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Results for “HLA polymorphism”

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PubMed1998

Enhancement of tumor cell lysis by natural killer cells after blocking of HLA-monomorphic determinant using F(ab')2 fragment of W6/32.

It has been known that negative signal of natural killer (NK) cells is triggered by HLA-polymorphic determinant (PMD) of target cells. However, it is not clear whether or not the negative signal is triggered by HLA-monomorphic determinant (MMD). In this study, we determined the interaction of NK receptor and MMD by mean of a blocking test. For the blocking, W6/32, which is an antibody to the MMD, was used. As target cells, we used a tumor cell line H42 and several cell lines. The H42 was established from a bladder cancer patient after radiation therapy. This cell line was demonstrated to be PMD negative but MMD positive and showed NK sensitivity. We had established one more cell line, H41, from the same patient before the radiation therapy. However, the H41 possessed both the PMD and MMD and exhibited NK resistance. Thus, the NK sensitivity of the H42 may be due to depression of the PMD. We performed a blocking test against the MMD of these cell lines. When the H42 was pretreated with F(ab')2 fragment of the W6/32, the killing by NK cells increased. Other cell lines, EB33, KMT-1, and HMy2-C1R, which possessed low levels of PMD, were killed moderately after the pretreatment, although the H41 and other cell lines (KO, MT-2, OKM-3T), which possessed high levels of PMD, were killed only slightly. These findings suggest that the negative signal may be triggered not only by the PMD but also by the MMD.

Adult↗

PubMed1980

HLA segregation of tuberculoid leprosy: confirmation of the DR2 marker.

Families with multiple cases of leprosy were tested for HLA (histocompatibility leukocyte antigen)-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR2. Thirty-one non-HLA genetic markers were also examined for indications of non-HLA-linked genetic factors that might control susceptibility to tuberculoid leprosy. A significant (P = 0.002) preferential inheritance of HLA-DR2 by siblings affected with tuberculoid leprosy, but not by healthy siblings nor by siblings affected with lepromatous leprosy, was observed. In addition, combined family data showed a significant (P less than 0.0025) excess of identical HLA haplotypes inherited from healthy parents by siblings affected with tuberculoid leprosy. Segregation on non-HLA polymorphisms did not deviate significantly from what would have occured randomly. These data are compatible with a recessive inheritance of HLA-linked susceptibility to tuberculoid leprosy. The preferential segregation of DR2 observed in children with tuberculoid leprosy (P less than 0.001 for the combined data from India) indicates that the HLA-linked susceptibility gene is either DR2 or in linkage disequilibrium with it.

Epitopes↗

PubMed1994

Anti-beta-receptor antibodies in familial cardiomyopathy: correlation with HLA-DR and HLA-DQ gene polymorphisms.

The presence of beta-receptor autoantibodies and their relationship to restriction fragment length polymorphisms of the human leukocyte antigen (HLA) class II genes were studied in 42 affected and unaffected members of a family with a heritable disorder of the conduction system and cardiac muscle. Antibodies were detected in 34% of all members (59% of affected and 22% of unaffected; p < 0.01). Significant differences between affected and unaffected individuals and between anti-beta-receptor antibody positive and negative individuals were noted in the prevalence of polymorphisms obtained with Taq I for the HLA-DR beta and HLA-DQ alpha genes. In affected individuals, there was a strong positive correlation between these polymorphisms and the presence of anti-beta-receptor antibodies. These results suggest that autoimmune mechanisms under the control of the class II genes play an important role in the pathogenesis of familial cardiomyopathy.

Arrhythmias, Cardiac↗

PubMed1987

The isolation and characterization of murine monoclonal antibodies directed to polymorphic epitopes on HLA antigens.

Twenty-two murine monoclonal antibodies directed to distinct polymorphic epitopes on HLA class I or class II antigens have been isolated and characterized using a simple protocol for fusion and hybridoma selection. Thirteen MAbs directed to class I antigens are reported here for the first time. The majority of these MAbs reacted with multiple specificities, often revealing a surprising sharing of epitopes. MAbs directed against single classically defined alloantigenic specificities were also obtained.

Animals↗

PubMed2005

Association between migraine and HLA-DRB1 gene polymorphisms.

We examined the distribution of HLA-DRB1 alleles in a cohort of 255 Italian migraine patients and in a control group of 325 healthy subjects. The frequency of DRB1*12 allele was found to be significantly reduced (p=0.02) in patients with migraine while the DRB1*16 allele was significantly increased (p=0.04) in comparison with controls. When the patients were divided into disease subgroups (migraine with and without aura), HLA-DRB1**16 allele was significantly increased (p<0.05) only in migraine without aura patients. We conclude that, in Italian patients, migraine is associated with different alleles of the HLA-DRB1 locus. Our data suggest the presence of a genetic susceptibility factor for migraine within the HLA region.

