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Results for “HLA polymorphism”

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PubMed1997

HLA expression in a primary uveal melanoma, its cell line, and four of its metastases.

BACKGROUND: The level of HLA expression on a tumour may influence the immunological response against this tumour, and vice versa. HLA expression was determined in a primary uveal melanoma, its metastases, and on a cell line derived from this melanoma, and the presence and type of infiltrate in tissue sections were also studied. METHODS: Immunohistochemistry with monoclonal antibodies (MAbs) against HLA class I and II, T cells, NK cells, and macrophages. RESULTS: Primary and metastatic lesions, as well as the cell line showed high levels of expression of the monomorphic determinants of HLA class I. Expression of the polymorphic HLA-A2 and HLA-A3 antigens was decreased on metastases to the skin and liver. HLA-Bw4 expression was low on all lesions, as well as expression of HLA class II. Tumour infiltrating cells consisted mainly of CD3, CD4, and CD8 positive cells. Expression on the cell line corresponded to expression on the primary tumour. CONCLUSION: The primary uveal melanoma as well as the cell line showed a high expression of monomorphic and polymorphic HLA-A antigens, while metastases showed a high expression of monomorphic and a lower expression of polymorphic antigens. This variation in expression may support tumour cell escape from NK cells as well as CTL mediated lysis.

Aged↗

PubMed1984

Polymorphic and monomorphic HLA-DR determinants on human hematopoietic progenitor cells.

The expression of monomorphic Ia-like antigens and polymorphic (allotypic) HLA-DR determinants on CFU-GM, BFU-E, CFU-E, and CFU-GEMM was studied in bone marrow and peripheral blood cells from normal healthy individuals. Using various polyclonal and monoclonal anti-Ia-like antibodies, the presence of HLA-DR backbone antigens was shown on all hematopoietic progenitor cells (HPC) studied, both in complement-dependent cytotoxicity assays and in fluorescence-activated cell sorting (FACS). The expression of allotypic determinants was demonstrated on all HPCs, using the HLA-DR typing sera anti-HLA-DR1, 2, 3, 4, 5, and 7. The Class II antigen MT-2 was also shown on all HPCs, using both monoclonal and alloantisera, whereas the MB-1 (DC-1) determinant could not be demonstrated on HPCs. This might open the possibility of removing MB-1-positive malignant cells from the graft in autologous bone marrow transplantation.

Antilymphocyte Serum↗

PubMed1997

Different statistical models used in the calculation of the prevalence of insulin-dependent diabetes mellitus according to the polymorphism of the HLA-DQ region.

The use of three statistical models yielded different estimates of the odds ratio relative to the association between the polymorphism in the HLA-DQ region and insulin-dependent diabetes mellitus (IDDM). The models used were: (1) the allele-dosage model which assumes that the number of susceptibility alleles has a linear effect on the logarithm of the odds; (2) the reference cell coding method used with alleles of susceptibility as a risk factor; or (3) a model that uses a classification of alpha/beta heterodimers as a susceptibility factor. We suggest that models which imply a log-linear relationship between a susceptibility marker and disease such as the first model are not appropriate in the assessment of the HLA-IDDM association. In contrast, although both latter models are valid, the third model is more compatible with current hypotheses of the pathological process of the disease. Once an estimation of the odds ratio is chosen, we use such an estimation to calculate an approximation of the prevalence of IDDM according to the polymorphism in HLA-DQ region using the iterative procedure of Newton-Raphson. These approaches are illustrated with data from a case-control study previously conducted in the city of Santiago, Chile.

Alleles↗

PubMed2005

Association of HLA class I and class II polymorphisms with age-related macular degeneration.

