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PubMed1989

Alloreactive T cell recognition of the HLA-DR beta N-terminal polymorphic region.

T cell alloreactivity, originally discovered as a tissue transplantation effect, is believed to be a manifestation of the normal major histocompatibility complex (MHC) restriction of antigen presentation by accessory cells to T cells. The molecular features of the human class II-MHC proteins (HLA) which are recognized by alloreactive T cells are not at present understood, although they are clearly related to the polymorphic nature of the MHC proteins. Human CD4+ T cell clones were selected by response to the HLA-DR2 peptides beta 1-15 or beta 51-65, in an MHC-restricted manner. In addition, these clones respond to cell lines expressing the DR2 haplotype, without the requirement for accessory antigen presenting cells. DR2 beta peptide 1-15 blocks the T cell alloresponse and polymorphic residues are shown to stimulate the peptide-specific response of these clones. Thus, the polymorphic residues contained within the DR beta sequence 1-15 are demonstrated to be directly recognized by alloreactive T cells.

Amino Acid Sequence↗

PubMed2000

HLA class II DRB1, DQB1, DPB1 polymorphism and cardiomyopathy due to Trypanosoma cruzi chronic infection.

Trypanosomiasis is an important cause of cardiomyopathy in endemic rural areas of Latin America. Previous studies have suggested participation of HLA molecules in the immune response regulation of T. cruzi infection, and association of HLA antigens with heart damage. One hundred and eleven unrelated T. cruzi antigen-seropositive individuals were tested for HLA class II alleles by the polymerase chain reaction and sequence specific oligonucleotide (PCR-SSO) method. Patients were classified in 3 groups according to clinical and electrocardiographic characteristics: asymptomatics (group A), with arrhythmia (group B), and with overt congestive heart failure (group C). Statistical analysis confirmed the significant increment of the DRB1*01 DQB1*0501 haplotype (p = 0.03) previously reported by our laboratory in patients with cardiomyopathy. The DPB1*0401 allele frequency is also significantly increased in patients with heart disease (groups B + C) (p = 0.009) while DPB1*0101 frequency is higher among the asymptomatic group (p = 0.04) compared with individuals of group C. The DPB1*0401 allele in homozygous form or in combination with allele DPB1*2301 or 3901, was found present more often in patients of groups B and C. Thus, the combination of two of these three alleles, sharing specific sequence motifs in positions 8, 9, 76, and 84-87 confers a relative risk of 6.55 to develop cardiomyopathy in seropositive patients (p = 0.041). Furthermore, 32% of the cardiomyopathics have either DRB1*01 DQB1*0501 and/or DPB1*0401/*0401, 0401/*2301, or* 0401/*3901 compared with 9% of the seropositive asymptomatics (OR = 5.0; p = 0.006).

Amino Acid Sequence↗

PubMed1995

HLA and tumor necrosis factor beta gene polymorphisms in Okinawa lung cancer patients: comparative study with mainland Japan lung cancer patients.

The frequencies of HLA class I and II antigens and TNF-beta polymorphism in lung cancer patients were investigated in two areas with different immunogenetic backgrounds, in Okinawa and in mainland Japan (Honshu). In Okinawa frequencies of HLA-Cw3 in squamous cell lung carcinoma patients were higher and those of HLA-DR, both in all lung cancer and in adeno lung carcinoma patients, were lower compared to those of normal controls. Among serologic HLA-DR4-positive individuals, no difference of DRB1*04 gene allele frequency was shown between patients and controls. In Honshu no statistically significant difference of HLA-class I and II alleles frequencies was found; however, the frequency of TNF-beta 10.5-kb homozygote in lung cancer patients was lower than that of controls. For 2-year survival, there was no difference between DR4-positive and -negative individuals and also between each TNF-beta type in Okinawa. In contrast, Honshu patients with 10.5-kb homozygote showed an improved 5-year survival ratio compared to those with heterozygote. We postulate that different immunogenetic backgrounds or environments might have caused the varying HLA or TNF-beta association in the predisposition to or prognosis of lung cancer.

Adenocarcinoma↗

PubMed1999

Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative caucasian patients with ankylosing spondylitis.