Adult↗

PubMed1999

Monomorphic HLA class I-(non-A, non-B) expression on Ewing's tumor cell lines, modulation by TNF-alpha and IFN-gamma.

In this study, the expression of polymorphic and non-polymorphic MHC antigens in Ewing's tumor (ET) cells was examined by surface staining, Western blots and transcriptional analysis. Cell lines derived from Ewing's tumors largely lack polymorphic HLA class Ia antigens of both the HLA-A and the HLA-B loci but binding of monomorphic HLA antibodies indicates significant expression of HLA-C locus antigens and/or HLA class Ib molecules. HLA Ib molecules encoded by the HLA-E, -F or -G loci with a molecular mass of less than 44 kDa were not detected in lysates of either constitutive or TNF-alpha plus IFN-gamma treated ET cells. Two representative ET cell lines with either detectable HLA-A, -B antigens (A673) or absolutely non-detectable HLA-A, -B antigens (SK-ES-1) were further subjected to transcriptional analysis. A673 mRNA hybridized with HLA-A, -B, -C and HLA-E-specific probes in Northern blots. By contrast, mRNA specific for HLA-A, -B, -C was negative in SK-ES-1 but TNF-alpha plus IFN-gamma reconstituted HLA-A, -B, -C transcription in this cell line. HLA-E was transcribed in A673 but not in SK-ES-1. Combining mRNA and surface expression of HLA class Ia molecules results in a highly variable pattern of defective HLA class I expression in this type of neuroectodermal tumor. The involvement of the ET-specific fusion transcript EWS/Fli-1 in modulating the HLA-A and -B locus antigens is likely to occur by the upregulation of c-myc in these tumors. The exceptionally constant expression of HLA-C or some other non-A, non-B antigens (reactive with defined monoclonal antibodies) implies important consequences on tumor-cell resistance against specific CTL and NK activity in vivo.

Gene Expression↗

PubMed1994

Analysis of TAP2 and HLA-DP gene polymorphism in psoriasis.

TAP2 is a gene, located between HLA-DP and HLA-DQ, whose products form a transporter molecule involved in endogenous antigen processing. Polymorphic residues have been described in this gene. TAP2 is of particular interest because its involvement in antigen presentation makes it a candidate for a disease susceptibility gene. In psoriasis, two clinical subtypes analogous to the situation in diabetes type I with early onset and family history and type II with later onset and without family history have been described. We have previously shown that type I but not type II psoriasis is associated with the HLA-DRB1*0701/2, -DQA1*0201, -DQB1*0303 haplotype. To investigate whether this haplotype extends to include particular TAP2 and/or DP alleles, we tested the TAP2 and HLA-DP alleles of a control group (n = 199), patients with psoriasis type I (n = 66), and patients with psoriasis type II (n = 35) by hybridization with SSOs. Our data show that there is no significant correlation between TAP2 and/or HLA-DP gene polymorphism and psoriasis type I and/or type II. We conclude that disease association in type I psoriasis is associated with the extended haplotype HLA-B57, -Cw6, -DRB1*0701/2, -DQA1*0201, -DQB1*0303.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.

Over half of the inherited predisposition to insulin-dependent diabetes mellitus maps to the region of chromosome 6 that contains the highly polymorphic HLA class II genes which determine immune responsiveness. Analysis of DNA sequences from diabetics indicates that alleles of HLA-DQ beta determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against the insulin-producing islet cells.

Alleles↗

PubMed1992

Unusual HLA-B alleles in two tribes of Brazilian Indians.

The Kaingang and Guarani are culturally and linguistically distinct tribes of southern Brazil. Like all Amerindian groups they show limited HLA polymorphism, which probably reflects the small founder populations that colonized America by overland migration from Asia 11,000-40,000 years ago. We find the nucleotide sequences of HLA-B alleles from the Kaingang and Guarani to be distinct from those characterized in caucasian, oriental and other populations. By comparison, the HLA-A and C alleles are familiar. These results and those reported in the accompanying paper on the Waorani of Ecuador reveal that a marked evolution of HLA-B has occurred since humans first entered South America. New alleles have been formed through recombination between pre-existing alleles, not by point mutation, giving rise to distinctive diversification of HLA-B in different South American Indian tribes.

Alleles↗

PubMed1982

Alloantisera detect HLA-A-B-C and non-HLA differentiation antigens on human thymocytes.