PURPOSE: To evaluate whether HLA genotypes are associated with age-related macular degeneration (AMD). METHODS: HLA class I-A, -B, and -Cw and class II DRB1 and DQB1 principal allele groups were genotyped in two stages: initially for principal allele groups in a cohort of 100 AMD cases and 92 control subjects, and then, in the next 100 cases and controls from the same cohort, for alleles or allele groups with P < 0.1 on initial typing. Genotype frequencies were compared by 2 x 2 contingency tables. The strongest associations for individual HLA alleles were calculated with two-locus stratification analysis and logistic regression for all possible pair-wise HLA combinations. Bonferroni corrections were applied for multiple measurements (P(c)). Each HLA allele was subjected to logistic regression for known AMD covariates. HLA immunohistochemistry for class I antigens was performed on elderly donor eyes. RESULTS: Allele Cw*0701 (P = 0.004, P(c) = 0.036) correlated positively with AMD, whereas alleles B*4001 (P = 0.003, P(c) = 0.027) and DRB1*1301(P = 0.001, P(c) = 0.009) were negatively associated. These HLA associations were independent of any linkage disequilibrium. Immunohistochemistry demonstrated differential HLA class I expression in choriocapillary endothelial cells. CONCLUSIONS: Significant positive and negative associations exist between HLA alleles and AMD. HLA polymorphisms influence the development of AMD, possibly via modulating choroidal immune function.

Aged↗

PubMed1989

Ancient roots for polymorphism at the HLA-DQ alpha locus in primates.

The genes encoding the human histocompatibility antigens (HLA) exhibit a remarkable degree of polymorphism as revealed by immunologic and molecular analyses. This extensive sequence polymorphism either may have been generated during the lifetime of the human species or could have arisen before speciation and been maintained in the contemporary human population by selection or, possibly, by genetic drift. These two hypotheses were examined using the polymerase chain reaction method to amplify polymorphic sequences from the DQ alpha locus, as well as the DX alpha locus, an homologous but nonexpressed locus, in a series of primates that diverged at known times. In general, the amino acid sequence of a specific human DQ alpha allelic type is more closely related to its chimpanzee or gorilla counterpart than to other human DQ alpha alleles. Phylogenetic analysis of the silent nucleotide position changes shows that the similarity of allelic types between species is due to common ancestry rather than convergent evolution. Thus, most of the polymorphism at the DQ alpha locus in the human species was already present at least 5 million years ago in the ancestral species that gave rise to the chimpanzee, gorilla, and human lineages. However, one of the DQ alpha alleles may have arisen after speciation by recombination between two ancestral alleles.

Amino Acid Sequence↗

PubMed1994

Analysis of restriction fragment length polymorphism for the HLA-DR gene in Japanese patients with sarcoidosis.

BACKGROUND: It is commonly assumed that some immunological disorder may play a part in the pathogenesis of sarcoidosis. Previous studies by several groups have shown a significant association with HLA-DR antigens in patients with sarcoidosis. In this study, restriction fragment length polymorphism (RFLP) analysis of the HLA-DR gene was designed to confirm the association at the gene level and to look for a gene rearrangement which may influence susceptibility to sarcoidosis. METHODS: Thirty two unrelated Japanese patients with sarcoidosis were tested for HLA antigens and subjected to RFLP analysis after digestion with Eco RI, Pst I, Bam HI, Pvu II, and Hind III by using an HLA-DR beta cDNA probe. A group of 47 unrelated healthy Japanese subjects served as controls. Frequencies of each restriction fragment were compared between the patients and the control subjects. Correlation between fragment frequencies and clinical features were also analysed. RESULTS: No restriction fragments of HLA-DR beta gene were found specific to the patients with sarcoidosis. The RFLP analysis could detect polymorphism of HLA-DR beta genes that was not distinguishable by conventional serological methods. Several restriction fragments of the DR beta gene were seen only in DRw52 positive individuals, and showed higher frequencies in the patients than in control subjects. The patients with these DNA fragments were likely to have limited stage disease with no ophthalmic involvement. CONCLUSIONS: An association between HLA and sarcoidosis was noted at the DNA level, although no restriction fragments were specific for this disease. RFLP analysis of the HLA gene is a more useful method than the usual HLA typing, and should be the first step in identifying the gene sequence which is connected with susceptibility to sarcoidosis.

