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PubMed1987

Polymorphisms within the HLA-DRw6 haplotype. III. DQ alpha and DQ beta polymorphism associated with HLA-D.

We have studied HLA-DQ encoded antigens from HLA-DRw6 homozygous cells and analyzed the DQ region at the DNA level. HLA-DQ molecules were isolated from EBV transformed B-cell lines and analyzed for DQ alpha and DQ beta polymorphism. From the same set of cells, DNA was isolated and analyzed for RFLP. Polymorphism could be detected by both techniques, i.e., on the protein level and on the DNA. The variation in pI of the DQ alpha and beta chains correlated with the polymorphism as detected by HTC typing, as did the variation in molecular weight of the bands hybridizing to DQ specific cDNA probes; identical patterns were detected for cells of one HLA-D specificity and different patterns for different HLA-D types. Additionally, DQ reactive PLT reagents were raised against DRw6 positive cells. Panel studies revealed that these DQ reactive proliferative T cells can discriminate between the polymorphic DQ antigens on cells with different HLA-D specificities.

Antibodies, Monoclonal↗

PubMed1996

The influence of the HLA-DRB1*13 allele on measles vaccine response.

BACKGROUND: Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. METHODS: We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. RESULTS: The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different (p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%;p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). CONCLUSIONS: The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.

Alleles↗

PubMed1991

Transfected trophoblast-derived human cells can express a single HLA class I allelic product.

The human trophoblast-derived JAR cell line, that does not express polymorphic HLA class I antigens even after IFN induction, can be stably transfected by genomic clones encoding the entire HLA-A2, -A3 and -B7 alpha-chain genes. The transfected genes were expressed at the cell surface in association with endogenous beta 2-microglobulin (shown by FCM analysis) as a single allelic product without reexpression of any endogenous class I gene (shown by 1D.IEF analysis). Furthermore, TNF-alpha and IFN-gamma, alone and synergistically, increase cell surface expression of transfected MHC class I/endogenous beta 2m heterodimers without induction of endogenous class I alpha-chain genes. These data show that the MHC class I-negative JAR human cell line might be used for transfections with the aim of establishing human cells expressing just one defined MHC class I allele for functional and regulatory studies. These findings are discussed in relation to the methylated status solely of endogenous class I alpha-chain genes in JAR cells and suggest that transfected class I genes are not regulated in the same fashion and, in particular, that constitutive and TNF/IFN inducible trans-acting regulatory factors able to bind to cis-promoter/enhancer sequences of class I DNA are likely to be present.

Alleles↗

PubMed1991

[Serologic polymorphism of the HLA Class 2 antigens in the Russian population].

Two hundred and thirty Russian Moscovities (108 healthy individuals and 122 cadaver kidney donors) were typed for antigens HLA-DR1-DRw10, HLA-DRw52-DRw53, and HLA-DQw1 and DQw3. HLA-DR1, 2, 3, 4, 5 and 7 were investigated in all individuals, the other having been only studied in portions of the material. The HLA class 2 antigens' polymorphism in Russian population has been shown to have features common to all Caucasians. Most widely distributed antigen is DR2 (phenotype frequency is 36%). Antigens DRw8, DR9 and DRw10 are rare. DR allele distribution demonstrated perfect fits to Hardy--Weinberg expectations. Antigens DR5 and DR4 are considered most difficult to define at early stage of the study.

Alleles↗

PubMed2001

HLA-DR and -DQ polymorphism in Cameroon.

HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) and/or DNA sequencing in 126 healthy individuals in Cameroon. Eighteen DRB1, 11 DQA1, and 18 DQB1 alleles were observed. The most common alleles at each locus were DRB1*1503 (29%), DRB1*1301 (13%); DQA1*0102 (38%), DQA1*0302 (11%), DQA1*0401 (11%); and DQB1*0602 (31%), DQB1*0301 (13%), DQB1*0501 (12%). Forty-four different haplotypes were identified including 12 novel haplotypes demonstrating the HLA class II diversity resulting from allele combinations in this population. A single predominant DRB1*1503-DQA1*0102-DQB1*0602 haplotype was observed with a frequency of 27%. In summary, this study of HLA class II polymorphism in Cameroon demonstrates the extent of diversity in this population.