Previously, we reported a triplet repeat polymorphism in the transmembrane region within the MICA gene closely linked to HLA-B in a limited number of B27-positive Caucasian patients with ankylosing spondylitis (AS) (N = 48). In this study, we enrolled much more patients including some negative for B27, 162 AS subjects consisting of 140 B27-positive, and 22 B27-negative patients. The microsatellite allele consisting of 4 repetitions of (GCT/AGC) (A4 allele) was present at a significantly higher phenotype frequency in the patient group than in the ethnically matched control group (Pc < 0.000001). However, the frequency of the A4 allele was not significantly higher in the B27-positive and B27-negative patient groups, as compared to the B27-positive and B27-negative control groups, respectively. The higher phenotype frequency of the A4 allele in the patient group was supposed to be due to a strong linkage disequilibrium between the MICA and HLA-B genes. Thus, the possibility that the MICA gene is involved in the pathogenesis of AS can be excluded, supporting the hypothesis of a primary association of AS with HLA-B27.

Case-Control Studies↗

PubMed1996

Polymorphic amino acid domains of the HLA-DQ molecule are associated with disease heterogeneity in myasthenia gravis.

The association between myasthenia gravis (MG) and polymorphic amino acid domains in the HLA-DQ molecule was studied in 79 Swedish patients and 155 unrelated, population-based controls. A domain unique for DQB1*0201 was positively associated in MG patients with thymic hyperplasia or an early disease onset, and two domains with residues common to DQA1*01 alleles or DQB1*05 and DQB1*06 alleles were negatively associated in patients with thymic hyperplasia or an early disease onset. Our results suggest that MG associated with thymic hyperplasia and thymoma differ in their HLA-DQ association and thus are likely to have different pathogenic mechanisms.

Adolescent↗

PubMed1984

Variability and conformation of HLA class I antigens: a predictive approach to the spatial arrangement of polymorphic regions.

Comparison of available sequences of HLA-A and HLA-B antigens shows that variable positions are predominantly localized in four segments spanning residues 63-85, 105-116, 138-156, and 177-194. The fourth segment is unique in that it contains no differences between antigens of the same locus. Secondary folding of HLA heavy chain was estimated by three independent predictive methods and areas of defined structure were correlated with the distribution of local hydrophobicity to outline putative internal and external portions. The three analyses each independently predict a high probability for beta structure in the alpha 1, alpha 2, and alpha 3 domains. A single alpha-helix is predicted within residues 146-160, a segment of likely importance in cytotoxic T cell recognition and graft rejection. Substitutions within this segment are spatially related by the helical turn. Variable residues usually lie in areas of high local hydrophilicity, and therefore they are probably on the surface of the molecule. The model predicts that they are frequently located in beta strands, beta-turns, or the above-mentioned alpha-helix, so that most substitutions would be accommodated within rigid frameworks that may impose structural constraints to variability. The secondary structure of alpha 1, alpha 2, and alpha 3 domains presents some analogies that suggest that they might share common features in their tertiary folding. The predicted structure of alpha 3 is strongly reminiscent of that of immunoglobulin constant domains. Possible arrangements of elements of secondary structure are discussed, as an attempt to situating the polymorphic regions of HLA class I antigens in a spatial context.

Amino Acid Sequence↗

PubMed1990

Characterization of three human monoclonal antibodies specific for polymorphic class I and class II HLA antigens.

Three human monoclonal antibodies were derived from a single polytransfused patient awaiting renal transplantation. In microcitotoxicity assays, the patient's serum displayed strong positive reactions against greater than 90% of a panel of cells representing the known HLA specificities. The donor's peripheral blood lymphocytes were infected with Epstein-Barr virus, cloned, and supernatants of the virus transformed cultures were screened for the presence of IgG antilymphocyte reactivity utilizing an enzyme-linked immunosorbent assay method. Positive cultures were recloned and fused with the human-mouse heteromyeloma SHM. Supernatants from three clones were selected for alloreactivity and characterized by indirect immunofluorescent staining and fluoroactivated cell sorter analysis on homozygous typing cells, including those from the Tenth International Histocompatibility Workshop core panel and on cell lines derived from selected families. Data obtained demonstrate that two human monoclonal antibodies have DQw1 specificity, one of them being reactive against several DQw7-positive cell lines, while one monoclonal antibody is specific for the A2 + A28 class I MHC antigens. Anti-DQw1 antibodies were of different light-chain subtypes.

