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Results for “HLA polymorphism”

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PubMed2006

[With genechip technique to investigate HLA-DQB1 gene polymorphisms in south and north regions of China].

OBJECTIVE: To research and compare HLA-DQB1 gene frequency(GF) and polymorphism distribution between south and north population of Chinese in China. METHODS: Combining PCR-sequence specific primers(SSP) and sequence specific oligonucleotide probe(SSOP) techniques and DNA Microarray Kit for HLA-DQB1 Low Res Genotyping from Shenzhen Yi-Shengtang Biological LTD. Co. was used to type HLA-DQB1 gene polymorphisms of 700 individuals living in south China and 320 individuals in north China. RESULTS: We inspected 10 alleles of HLA-DQB1 and got a series of comprehensive and accurate statistic data. CONCLUSION: It is tested that HLA-DQB1*02, 05, 0601, 0602, 0603 gene frequencies are different obviously(P<0.05) between south and north Chinese. And those data will be useful to kinds of research associated with disease relevant and anthropology research.

Alleles↗

PubMed2002

Role of HLA antigens in Rh (D) alloimmunized pregnant women from Mumbai, Maharashtra, India.

Immunogenetic studies in various diseases provide potential genetic markers. We have studied the incidence of HLA A, B, C, DR and DQ loci antigen in Rh (D) antigen isoimmunized mothers compared to those nonimmunized isoimmunized Rh negative mothers. Seventy six mothers who were immunized to Rh (D) antigen due to pregnancy (responders) and fifty four mothers who did not develop Rh (D) isoimmunization despite positive pregnancies (nonresponders) were selected for the study. Standard methods of serological HLA typing, ABO and Rh (D) groups, and screening for Rh D antibodies were used. 392 unrelated individuals from the population were compared as controls. In addition 45 unrelated individuals from the same population were typed for HLA DRB and DQB gene using PCR-SSP kits. The genotype frequencies of HLA A2, A3, A28, B13, B17, B35, B52, B60, Cw2, Cw6, DR4, and DQ3 were significantly increased, while the frequencies of the HLA A11, A29, A31, B7, B37, B51, Cw1 and DR9 were decreased in the responder women when compared to the non-responder women. HLA A30 (19) split antigen was not identified in immunized women while HLA A23 (9) split antigen was not identified in non immunized women. HLA A3, B17, Cw2 and DR4 showed a significant relative risk among the immunized responder women. When compared with Rh immunized women (responders) reported from USA, England and Hungary the phenotype frequencies of HLA A11, A24, A28, B5, B17, B40, DR2 and DR5 were increased while HLA A23, B8, B18, and DR6 were decreased in the Indian Rh immunized women. Two locus haplotype frequency analysis observed among the responders women revealed that among the significant haplotypes expressed A2-B5, B7-Cw1, DR2-DQ1 were highly significant haplotypes in positive linkage, while A1-B5, and A1-B7 were in significant negative linkage disequilibrium. The haplotype frequencies were <or= one when these common hapoltypes were compared with control population. Thus in the present study it is evident that the inheritance of HLA A3, B17, Cw2 and DR4 increases the relative risk factor by 2.6 times among Indian Rh isoimmunized women. Further, it is evident that there are significant differences in the observed HLA antigen frequencies and two locus haplotypes in Rh isoimmunized women when compared to women from USA, UK and Hungary due to extreme HLA polymorphism in different populations of the world.

Female↗

PubMed2002

[Determination of HLA-DRB1 gene polymorphism by PCR-SBT in Lahu ethnic group of Yunnan, China].

The HLA-DRB1 gene polymorphism in Lahu ethnic of Yunnan, China was the first time investigated using high resolution PCR-SBT method, which is based on sequences of HLA-DRB1 Intron 1 and Intron 2 and with our improvement. From 55 individuals of Lahu ethnic 16 DRB1 alleles were detected. The three most common alleles were HLA-DRB1 * 12021(30.909%), 09012(15.455%), 15011(13.636%), and they covered 60% of the total alleles detected from Lahu ethnic.HLA-DRB1 * 1413, * 11081, * 1312, * 1418, * 1504 were the first time detected in the Chinese, and were very rare in worldwide ethnic groups. With comparison of HLA-DRB1 gene frequencies between various ethnic groups we analyzed the characteristics of HLA-DRB1 gene distribution in worldwide populations,and constructed the phylogenetic tree by Neighbor-joining method and Nei measure of genetic distance. The result showed Lahu ethnic obviously belong to the Chinese South ethnic groups and can't trace its origin from northern groups with the HLA-DRB1 genetic data. The preliminary explanations about the contradiction were given in this paper.