Adolescent↗

PubMed1999

HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients.

The MHC region has been shown to contain a susceptibility locus for multiple sclerosis (MS). While the strongest association to date has been between HLA-DRB1*1501 and MS, the exact nature of the MHC association in MS remains unclear. Two candidate polymorphic loci within the MHC class II region, the HLA-DMB gene and the HLA-DRA promoter, which lie close to HLA-DRB1, were therefore examined in an Australian MS population. The HLA-DMB*0103 phenotype was increased in the MS patients (46% vs. 30%) and the frequency of the HLA-DRA promoter A allele was also increased (81% vs. 68%). When the subjects were stratified into HLA-DRB*1501 positive and negative individuals these associations were not significantly different. This is a result of the strong linkage disequilibrium between HLA-DRB*1501 and both HLA-DMB*0103 and the HLA-DRA promoter A allele. The complete linkage between DRB1*1501 and the HLA-DRA promoter A allele indicates that the MS susceptibility haplotype (DRB1*1501-HLA-DQB1*0602-HLA-DQA1* 0102) can be extended out to promoter of the HLA-DRA locus. Interactions between both HLA-DMB and the HLA-DRA promoter and other reported MS susceptibility loci were examined (TCRBV polymorphisms, HLA-DQA1 and HLA-DQB1). Some interactions between specific TCRBV polymorphisms and the HLA-DRA promoter were observed, which is consistent with other published reports suggesting an epistatic interaction between TCRBV and HLA-DRB1.

Australia↗

PubMed1992

HLA class II gene polymorphism contributes little to Hashimoto's thyroiditis.

UNLABELLED: Previous studies of HLA and Hashimoto's thyroiditis have shown weak associations between the disease and various HLA-DR antigens. OBJECTIVE: To define better the contribution of HLA class II alleles to susceptibility to Hashimoto's thyroiditis. DESIGN AND MEASUREMENTS: Comparison of HLA-DRB, DQA and DQB restriction fragment length polymorphisms in patients with Hashimoto's thyroiditis and control subjects, and meta-analysis of this and other published studies. PATIENTS: Fifty Caucasian patients with Hashimoto's thyroiditis and 93 racially-matched control subjects. RESULTS: A 4.6 kb Taq 1 DQA restriction fragment length polymorphism occurred in 60% of patients compared with 35.5% of controls, Pc < 0.025. No other restriction fragment length polymorphism was significantly associated with the disease. Meta-analysis of several studies demonstrated weak, positive associations between the disease and DR3 and DR4. An association with DR5 was not significant. CONCLUSIONS: DR antigens are unlikely to determine disease susceptibility directly. These findings indicate that any contribution of HLA genes to inherited susceptibility to Hashimoto's thyroiditis is small and requires confirmation in family studies.

Disease Susceptibility↗

PubMed1991

Diversity among DRw13 DQw7 haplotypes as revealed by serology Dw typing and restriction fragment length polymorphism.

HLA-DRw13 is in linkage disequilibrium with DQw6; an unusual association, DRw13 DQw7, is found in 2% of our Caucasoid population. Investigation of genotyped individuals and of families by two allosera and by Dw typing revealed two subtypes: one recognized by homozygous typing cell HAG and by two allosera, the other subtype remained unreactive with both reagents. Analysis of DNA fragments with DNA probes indicated that the HAG-negative subset had DNA fragments in common with DRw6 while the HAG-positive subset shared DNA fragments with DR5. However, all DRw13 DQw7 cells are Dw24 as seen by hybridization with DRB probe.

Genetic Variation↗

PubMed1995

Tests of random mating for a highly polymorphic locus: application to HLA data.

