province of Parma. The results confirm an HLA homogeneity of populations living it the western territories of the Emilia Region.

Genetics, Population↗
PubMed1989

Diversity and diversification of HLA-A,B,C alleles.

The nucleotide sequences encoding 14 HLA-A,B,C and 5 ChLA-A,B,C molecules have been determined. Combining these sequences with published data has enabled the polymorphism in 40 HLA-A,B,C and 9 ChLA-A,B,C alleles to be analyzed. Diversity is generated through assortment of point mutations by recombinational mechanisms including gene and allelic conversions. The distribution and frequency of silent and replacement substitutions indicate that there has been positive selection for allelic diversity in the 5' part of the gene (exons 1 to 3) and for allelic homogenization and locus specificity in the 3' part of the gene (exons 4 to 8). These differences may correlate with the lengths of converted sequences in the two parts of the gene and frequency of the CpG dinucleotide. Locus-specific divergence of HLA-A,B, and C demonstrates that recombinational events involving alleles of a locus have been more important than conversion between loci. This contrasts with the predominance of gene conversion events in the evolution of mutants of the H-2Kb gene. However, a striking example of gene conversion involving HLA-B and C alleles of an oriental haplotype has been found. Comparison of human and chimpanzee alleles reveals extensive sharing of polymorphisms, confirming that diversification is a slow process, and that much of contemporary polymorphism originated in ancestral primate species before the emergence of Homo sapiens. There is less polymorphism at the HLA-A locus compared to HLA-B, with greater similarity also being seen between HLA-A and ChLA-A alleles than between HLA-B and ChLA-B alleles. Although greater diversity is seen in the 5' "variable" exons of HLA-B compared to HLA-A, there is increased heterogeneity in the 3' "conserved" exons of HLA-A compared to HLA-B.

Alleles↗
PubMed1993

High-resolution HLA-DPB typing based upon computerized analysis of data obtained by fluorescent sequencing of the amplified polymorphic exon 2.

To differentiate 32 HLA-DPB alleles, conventional techniques such as serology and cellular typing are inadequate for high-resolution DPB typing. The most refined DNA typing until now is SSO typing and new selected oligonucleotides can be added to this system to distinguish new allele sequences. DNA sequencing, however, reveals directly the sequence information of all polymorphic HVRs and has the advantage of being independent from exon polymorphisms. We have developed a new DNA-based typing approach that is rapid, fully automated, and therefore suitable for routine typing. The system is based upon direct sequencing of amplified DNA with fluorescent-labeled primers. The designation of alleles is obtained by a comparison of all polymorphic positions in the determined sequence with all known allele sequences retained in a database along with their heterozygous combinations. Sequence data at both constant and polymorphic positions are used for quality control. In this study, the typing results of a panel of 91 previous SSO-typed DNA samples are described. After comparison with the SSO-typing results, we conclude that with this SBT system allele assignment is reliable. The method is easy to perform since both sequencing and assignment are automated. Furthermore, the system is easily applicable to other gene systems.

Base Sequence↗
PubMed2000

[Study on human leucocyte antigen-DQ region gene polymorphism in cases of habitual abortion with anticardiolipin antibody].

OBJECTIVE: To investigate the relationship between human leucocyte antigen(HLA)-DQ region gene polymorphism and habitual abortion with anticardiolipin antibody(ACL). METHODS: Polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) was used to type HLA-DQA1 and HLA-DQB1 alleles in 30 cases of habitual abortion with anticardiolipin antibody and 90 women with normal pregnancy history. RESULTS: The frequency of DQB1 * 0303 was found to be significantly higher in ACL(+) habitual abortion group (33.3%) than those in normal control group (P < 0.05). Whereas, there was no significant difference found not only in frequency of other DQB1 alleles, but also in frequency of DQA1 alleles and DQA1-DQB1 haplotypes between two groups. CONCLUSION: The results show an association between ACL(+) habitual abortion and HLA-DQB1 * 0303, which suggest DQB1 * 0303 may be susceptible gene to ACL(+) habitual abortion.