Adult↗

PubMed2002

Human lymphocyte antigen molecular typing: how to identify the 1250+ alleles out there.

The human lymphocyte antigen (HLA) typing community was one of the early groups to adopt molecular testing. This action was borne out of the need to identify the many alleles of the highly polymorphic HLA system. Early paradigms used restriction fragment length polymorphism regimes, but the polymerase chain reaction method of amplification quickly replaced that less-than-discriminating choice. Methods currently in use for HLA typing, with commercial kits available, are sequence-specific oligonucleotide probe (both dot blot and the reverse blot dot), sequence-specific primer amplification, restriction fragment length polymorphism of amplified products, double-stranded sequence conformation polymorphism (with and without reference strand), sequence-based typing, and microarray technologies. More than 1250 alleles are recognized by the World Health Organization and meet their criteria for assignment. These alleles can be identified by molecular methods and represent alleles present at class I and class II loci of the HLA complex. On occasion, ambiguous results still persist, even with the best molecular typing methods. Therefore, it is clear to the HLA typing community that a combination of the above methods may be needed to allow true discrimination of the possible alleles an individual carries in their genetic makeup. It is also clear that a typing laboratory may need to resort to nonmolecular serology to understand the significance and impact of the type generated by the HLA molecular typing laboratory.

Alleles↗

PubMed1987

Structural analysis of an HLA-B27 population variant, B27f. Multiple patterns of amino acid changes within a single polypeptide segment generate polymorphism in HLA-B27.

The structure of a new HLA-B27 variant, B27f, distinguishable from other HLA-B27 subtypes by isoelectric focusing and serologic criteria, has been established by comparative peptide mapping and radiochemical sequence analysis. HLA-B27f differs from the major B27.1 subtype in three clustered amino acid replacements: Asp74, Asp77, and Leu81 in B27.1 are changed to Tyr74, Asn77, and Ala81, respectively in B27f. This pattern of differences is analogous to that of HLA-B27.2 in that this subtype also differs from B27.1 in multiple clustered substitutions within the same segment. Thus, polymorphism within the HLA-B27 system is being achieved by introducing different sets of amino acid changes within a particular short segment of the alpha 1 domain. The most likely mechanism for the introduction of multiple changes within this segment is a nonreciprocal recombination event, such as gene conversion. The structural analogies and ethnic distribution of B27f and B27.2 as compared with those of B27.3, and B27.4 support a dynamic model of HLA-B27 evolution in which polymorphism has been created after the separation of the major ethnic groups. In this model, a Caucasian branch would be characterized by subtypes differing from B27.1 in a few changes within the alpha 1 domain, which were probably generated by single genetic steps. An Oriental branch would include those subtypes which differ from B27.1 by changes in both alpha 1 and alpha 2, involving multiple genetic steps for their generation.

Amino Acid Sequence↗

PubMed2002

Origin and affinities of indigenous Siberian populations as revealed by HLA class II gene frequencies.

Gene frequencies of eight Siberian populations (Mansi, Tuva, Todja, Tofalar, Buryat, Okhotsk Evenki, Ulchi, and Negidal) were determined for the three most polymorphic HLA class II loci ( DRB1, DQA1, and DQB1) by a combination of single-stranded conformational polymorphism typing and DNA sequencing. The number of alleles per population ranged from 16 to 25, from seven to eight, and from nine to 14 for the DRB1, DQA1, and DQB1 loci, respectively. The alleles at the three loci occurred in 66 different combinations (haplotypes), most of which appeared to be of ancient origin, but some may have arisen within the Siberian populations. Phylogenetic analysis of the frequency data suggests that the HLA genes of Asian and indigenous American populations stem from a single pool distinct from the gene pools of European and African populations. The Asian populations separate into two clusters, one of which encompasses nearly all the Siberian populations and all the indigenous American populations tested, while the other consists of Central, Eastern, and Southeastern Asian populations. The position of the Tuva people appears to be near the node from which the two clusters diverge. The divergence time of the two clusters is estimated to be 21,000-24,000 years BP. Three different branches of the native Siberian peoples seem to have contributed founders for the indigenous American ethnic groups.