Testing for random mating at an HLA locus is a difficult problem because of the highly polymorphic nature of the HLA loci. We discuss some methodological issues and propose several tests. A simulation study is conducted to evaluate these tests. The single allele test and the shared allele test deal with small sample sizes by aggregating the data in different ways. The shared allele test is found to be a more powerful method of detecting non-random mating patterns involving a deficiency or an excess of similar genotypes than the single allele test. We show that random mating of couple at the genotype level implies the random mating of couple at the allele level. Several multi-allele approaches are proposed for large population-based data sets. Among them, the corrected allele-table test performs better than the generalized Wald test in terms of power and size. These methods are then applied to an HLA data set of Caucasian couples, and no solid evidence for non-random mating at the HLA A, B, and DR loci is found.

Alleles↗

PubMed2006

Homozygous status for HLA-E*0103 confers protection from acute graft-versus-host disease and transplant-related mortality in HLA-matched sibling hematopoietic stem cell transplantation.

BACKGROUND: The posttransplant period following hematopoietic stem cell transplantation (HSCT) is potentially high risk for developing survival-compromising complications, many of which are known to be under the control of immunogenetic factors. Given the dual role of human leukocyte antigen (HLA)-E molecules in innate and adaptive immune processes, we analyzed the impact of HLA-E polymorphism in genoidentical HSCT setting. METHODS: We analyzed 187 HLA-genoidentical sibling pairs for HLA-E polymorphism. To explore its potential association with the incidence of acute and chronic graft versus host disease (aGVHD, cGVHD), severe infections, risk for transplant-related mortality (TRM), and overall survival, HLA-E locus was genotyped by a polymerase chain-reaction-sequence-specific primer (PCR-SSP) strategy. RESULTS: Multivariate analysis, taking into account the patient-, donor- and transplant-related factors, showed that the incidence of aGVHD and TRM at day 180 were low when the genotype was HLA-E*0103/E*0103, either in the donor or in the recipient, the pairs being identical for HLA-E alleles (hazard ratio [HR]=0.71, P=0.009; and HR=0.42, P=0.04, respectively). We also found a trend towards association between E*0103 homozygosity and improved survival (P=0.05). There was no association between HLA-E polymorphism and incidence of severe infections. CONCLUSIONS: These data suggest that the homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against aGVHD and TRM and likely contributes to improved survival in HLA-genoidentical bone marrow transplantation.

Acute Disease↗

PubMed1998

Sequence-based typing provides a new look at HLA-C diversity.

Although extensive HLA-A and HLA-B polymorphism is evident, the true diversity of HLA-C has remained hidden due to poor resolution of HLA-C Ags. To better understand the polymorphic nature of HLA-C molecules, 1823 samples from the National Marrow Donor Program research repository in North America have been typed by DNA sequencing and interpreted in terms of HLA-C diversification. Results show that HLA-Cw*0701 was the most common allele with a frequency of 16%, whereas 28% of the alleles typed as Cw12-18 (serologic blanks). The frequency of homozygotes was 9.8% as compared with previous studies of 18% for sequence-specific primers and 50% for serology. Most startling was the frequency at which new alleles were detected; 19 new HLA-C alleles were detected, representing a rate of approximately 1 in 100 samples typed. These new HLA-C alleles result from 29 nucleotide substitutions of which 4 are silent, such that coding substitutions concentrated about the Ag-binding groove predominate. Polymorphism at the HLA-C locus therefore resembles that at the HLA-A and HLA-B loci more than previously believed, indicating that antigenic stress is driving HLA-C evolution. However, sequence conservation in the alpha-helix of the first domain and a clustering of unique amino acids around the B pocket indicate that HLA-C alleles respond to antigenic pressures differently than HLA-A and HLA-B. Finally, because the samples characterized were predominantly from Caucasians, we hypothesize that HLA-C polymorphism will equal or exceed that of the HLA-A and -B loci as DNA sequence-based typing is extended to include more non-Caucasian individuals.

Alleles↗

PubMed2002

Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis.