Human thymocytes (THY) were examined for the expression of HLA-A,B,C antigens on their cell surface by using tissue typing alloantisera in the microcytotoxicity assay. Approximately 80% of the total THY population demonstrated antibody-mediated, C-dependent lysis with several alloantisera for each HLA-A,B,C specificity. The HLA phenotype of THY was verified by HLA typing autologous peripheral blood lymphocytes (PBL) from the thymus donor. Thymus tissue and PBL were obtained from cardiac surgical patients ranging in age from 3 mo to 12 yr. The capacity of THY to absorb HLA alloantibody was also demonstrated. Cross-absorption studies performed on PBL and THY by using HLA typing sera produced two important findings: 1) HLA typing sera that are devoid of non-HLA THY-specific antibody can be used to HLA type THY and 2) selected non-HLA sera from multiparous women, and selected HLA typing sera absorbed with PRL or platelets can be used to detect THY differentiation antigens. Taken together, cytotoxicity data, absorption capacities, cross-absorption studies, and statistical analysis indicate that HLA-A,B,C alloantigens and non-HLA polymorphic differentiation antigens detected by alloantisera are co-expressed on the cell surface of the majority of human THY.

Antibody Specificity↗

PubMed2001

How selection shapes variation of the human major histocompatibility complex: a review.

The nature of polymorphism and molecular sequence variation in the genes of the human major histocompatibility complex (MHC) provides strong support for the idea that these genes are under selection. With the understanding that selection shapes MHC variation new questions have become the focus of study. What is the mode of selection that accounts for MHC polymorphism? Is variation maintained by pathogen pressure or by reproductive mechanisms? Discerning between these requires drawing on information from studies on association between HLA genes and infectious diseases, reproductive success and mating preferences relative to HLA genotypes, and theoretical studies that compare the outcomes of different selection regimes. The pattern that has emerged suggests that several types of selection are plausible for the maintenance of HLA polymorphism.

Alleles↗

PubMed2002

Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC. METHODS: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred. RESULTS: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.

Adult↗

PubMed1995

Study of HLA class I/IL and T lymphocyte subsets in Kuwaiti vitiligo patients.

HLA polymorphisms of class I and class II MHC were investigated in 40 Kuwaiti vitiligo patients and in 40 controls using microcytotoxicity assay. HLA-B21, Cw6 and DR53 were increased significantly in patients compared to controls (P = 0.00001, 0.00001 and P = 0.0053 respectively) while HLA-A19, DR52, were significantly decreased (P = 0.00236, 0.05, respectively). Total T-cells, T4 and T8 were measured as CD2, CD4 and CD8 respectively by flow cytometry. Vitiligo patients showed significant increase in CD4 compared to controls (P = 0.03). Our findings suggest that HLA-B21 and Cw6 and DR53, are susceptible genes of vitiligo, while A19 and DR52 are protective genes in the Kuwaiti population.

Disease Susceptibility↗

PubMedDate not supplied

Soluble HLA class I antigens in serum of healthy individuals--population study.

Variability of concentrations of s-HLA-I depending on allelic specificity substantiated realisation of research in population of 248 healthy, unrelated individuals. Defined phenotypes from tissue typing of polymorphic HLA complex enabled concentrations measurements of 1553 serum samples for HLA--A, B, and C loci determined antigens. Semi-quantitative technique of inhibition microcytotoxic reaction according to Tait et al. (1981) and Mclean et al. (1983) with usage of policlonal sera anti-HLA was applied. For most of numbers of the allelic specificity the concentration of antigen material in soluble form (s-HLA-I) in blood serum were nominally very high and high. For certain numbers of specificity e.g. HLA--A26, A29, B39, B52, B56, Cw5, Cw6 the percentage of sera, where the s-HLA concentrations were decreased was observed. The results were presented as mean values of inhibition microcytotoxic reaction--according to NIH classification. Authors point on usefulness of results for s-HLA comparative analysis of particular HLA allelic specificity, specific for certain diseases e.g. Cw7 for SNHL patients and B27 for ankylosing spongilitis.

Adult↗

PubMed2003

Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer.

The enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population-dependent, implying the involvement of additional genetic cofactors. This study was designed to investigate the association between E6 variants and human leukocyte antigen (HLA) polymorphism within a Japanese population. Fifty-seven women with HPV16-positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n = 138) and published controls (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV16 E6 prototype (n = 11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n = 25), although we could not find a significant association between HLA class II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16-related cervical carcinogenesis.

Carcinoma in Situ↗

PubMed2003

HLA-A gene polymorphism defined by high-resolution sequence-based typing in 161 Northern Chinese Han people.