English Abstract↗

PubMed1991

Prenatal diagnosis of 21-hydroxylase deficiency by RFLP analysis of the 21-hydroxylase, complement C4, and HLA class II genes.

In 19 pregnancies at risk for 21-hydroxylase deficiency (21OHD) in 18 families with at least one affected child, prenatal diagnosis was performed by RFLP analysis using the enzymes Taq I and EcoRI and the DNA probes specific for the 21OH genes, the closely linked complement C4 genes and the highly polymorphic HLA class II genes DRB, DQB, and DPB. For fetal DNA analysis either chorionic villi or cultivated amniotic cells were used. In all 19 cases, a clear prenatal diagnosis was possible either with the 21OH probe alone or in most cases, by combining the results of the different closely linked loci.

Adrenal Hyperplasia, Congenital↗

PubMed2006

Permanent, lowered HLA class I expression using lentivirus vectors with shRNA constructs: Averting cytotoxicity by alloreactive T lymphocytes.

Transplantation of many tissues requires histocompatibility matching of human leukocyte antigens (HLA) to prevent graft rejection, to reduce the level of immunosuppression needed to maintain graft survival, and to minimize the risk of graft-versus-host disease, particularly in the case of bone marrow transplantation. However, recent advances in fields of gene delivery and genetic regulation technologies have opened the possibility of engineering grafts that display reduced levels of HLA expression. Suppression of HLA expression could help to overcome the limitations imposed by extensive HLA polymorphisms that restrict the availability of suitable donors, necessitate the maintenance of large donor registries, and complicate the logistics of procuring and delivering matched tissues and organs to the recipient. Accordingly, we investigated whether knockdown of HLA by RNA interference (RNAi), a ubiquitous regulatory system that can efficiently and selectively inhibit the expression of specific gene products, would enable allogeneic cells to evade immune recognition. For efficient and stable delivery of short hairpin-type RNAi constructs (shRNA), we employed lentivirus-based gene transfer vectors, which provide a delivery system that can achieve integration into genomic DNA, thereby permanently modifying transduced graft cells. Our results show that lentivirus-mediated delivery of shRNA targeting pan-Class I and allele-specific HLA can achieve efficient and dose-dependent reduction in surface expression of HLA in human cells, associated with enhanced resistance to alloreactive T lymphocyte-mediated cytotoxicity, while avoiding MHC-non-restricted killing. We hypothesize that RNAi-induced silencing of HLA expression has the potential to create histocompatibility-enhanced, and, eventually, perhaps "universally" compatible cellular grafts.

Base Sequence↗

PubMed2000

Limiting dilution analysis of human IL-2 producing T-cell precursors. Determination of hierarchical alloantigenic potential of human leukocyte antigens and evaluation of alloimune responses to single HLA-DP molecules.

Twenty nine healthy unrelated individuals were carefully selected and divided into three groups according to their HLA (Human Leukocyte Antigens) phenotypes. A sensitive and reproducible limiting dilution analysis (LDA) based bioassay using CTLL-20 cells for detection of human IL-2 was set up and used to assess the hierarchical impact of highly polymorphic HLA molecules on individual's alloreactivity. Our main interest was to evaluate the role of HLA-DP molecules in this process. By calculating frequencies of IL-2 producing helper T cell precursors (HTLp) and amounts of IL-2 produced in each experiment, we were able to confirm that HLA-DR molecules are the most potent alloantigens. In 29 different combinations where a single HLA-DP mismatch between stimulating and responding cells was evaluated, some were reasonably tolerant, while the other ones evoked moderate to relatively strong alloimmune responses. Finally, two groups with statistically significant difference in alloimmune responses to stimulating HLA-DP molecules carrying D,E,A,V or G,G,P,M amino acid sequences at positions 84,85,86 and 87 in the sixth variable region F of the molecule could be formed, according to HTLp frequencies and amounts of IL-2 detected. Data presented are of great importance for the selection of unrelated as well as related bone marrow donors for haematological patients.