OBJECTIVES: To investigate polymorphisms in the genes for tumour necrosis factor alpha (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement. METHODS: One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions -308, -238, +488), IL10 (-1082, -819, -592) and in the 3'-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions. RESULTS: HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P<0.05) and was associated with younger age of onset of psoriasis (P<0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele -238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele -238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA -238A alleles (23/23) in patients with PsA were HLA-Cw*0602-positive (P<0.0001). CONCLUSIONS: An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA -238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted.

Adult↗

PubMed2005

Tumor necrosis factor-alpha -308 promoter polymorphism contributes independently to HLA alleles in the severity of rheumatoid arthritis in Mexicans.

The aim of this study was to determine the frequency and potential relevance of the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha) in the severity of rheumatoid arthritis (RA) in Mexicans. HLA-DR and polymorphisms at positions -238 and -308 of TNF-alpha gene were determined in 137 Mexican RA patients (44 with severe and 93 with non-severe RA) as well as in 169 healthy controls (99 were typed for HLA-DR). We observed an increased frequency of HLA-DR4 in severe RA compared to healthy controls (pC=0.02, OR=2.33). TNF polymorphism analysis showed a significant increased frequency of TNF -238 GG genotype in the whole group of RA patients when compared to healthy controls (pC=0.007, OR=4.71). When the analyses were carried out separately in severe and non-severe RA patients, the increased frequency of -238 GG genotype only was observed in patients with non-severe forms of the disease. Analysis of -308 polymorphism showed increased frequency of -308 T2 (A) allele in severe RA when compared to non-severe disease (pC=0.011, OR=3.29) and to healthy controls (pC=0.002, OR=3.97). The data demonstrate that -308 T2 (A) allele is associated with susceptibility to develop severe RA in Mexicans. This association could be independent from HLA-DR alleles and might be used as a prognostic marker for severe RA.

Alleles↗

PubMed2006

HLA-G 14-bp polymorphism regulates the methotrexate response in rheumatoid arthritis.

OBJECTIVE: Methotrexate (MTX) represents the antirheumatic drug mainly used in rheumatoid arthritis (RA). HLA-G antigens are inducible nonclassical major histocompatibility complex class Ib molecules important for maintaining anti-inflammatory conditions. The HLA-G gene is characterized by a deletion/insertion polymorphism of 14 bp that controls specific mRNA stability and protein levels. It has been reported that MTX therapy mediates an increase of interleukin-10-producing cells. This cytokine up-regulates HLA-G expression. For this, we tested the hypothesis of an MTX-mediated HLA-G production and the possible relationship with the HLA-G 14-bp polymorphism. METHODS: Peripheral blood mononuclear cells from healthy individuals and non-MTX-treated RA patients were activated with different MTX concentrations, and soluble HLA-G (sHLA-G) and interleukin-10 production was investigated by specific immunoenzymatic assay. HLA-G 14-bp polymorphism genotyping was performed in healthy individuals and RA patients, defined as 'responders' and 'nonresponders' to the MTX therapy. RESULTS: MTX activation induces the production of sHLA-G molecules. A significant association was observed between the highest sHLA-G1 concentrations and the -14/-14 bp genotype. The analysis of the HLA-G 14-bp polymorphism in MTX-treated RA patients has confirmed an increase of the -14/-14 bp genotype in the responder group (chi=6.12, P=0.02; chi test) (odds ratio=2.46 (95% confidence interval, 1.26-4.84) P=0.009; logistic regression model). CONCLUSION: Our results propose that the MTX induces the production of the anti-inflammatory sHLA-G molecules that concur with the therapy response. Furthermore, the association between -14/-14 bp genotype and MTX clinical outcome proposes this polymorphism as a therapy marker in the early phases of the disease.

Aged↗

PubMed1986

Selective removal of clonogenic neoplastic B cells from human bone marrow using anti-HLA-DQ antibodies and complement.