Alleles↗

PubMed1983

A critical analysis of paternity determination using HLA and five erythrocyte antigen systems.

Five hundred and thirty-seven cases of disputed paternity in North Carolina were tested for five erythrocyte polymorphisms, HLA antigens, or both. The data were analyzed to evaluate the ability of the tests to exclude the alleged father or to include the alleged father as the biological father. Incompatibility between the phenotypes of the alleged father, and those of the mother and child, were found in 40.6% of black males and 30.3% of white males (P less than 0.005). The rates of exclusion appeared to vary between countries in which the cases originated, although the significance of the differences could not be determined because of the small sample size. Using a Bayesian approach and 0.5 as the prior probability of paternity, we calculated the posterior probability of paternity for HLA and five erythrocyte systems combined as well as for HLA and erythrocyte systems separately. The probability of paternity values based on the combined HLA and RBC tests exceeded 95% in 299 of the 345 nonexcluded cases as compared to only 218 cases based on HLA tests alone and 36 cases based on erythrocyte tests alone. We conclude that in approximately 10% of paternity cases in the population served by this laboratory, the information obtained is inconclusive. To resolve these cases, additional polymorphisms and/or a panel of genetic tests systems which can provide greater than 95% probability of exclusion is required.

Bayes Theorem↗

PubMed2001

[Histocompatibility HLA system of man. Considerations in the light of current concepts. VI. HLA-G antigen polymorphism].

The results of hitherto researches over gene products of HLA-G locus, i.e. membrane bound forms (M*HLA-G) and soluble forms (S*HLA-G) were verified. Current opinions connected with synthesis and molecular organisation of five HLA-G isoformic molecules (HLA-G1, -G2, -G3, -G4, -G5) were presented. The polymorphism of HLA-G gene and its expression were qualified. Special attention has been turned on presumably significant function of HLA-G in maintenance of maternal-placenta immunological tolerance, binding of monomeric peptides, and antigens presentation, taking into consideration cytomegaloviruses (CMV). In spite of significant progress in the understanding of mutual relationship between mother and placenta many phenomena with participation of HLA-G gene products, especially in pathological conditions, are still unknown.

Female↗

PubMed1993

Restrictions in the repertoire of allospecific T cells. Contribution of the alpha-helical sequence polymorphism of HLA-DR molecules.

We have studied the molecular diversity of the allogeneic TCR repertoire specific for the HLA-DR4 variant, DRB1*0404, by analyzing the V beta gene segment usage of CD4+ T cell clones from nine different donors and comparing the V beta repertoire in allospecific and unselected T cell populations. To investigate the forces shaping the repertoire of the alloreactive T cell response we compared the diversity of TCR specificities utilized in very similar and in disparate responder/stimulator combinations. Six of the responders shared the HLA-DRB1*0401 allele, which differs from the HLA-DRB1*0404 allele by only two amino acid substitutions at positions 71 and 86 of the HLA-DR beta 1 chain; three responders expressed HLA-DRB1 alleles with extensive polymorphisms compared with the stimulator HLA-DRB1 allele. In all nine responders, TCR specificities recruited to recognize HLA-DRB1*0404 were strongly biased toward the dominant usage of one to three V beta elements. Despite some degree of heterogeneity between different responders, the overall pattern was very similar with a hierarchy of TCR V beta elements expressed by HLA-DRB1*0404 specific T cells. A core group of V beta elements (V beta 6, 5, 2, 13.2, 18, and 7) was preferentially used, whereas other V beta elements including V beta 3, 4, and 8 were infrequently used or not used at all. Sequencing of the VDJ beta region from selected T cell clones showed no junctional bias associated with the preferential V beta gene segment usage. Surprisingly, the T cell diversity in focused and in complex alloreactive responses were equally biased. The finding that HLA-DR4+ and DR4- donors exhibited a similar bias supports the interpretation that the alpha-helical HLA-DR structure of the stimulator cell has a dominant contribution in shaping the alloreactive repertoire.

Amino Acid Sequence↗

PubMed1998

HLA-B27 and the seronegative spondyloarthropathies.