Cell Line↗

PubMed1985

HLA-B locus polymorphism: studies with a specific hybridization probe.

The large number of class I histocompatibility genes (HLA) and their extensive homology has made it difficult to assign bands on genomic Southern blots to known genes. Therefore, we have tried to obtain nucleic acid probes for class I genes that are locus specific or have restricted locus specificity. Computer sequence-homology analysis was used to compare the nucleic acid sequences of two genomic clones, one coding for the HLA-B7 antigen (JY150) and one containing a class I pseudogene (pHLA12.4). A sequence in the 3' untranslated region with very low homology was identified. This sequence from the HLA-B7 gene was subcloned into M13 phage. This fragment, JY150/C5, hybridized with two genomic bands in DNA from human HLA homozygotes--presumably the HLA-B locus gene and a closely related gene. The probe was used to assess restriction fragment polymorphism at the HLA-B locus in homozygous consanguineous cell lines. This analysis permitted the association of certain polymorphic restriction enzyme fragments with some alleles of this locus. However, many HLA-B alleles have identical restriction fragments produced by a number of restriction endonucleases.

Alleles↗

PubMed2001

[HLA-DRB1 gene polymorphism of Naxi ethnic group of Yunnan Province, China and its ethnological evolution analysis].

The HLA-DRB1 gene polymorphism of Naxi ethnic group of Yunnan Province, China was investigated for the first time using high resolution PCR-SBT method, which is based on sequences of HLA-DRB1 Intron 1 and Intron 2 with our improvement. From 60 individuals of Naxi 37 DRB1 alleles were detected. The distribution of allele frequencies is evenly spread for most of alleles detected in Naxi. However, the gene frequency for HLA-DRB1 * 12021 is 17.50%. The other common alleles (> 5%) were HLA-DRB1 * 1404(7.50%), 1504(5.83%), 04051(5.83%), 08032(5.83%), 09012(5%), 03011(5%), and they covered 35% of the total alleles detected from Naxi, and 52.49% after adding the frequency of HLA-DRB1 * 12021. HLA-DRB1 * 0305, 0438, 1123, 1132, 1310, 0812 were detected in Chinese for the first time, and were very rare in other ethnic groups worldwide. Using the HLA-DRB1 gene frequencies of various ethnic groups, we constructed the phylogenetic tree by Fitch-Margoliash and Least-Squares Distance Methods and Cavalli-Sforza's chord measure of genetic distance. In our dendrogram, the South China populations were clustered together, and Siberian, Japanese and Minority of North China were clustered together, in which two big clusters we thought represented the ancient Southern and Northern Mongolian. Our results showed Naxi was clustered with Lahu and Yao ethnic groups, which were in the cluster of South China population. Obviously Naxi belongs to the South China ethnic groups and can't trace its origin from northern ethnic groups with the HLA-DRB1 genetic data. But based on Naxi's historical folklore, it was down to Southern China from Northwest China. The preliminary analysis about its origin conundrum was discussed in this paper based on our genetic data in relationship with its history and ethnology studies.

China↗

PubMed2005

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians.

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.

Adult↗

PubMed2006

HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection: a long-term prospective sibling cohort study in Taiwan.

OBJECTIVE: To conduct a prospective cohort study to clarify the relationship between human leukocyte antigen (HLA) polymorphisms and the seroconversion of hepatitis B e antigen (HBeAg). STUDY DESIGN: In the prospective cohort study, 81 HBeAg-positive children with chronic hepatitis B virus (HBV) infection from 40 unrelated families were recruited and followed-up regularly for a mean period of 17.70 +/- 3.23 years. The association between HLA antigen and the age at HBeAg seroconversion was analyzed using Cox regression model with shared frailties under left truncation and right censorship. RESULTS: HLA-B61 and HLA-DQB1*0503 antigens predicted a higher HBeAg seroconversion rate (relative incidence = 6.17 and 3.22, P = .024 and .017, respectively). Within-family frailty in our sibling cohort study demonstrated a negligible or a low degree of within-family correlation with spontaneous HBeAg seroconversion in each HLA antigen. CONCLUSIONS: HLA class I antigen B61 and class II antigen DQB1*0503 are associated with earlier HBeAg seroconversion in Taiwanese children with chronic HBV infection.

Adolescent↗

PubMed1994

[Association of polymorphism for HLA-DQA1 promotor region (QAP) with IDDM].