Polymorphic HLA-DQ (DC/MB) determinants appeared to be not expressed on human hematopoietic progenitor cells (HPC), using several murine monoclonal and human polyclonal antibodies in a complement-dependent cytotoxicity (CDC) assay. Since mature HLA-DR-positive malignant lymphoma cells prove to be HLA-DQ positive, an attempt was made to remove clonogenic neoplastic DQwl-positive B cells selectively from DQwl-positive marrow samples without affecting hematopoietic progenitor cells. Using a combination of a clonogenic tumor cell assay, an HPC culture assay, and a mixed-tumor-cell-HPC culture assay, selective elimination of more than 98% of clonogenic neoplastic cells from tumor-cell-contaminated bone marrow suspensions was achieved with monoclonal anti-DQ antibodies and complement without depletion of HPC. These results indicate that anti-HLA-DQ antibodies can be used in autologous bone marrow transplantation to deplete the bone marrow cell suspension of DQ-positive malignant cells.

Antibodies, Monoclonal↗

PubMed1987

Restriction fragment length polymorphism at the HLA-C locus.

We have used the HLA-C-specific DNA probe pC250 to investigate restriction fragment length polymorphism (RFLP) at the HLA-C locus. Genomic Southern blot hybridization included DNA prepared from a panel of homozygous typing cells representing serological specificities Cw1 to Cw8 and also from samples representing Cw blanks. Although many restriction nucleases failed to reveal any polymorphism, RFLPs were evident with Taq I, Pvu II, Bst XI, Nde I, and Nci I in addition to the previously reported Eco RI. In the case of Bst XI, a unique RFLP defined a subset of serologically defined Cw blanks. Comparison of RFLP sizes with restriction fragment lengths obtained from the known HLA-Cw3 gene sequence permitted the localization of intragenic C locus RFLPs and the identification of a variable Taq I site in the second intron, a variable Nci I site near the end of the fourth exon, and a variable Pvu II site in the fifth intron.

Chromosome Mapping↗

PubMed2002

[Relationship between HLA-DQA1, -DQB1 genes polymorphism and susceptilibity to bronchial asthma among Northern Hans].

OBJECTIVE: To investigate the relationship between human leukocyte antigen (HLA)- DQA1, -DQB1 genes polymorphism and susceptibility to bronchial asthma among the Hans in the northern China. METHOD: Sequence-specific primer polymerase chain reaction was used to gene frequencies of HLA-DQA1 and HLA-DQB1 genes among 125 unrelated asthmatics, 12 of which being probands of asthmatic pedigrees, and 96 healthy controls, all of Han nationality and living in Beijing or nearby areas for a long time. Radioimmunosorbent test was used to examine the serum IgE and TigE. The ventilatory function was test among the asthmatics. RESULTS: The frequencies of HLA-DQA1 0104 and HLA-DQB1 0201 were 0.204 and 0.284, significantly higher than those in the healthy controls (0.089 and 0.096 respectively, both P < 0.01). Conversely, the frequencies of HLA-DQA10301 and HLA DQB101301 in the asthmatics were 0.148 and 0.20, significantly lower than those in the controls (0.25 and 0.282 respectively, P < 0.01 and < 0.05). The correlation coefficients between HLA-DQA1 * 0104 and atopy, HLA-DQB1 * 0201 and atopy, and HLA-DQA1 * 0301 and atopy were 0.813 (P < 0.01), 0.289 (P < 0.01), and -0.168 (P < 0.05) respectively. Multi-variate logistic regression asthma. CONCLUSIONS: The alleles HLA-DQA1 * 0104 and HLA-DQB1 * 0201 are correlated with the susceptibility to asthma among Northern of Han nationality. HLA-DQA1 * 0104 is an independent risk factor of onset of asthma. The alleles HLA-DQA1 * 0301 and HLA-DQB10301 are correlated with resistance against asthma. HLA-DQ genes are involved in the regulation of human specific immune responses.

Adult↗