Human leukocyte antigen (HLA) system is the most polymorphic region known in the human genome. In the present study, we analyzed for the first time the HLA-A gene polymorphisms defined by the high-resolution typing methods-sequence-based typing (SBT) in 161 Northern Chinese Han people. A total of 74 different HLA-A gene types and 36 alleles were detected. The most frequent alleles were A*110101 (GF=0.2360), A*24020101 (GF=0.1646), and A*020101 (GF=0.1553); followed by A*3303 (GF=0.1180), A*3001 (GF=0.0590), and A*310102 (GF=0.0404). The frequencies of following alleles, A*0203, A*0205, A*0206, A*0207, A*030101, A*2423, A*2601, A*3201, and A*3301, are all higher than 0.0093. The homozygous alleles include A*020101, A*110101, A*24020101 and A*310102. Heterozygosity (H), polymorphism information content (PIC), discrimination power (DP) and probability of paternity exclusion (PPE) of HLA-A in the samples were calculated and their values were 0.8705, 0.8491, 0.6014, and 0.9475, respectively. These results by SBT analysis of HLA-A polymorphism in Northern Chinese Han population, especially the allele subtypes character, will be of great interest for clinical transplantation, disease-associated study and forensic identification. Implementation of high-resolution typing methods allows a significantly wider spectrum of HLA variation including rare alleles. This spectrum will further be extensively utilized in many fields.

Alleles↗

PubMed1993

The value of variable number of tandem-repeat polymorphisms in cases of disputed paternity not resolved by conventional markers: two case reports.

Disputed paternity cases are routinely tested in the authors' laboratory for red cell antigen, plasma protein, red cell enzyme, and HLA polymorphisms. This report concerns two cases in which the above test results made exclusion of paternity doubtful. In one case, exclusion of paternity was based on one discrepancy in the Duffy blood group system only, a unique situation in the investigators' experience of more than 2500 cases; the investigators were, therefore, reluctant to use this as the only evidence of exclusion. In the other case, it was necessary to postulate the presence of a rare haplotype, MSu, in the MNS blood group system to explain paternity. It was therefore decided to investigate allelic variable number of tandem-repeat (VNTR) DNA polymorphisms in these disputed paternity trios. VNTR DNA typing convincingly excluded these accused men from paternity.

Blood Group Antigens↗

PubMed2001

HLA phenotypes of ESRD patients are risk factors in the panel-reactive antibody (PRA) response.

To determine whether recipient HLA phenotypes are correlated with an increased or decreased risk of alloantibody sensitization in end-stage renal disease (ESRD) candidates for first or repeat kidney transplantation; we analyzed 19440 kidney allograft recipients consisting of 13,216 Caucasians and 6224 non-Caucasians transplanted between 10/87 and 11/98 at South-Eastern Organ Procurement Foundation (SEOPF) member institutions. Relative risk values and 95% confidence limits were obtained using Wolfe's method. Logistic regression was used to adjust for covariates that influence sensitization, i.e. ethnicity, gender, age, pregnancies, transfusions, primary/repeat transplant and living versus cadaver donor. Univariate analysis of the entire cohort indicated that nine HLA allelotypes (DR1,4,7; B8,12,40; A1,2,11) were associated with a significantly reduced risk of sensitization, and five allelotypes (B42,B53; A 10,19,36) were associated with an increased risk of PRA responses. Corrected for the number of statistical comparisons, recipients with DR1, DR4, A1 or A2 were 15% less likely to be sensitized per allelotype. Recipients with B42, B53 or A36 were at increased risk of preformed antibodies, after correction of the P value, for an average of 38% increased risk per allelotype. In the multivariate analysis, HLA phenotypes identified as independent risk factors associated with protection against sensitization were DR1,4,7; B12(44,45); and A1,2, with an average reduced risk of 9% per allelotype. The only independent susceptibility allelotype was A36 with an increased risk of 29%. The A10 (25,26,34,66) group reached borderline significance. We also looked for HLA-DR,-B,-A combinations that could potentially represent protective or at risk haplotypes/genotypes. Stepwise logistic regression identified five combinations associated with protection: DR1-B35-A3; DR1-B35-A2; DR1-B44-A2; DR4-B44-A2; DR7-B57-A1 (RR range 0.83-0.63) with 27% average reduced risk per combination. Phenotype combinations associated with an increased risk of sensitization were: DR2-B44-A2; DR2B53-A2; DR3-B8-A1: DR3-B42-A30; DR6-B42-A30; DR11-B53-A30 (RR range 2.76-1.48) with an average increased risk of 70% per combination. This study provides strong evidence that HLA-linked genes influence the anti-HLA PRA response. The magnitude of the altered PRA response risk in DR-B-A combinations was approximately twice that of the allelotypes at individual loci. HLA-DR genes seemed to contribute most of the altered risk. The correlations between DR types and PRA responsiveness are consistent with the DR types previously regarded as predictors of kidney graft survival. The magnitude of increased PRA risk attributable to an allelotype or combination was approximately twice that associated with a decreased risk. We conclude that some HLA class II-linked genes modulate the PRA response in a clinically significant manner. This immune response gene (Ir) regulation probably operates through polymorphic HLA molecules in their physiologic roles of antigen processing and presentation to helper T cells.

Adult↗