We have identified the DNA polymorphism for the HLA-DQA1 promotor region (QAP) in patients with early and late onset insulin-dependent diabetes mellitus (IDDM) by PCR direct sequencing. The result showed that single nucleotide substitution at position-92(C-->T-92) and -146 (T-->C-146) were detected in QAP for early and late onset IDDM respectively. These findings suggests that the mutation seems to alter the conformation of QAP so that these are likely to influence the aberrant expression of MHC-class II loci in beta-pancreatic islet cells.

Base Sequence↗

PubMed1990

Are soluble monocyte-derived HLA class II molecules candidates for immunosuppressive activity?

Supernatants of human blood monocyte cultures suppressed PHA responses (IL-2 synthesis, IL-2R expression, DNA synthesis) of autologous and allogeneic lymphocytes. The main suppressive activity was found in the 65-kDa (and 23-kDa) range. It could be incompletely neutralized by mAb specific for a non-polymorphic HLA DR determinant and could also be adsorbed to and eluted from an anti-DR immunoabsorbent column. On blots of monocyte lysates and monocyte culture supernatants, the mAb RoDR recognized antigens of nearly the same Mr. The hypothesis that soluble HLA DR alpha beta heterodimers or beta chains are likely candidates for the suppressor factor was confirmed by analogous effects of purified HLA DR molecules. We favor a model in which soluble MHC class II molecules (in contrast to surface-bound ones) may interfere with the association and cross-linking processes necessary for T cell activation by competing for CD4 binding sites.

Antibodies, Monoclonal↗

PubMed1997

Expression of killer cell inhibitory receptors on human uterine natural killer cells.

The establishment of the human placenta in early pregnancy is characterized by the presence of large numbers of natural killer (NK) cells within the maternal decidua in close proximity to the fetally-derived invading extravillous trophoblast which expresses at least two HLA class I molecules, HLA-G and HLA-C. These NK cells have an unusual phenotype, CD56(bright) CD16, distinguishing them from adult peripheral blood NK cells. They may control key events in trophoblast migration and therefore placentation. Human NK cells in peripheral blood express receptors for polymorphic HLA class I molecules. This family of receptors, known as killer cell inhibitory receptors (KIR), are expressed on overlapping subsets of NK cells to give an NK cell repertoire which differs between individuals. Using a panel of monoclonal antibodies to several members of the KIR family and analysis by flow cytometry, we have found that KIR are expressed by decidual NK cells. There is variation in both the percentage of cells expressing a particular receptor and the density of receptor expression between decidual NK cells from different individuals. Comparison of NK cells from decidua and peripheral blood of the same individual showed that NK cells from these two different locations express different repertoires of KIR. Receptors are present in individuals who do not possess the relevant class I ligand, raising the possibility that these NK receptors may be involved in recognition of the allogeneic fetus by the mother at the implantation site.

Adult↗

PubMed1983

Human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis and association with HLA-DR types.

To demonstrate human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis, 25 multiple-case families were tissue typed for class I and class II HLA specificities. Eight non-HLA genetic markers were also examined for any indication of other genetic factors that might influence the Mycobacterium tuberculosis infection. Observations on estimated HLA haplotype segregation in the sibs suggest that 84% of the affected sibs shared significantly more often than expected a common haplotype with each other than the normal unaffected sibs (P less than 0.001). Also, there was a skewed transmission of DR2 to diseased offspring from diseased parents (21 of 27) and to diseased offspring from healthy parents (15 of 17) in contrast to the transmission of DR2 from either group of parents to healthy offspring (six of 15 and 10 of 16, respectively). The segregation of non-HLA polymorphisms did not deviate significantly from the expected figures. These data provide strong evidence in favor of DR2-associated susceptibility to pulmonary tuberculosis.

Adult↗

PubMed1993

HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation.