Abortion, Habitual↗
PubMed1980

Molecular characterization of HLA-A, B homologues in owl monkeys and other nonhuman primates.

Mouse anti-HLA-A, B monoclonal antibodies have been used to study the homologues of HLA-A, B antigens in other primate species. Immunoprecipitates of primate histocompatibility antigens from extracts of radioactively labeled lymphocytes were analyzed by SDS-polyacrylamide electrophoresis. Primate histocompatibility antigens appear to have similar molecular structure to human HLA antigens. Owl monkeys, which react polymorphically with some monomorphic anti-HLA antibodies, showed biochemical differences which correlated with the serological polymorphism. An antibody (W6/32) which only reacts with the HLA/beta 2-microglobulin complex in humans and not with the free HLA heavy chain has the reverse specificity in some owl monkeys.

Animals↗
PubMed1987

Detection of disease-specific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region.

Pemphigus vulgaris in Israeli Ashkenazi and non-Ashkenazi Jews and in Austrian non-Jewish patients is strongly associated with the DR4 and DRw6 alleles of the HLA-D region class II genes. Restriction fragment length polymorphism analysis was undertaken with DQ beta, DQ alpha, and DR beta cDNA probes. Hybridization with the DQ beta probe identifies Pvu II, BamHI, and EcoRV fragments that absolutely discriminate pemphigus vulgaris patients from healthy DR-, DQ-, and ethnic-matched controls. In contrast the DQ alpha and DR beta probes failed to identify disease-specific restriction fragment length polymorphism fragments. These studies indicate that DQw1 and DQw3 polymorphisms carried by pemphigus vulgaris patients may be directly involved in predisposition to the disease or may be tightly linked to the susceptibility gene itself. To our knowledge, this is the first example of an HLA restriction fragment length polymorphism that is highly associated with susceptibility to autoimmune disease.

Alleles↗
PubMed1998

Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program.

BACKGROUND: The requirements with respect to HLA compatibility and the relative importance of matching for individual class I and class II HLA alleles in the transplantation of hematopoietic stem cells from unrelated donors have not yet been established. METHODS: We performed retrospective DNA typing of alleles at 11 polymorphic loci of HLA genes in 440 recipients of hematopoietic stem cells from unrelated donors who were serologically identical with their respective recipients for HLA-A, B, and DR antigens. Of these recipients, 80 percent had leukemia; the rest had lymphoma, marrow failure, or a congenital disorder. RESULTS: Multivariate analysis showed that incompatibility for HLA-A alleles and incompatibility for HLA-C alleles were independent risk factors for severe acute graft-versus-host disease (GVHD) (HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, but not of HLA-C, alleles was an independent risk factor for death (P<0.001). Matching [corrected] of HLA-C alleles was a significant risk factor for relapse of leukemia (P=0.035). HLA-B disparity was a significant risk factor for both GVHD and death in the univariate analysis, but not in multivariate analysis. Disparities in class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1 loci were not identified as significant risk factors for acute GVHD or death in the multivariate analysis. CONCLUSIONS: Genomic typing of class I HLA alleles adds substantially to the success of transplantation of hematopoietic stem cells from unrelated donors, even if the donors are serologically identical to their recipients with respect to HLA-A, B, and DR antigens.

Adolescent↗
PubMed1989

Exclusion of paternity by DNA analysis in addition to blood group testing in a family case.

Three men, all related to the mother were involved in a paternity case. Only one of them, an uncle of the mother, could be excluded by conventional blood testing of 22 polymorphic systems including HLA and Gm. Because it was not possible to exclude the other men (the brother and the father of the mother) by these systems restriction fragment length polymorphisms as detected by the probes YNH24 and hMF1 were analyzed. The results with probe hMF1 did not reveal additional information. Both Taq I and Pst I digests, probed with YNH24 excluded the father of the mother from paternity of the child under investigation.

Blood Group Antigens↗