In the 25 years since the initial reports of the association of HLA-B27 with ankylosing spondylitis (AS) and subsequently with Reiter's syndrome, psoriatic spondylitis, and the spondylitis of inflammatory bowel disease, the association of HLA-B27 with the seronegative spondyloarthropathies has remained one of the best examples of a disease association with a hereditary marker. HLA-B27 has been recognized as representative of a spectrum of diseases, ranging from the majority of HLA-B27-positive individuals who have no disease at all, through those with isolated eye or skin involvement, to those with critical eye, heart, and peripheral joint compromise of full-blown AS. Yet HLA polymorphism has evolved in response to environmental stresses, and even the presence of HLA-B27 itself appears to confer advantages in certain infectious diseases, such as acquired immune deficiency syndrome (AIDS). This article will review what is currently known about HLA-B27 and disease, especially in the seronegative spondyloarthropathies. The structure-function relationship of HLA-B27 will be presented, including differences between the B27 subtypes both in their ethnic variation and possible disease implications. The disease spectrum conferred by the presence of HLA-B27 will also be discussed, and the theories of how HLA-B27 contributes to the pathogenesis of the spondyloarthropathies will be considered.

Amino Acid Sequence↗

PubMed2004

The acceptable mismatch program as a fast tool for highly sensitized patients awaiting a cadaveric kidney transplantation: short waiting time and excellent graft outcome.

There are many highly sensitized patients on the kidney waiting lists of organ exchange organizations because it is difficult to find a crossmatch negative cadaver kidney for these patients. Recently, several protocols have been developed to remove the donor-specific human leukocyte antigen (HLA) antibodies from the serum of these patients before transplantation. These approaches, including the use of intravenous immunoglobulins, plasmapheresis and immunoglobulins (plasmapheresis-cytomegalovirus-immunoglobulin), and immunoabsorption, seem to lead to a certain success rate, although the additional immunosuppression necessary to remove and control the production of donor-specific alloantibodies may have its impact on the short-term (infections) and long-term (incidence of cancer) immune surveillance. Furthermore, some of these therapies represent a considerable financial burden for patients and society. In the present report, we advocate selection of crossmatch negative donors on the basis of the Acceptable Mismatch Program, as the first and best option for highly sensitized patients to undergo transplantations. No additional immunosuppression is necessary, and graft survival in this group of "difficult" patients is identical to that of nonsensitized recipients. Because the nature of the HLA polymorphism does not allow all patients to profit from this approach, removal of circulating HLA antibodies can be considered as a rescue therapy for those patients for whom the Acceptable Mismatch Program does not give a solution.

Cadaver↗

PubMed2003

Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection.

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was associated with viral clearance. The class II allele DRB1*1302 was also associated with clearance (OR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03), but its significance decreased in a multivariate model that included other alleles associated with disease outcome as covariates. B*08 was associated with viral persistence both independently (OR, 1.59; 95% CI, 1.04 to 2.43; P = 0.03) and as part of the conserved Caucasian haplotype A*01-B*08-DRB1*03. The B*44-Cw*1601 (OR, 2.23; 95% CI, 1.13 to 4.42; P = 0.02) and B*44-Cw*0501 (OR, 1.99; 95% CI, 1.22 to 3.24; P = 0.006) haplotypes were also associated with viral persistence. Interestingly, both the B*08 haplotype and DR7, which forms a haplotype with B*44-Cw*1601, have been associated with nonresponse to the HBV vaccine. The associations with class I alleles are consistent with a previously implicated role for CD8-mediated cytolytic-T-cell response in determining the outcome of an acute HBV infection.

Adult↗

PubMed2004

Lung function changes in workers exposed to cobalt compounds: a 13-year follow-up.