HLA-DQ class II molecules are complex heterodimers in which polymorphic alpha- and beta-polypeptides form noncovalent associations leading to cell surface expression. Using gene transfer with retroviral vectors, we demonstrate that surface expression of heterodimers among various DQ alpha and -beta polypeptides is not universal. Two types of allele-specific constraints were found: DQ beta chains that are associated with the DQw1 specificities do not form stable cell surface heterodimers with DQ alpha chains encoded on haplotypes that are associated with DQw2, DQw3, or DQw4. Similarly, surface expression of heterodimers composed of DQw2- or DQw3-associated DQ beta chains and DQw1 DQ alpha chains were not detected. The formation of mixed isotype heterodimers also showed allelic preference: DR alpha/DQw1 beta dimers were detected on the cell surface, but DR alpha/DQw3 beta dimers were not. Failure to express class II heterodimers on the cell surface was apparently due to either inefficient assembly of the alpha- and beta-chains or retention of the mismatched dimers in an intracellular compartment. DQ beta cDNA encoding DQw1- and DQw3-associated beta-polypeptides were modified to create chimeric expression vectors in which portions of the DQ beta polypeptides were exchanged between different alleles. The resulting chimeric DQ beta polypeptides were tested for their ability to form stable heterodimers with different DQ alpha polypeptides. A cluster of polymorphic amino acid residues encoded by the 3' end of the DQB1 second exon, corresponding to residues 60 to 91 in the DQ beta polypeptide, were found to be critical determinants constraining stable cell surface heterodimer formation among preferential alpha- and beta-combinations.

Alleles↗

PubMed2025

Human Genome REWRITE for Off-the-Shelf Stem Cells Reveals an "Epigenetic Ghost".

Human leukocyte antigen (HLA) polymorphism hinders off-the-shelf cell therapies. We developed REWRITE, a modular platform for iterative, scar-minimized genome writing of synthetic constructs >100 kb in human pluripotent stem cells (hPSCs). Using REWRITE, we deleted 105-209 kb of the HLA locus and installed synthetic 24 kb or 100 kb HLA haplotypes, and a 62 kb antigen-processing locus. This uncovered a persistent, heritable "epigenetic ghost" - an active state lingering despite genetic removal - whose resolution to a silenced default state is driven by native intergenic DNA. These loci restored inducible expression in key lineages, sparing cells from NK-mediated killing and establishing HLA-matched T-cell tolerance, enabling off-the-shelf cell therapies. REWRITE facilitates extensible programming of multigenic functions in allogeneic human cells - from immune design to genome architecture discovery.

Journal Article↗

PubMedDate not supplied

[The role of genetic factors in the etiopathogenesis of psoriasis].

Psoriasis is a chronic skin disease characterized by epidermal hyperproliferation that is probably mediated by an immunologic reaction to particular epidermal, dermal or circulating immunogenic peptide. The inheritance of psoriasis within some families suggests the importance of genetic factors in the pathogenesis of the disease. Population based studies revealed that psoriasis is associated with HLA genes class I and II located on the chromosome 6. The highest risk of developing psoriasis carries the HLA-Cw*0602 gene. The analysis of HLA polymorphism in Croatian patients also showed the importance of Cw*0602 allele in psoriasis susceptibility. Until now, eight different gene loci for psoriasis are mentioned in the OMIM (Online Mendelian Inheritance in Men) data base. Even though, the psoriasis association with HLA genes is doubtless, only some carriers of susceptible genes develop the disease. Therefore, some other genes except HLA genes as well as some environmental factors have a role in the pathogenesis of psoriasis.

Genetic Predisposition to Disease↗

PubMed1988

Direct and indirect nickel-specific stimulation of T lymphocytes from patients with allergic contact dermatitis to nickel.

Fourteen T lymphocyte clones (TLC) specific for the contact allergen nickel were prepared either from lesional tissue biopsies or from peripheral blood of patients with allergic nickel-contact dermatitis. Two nickel-specific TLC, obtained from lesional tissue, responded to nickel without the participation of antigen-presenting cells (APC). This direct stimulation by nickel was not restricted by major histocompatibility complex-encoded molecules, since antibodies against HLA class I and II molecules did not block nickel-specific proliferation. Proliferation of other nickel-specific TLC was dependent on the presence of APC and was diversely restricted by HLA class II molecules. With one exception, the restriction determinants were present on HLA-DR and HLA-DQ molecules. Four TLC recognized nickel in association with subtypes of these serologically defined molecules. Five TLC seemed to recognize nickel in the context of highly unusual restriction determinants, since their restrictions could not be explained by the function of single polymorphic HLA class II epitopes. The absence of HLA class II restrictions and the occurrence of deviant HLA class II restrictions in part of the nickel-specific TLC are suggested to result from direct interactions of nickel with critical immune response molecules.

Antigen-Presenting Cells↗