The objective of the study was to examine the influence of cobalt exposure on lung function changes in workers from a cobalt-producing plant in a health monitoring program implemented between 1988 and 2001. A total of 122 male workers with at least 4 (median = 6) lung function tests (FEV(1) and FVC) during the follow-up period were assessed longitudinally. Cobalt exposure significantly decreased over the follow-up period, as reflected by the measurements in air and urine. The possible association of spirometric changes with cobalt exposure was examined by a random coefficients model, taking into account other potential influential variables, such as smoking, age, previous respiratory illness, exposure to other lung toxicants, or the presence of glutamate in position 69 in the HLA-DP beta-chain, an HLA polymorphism possibly associated with hard-metal-induced lung diseases. The main finding of the follow-up study was that cobalt exposure contributed to a decline in FEV(1) over time, and only in association with smoking. No influence of glutamate in position 69 in the HLA-DP beta-chain polymorphism was detected. Although the amplitude of the additional FEV(1) decrement associated with smoking exposure was relatively small (< 20%) compared with the expected decline in a non-cobalt-exposed smoker, the results indicate that further efforts to reduce cobalt exposure and to encourage workers to quit smoking are still warranted.

Belgium↗

PubMed1979

HLA histocompatibility antigens in a Polynesian population -- Cook islanders of Mauke.

Polynesians living on the island of Mauke in the Cook Island group were typed for HLA-A and -B locus antigens. The Mauke population has restricted HLA polymorphism, with five A-locus antigens and four B-locus antigens accounting for a majority of the HLA phenotypes. Although some differences in antigen frequency were found when Mauke Islanders were compared with Polynesians from Easter Island and Samoa, the Mauke Islanders were closer in their HLA antigenic profile to polynesians than to Melanesians.

Epitopes↗

PubMed1989

HLA-B27 and HLA-A2 subtypes: structure, evolution and function.

Beyond the resolution of tissue typing serology, HLA class I antigens display a certain level of structural microheterogeneity, that allows their subdivision into subtypes. The structure of these subtypes shows that multiple mechanisms operate in the generation of HLA polymorphism and suggests possible evolutionary pathways for subtype diversification. In addition, subtype polymorphism critically affects cellular allorecognition and antigen presentation to self-restricted T cells. These properties are used to define the structure and diversity of T-cell epitopes. In this review, José López de Castro discusses the nature and evolution of this polymorphism and its modulation of antigen recognition by cytolytic T lymphocytes.

HLA-A2 Antigen↗

PubMed2002

The number of amino acid residues mismatches correlates with flow cytometry crossmatching results in high PRA renal patients.

Highly sensitized renal transplant candidates present a group at high risk for acute and chronic rejection. The probability of finding compatible donors for these recipients is significantly lower in comparison to those who have low PRA values. As a consequence, these patients spend longer time on the waiting list and become tethered to dialysis. The results of final cross match (XM) are critical for making a decision about whether such a candidate receives an organ or not. The degree of donor and recipient HLA compatibility predicts the results of XM. The goal of this study was to expand a variety of acceptable HLA-AB mismatches (MM) for high PRA kidney recipients using the HLAMATCHMAKER algorithm. This strategy focuses on the fine structural features of HLA polymorphism comprising amino acid residues or triplets (AAT), which are located in alpha-helical coils of HLA molecules and are available to antibodies. We analyzed serum samples from thirty-nine highly alloimmunized recipients (PRA > or = 85%). The level of sensitization was detected using FlowPRA Class I Screening Test. This group of transplant candidates included thirteen recipients who demonstrated negative results of final T/B FCXM and twenty-six, who were FCXM positive. The application of the HLAMATCHMAKER algorithm based on the HLA class I donor and recipient typing allowed us to detect the total number of AATMM as well as the number of immunogenic AAT in both FCXM negative and FCXM positive groups of recipients. Significantly greater numbers of both total and highly immunogenic AATMM have been emerged in the group of FCXM positive patients. Furthermore, the results of this analysis have shown a high degree of probability of positive FCXM if the number of highly immunogenic AATMM was > or = 1 (chi(2) = 22.9 Yate's correction; p = 0.000001). We did not observe overlapping between antibody specificity and permissible HLA-AB MM detected using the HLAMATCHMAKER strategy. Thus, the number of highly immunogenic AATMM can serve as a reliable predictive value for final FCXM results in highly sensitized renal transplant candidates. The HLAMATCHMAKER algorithm appears to be the proper strategy to find donors for high PRA recipients.

Adolescent↗