Antibodies, Monoclonal↗

PubMed1992

Diverse locations of amino acids in HLA-DR beta chains involved in polymorphic antibody binding epitopes on DR(alpha, beta 10101), DR(alpha, beta 11101), and DR(alpha,beta 3*0202) molecules.

In a previous study, we used transfectants expressing hybrid HLA-DR(beta 1*0403)/DR(beta 1*0701) chains to map sequences involved in polymorphic antibody binding epitopes on DR(alpha, beta 1*0403) or DR(alpha, beta 1*0701) molecules. Amino acids 1-40 of the beta 1 domain were found to make the major contributions to most of the antibody binding epitopes studied. To begin to localize sequences that contribute to polymorphic antibody epitopes on DR(alpha,beta 1*0101), DR(alpha,beta 1*1101) and DR(alpha,beta 3*0202) molecules, we used indirect immunofluorescence and flow cytometry to assess the binding of mAb to transfectants expressing hybrid DR(beta 1*0101)/DR(beta 1*1101) or DR(beta 1*1101)/DR(beta 3*0202) chains that divide the DR beta chain into three segments: amino acids 1-40, 41-97, and the beta 2 domain. The results indicate that amino acids 41-97 of the beta 1 domain on DR(beta 1*0101), DR(beta 1*1101), or DR(beta 3*0202) are critical in most of the epitopes, including those recognized by human antibodies MP4 and MP12, and mouse mAb GS88.2, I-LR1, 21r5, and 7.3.19.1, whereas amino acids 1-40 of DR(beta 1*1101) are critical in the epitope recognized by the MCS-7 mAb, and both segments 1-40 and 41-97 of DR(beta 1*1101) are important in the epitopes recognized by the I-LR2 and UL-52 mAbs. Based on these data and comparison of DR beta allelic protein sequences, the residues that may play critical roles in these antibody binding epitopes are predicted.

Amino Acids↗

PubMed1977

The genetic polymorphism of the fourth component of human complement: methodological aspects and a presentation of linkage and association data relevant to its localization in the HLA region.

The C4 polymorphism in man has been studied by immunofixation electrophoresis, crossed immunoelectrophoresis, and functional detection after agarose gel electrophoresis. It has so far not been possible to reveal this polymorphism by isoelectric focusing and functional detection of C4 bands. Three common alleles and one less frequently occuring allele have been identified. In a small population sample studied by all the different techniques and verified by family segregation, the following gene frequencies have been found: C4F: 0.46, C4S: 0.32, C4F1: 0.20, and C4M: 0.02. By linkage and association studies in a family material it has been shown that a structural C4 locus is situated in the HLA region of chromosome 6 very close to the HLA-B and Bf loci.

Adult↗

PubMed2006

Association of HLA class II DRB1, DPA1 and DPB1 polymorphism with genetic susceptibility to idiopathic dilated cardiomyopathy in Chinese Han nationality.

Although the aetiology of idiopathic dilated cardiomyopathy (IDC) remains unclear, many immunological abnormalities involving changes in cell-mediated and humoral immunity may be associated with cardiac impairment in IDC. Autoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of IDC and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, which are highly polymorphic, play an important role in the activating of immune responses and thus control the predisposition for or protection from IDC. This study explores the possible contribution of HLA-DRB and DP polymorphisms to IDC susceptibility. DNA genotyping for HLA-DRB1, DPA1 and DPB1 was performed using polymerase chain reaction-sequencing based typing (PCR-SBT) method in 198 IDC patients and 136 random selected healthy Han ethnic individuals living in Northern China. IDC patients were, sub-grouped into asymptomatics (subgroup A), with arrhythmia (subgroup B) and with overt congestive heart failure (subgroup C) according to the clinical manifestations and electrocardiogram or echocardiographic characteristics. ADP/ATP autoantibody was detected in IDC group by immunoblot analysis. The results revealed that HLA-DR15, -DPB*0601 frequencies were significantly elevated in IDC group compared with normal control. The DPB1*0601 allele in homozygous form or in combination with allele DPB1*2301 or *3901, was found present more often in IDC patients. The predominance of HLA-DR4 allele was observed in subgroup B after stratification. However, the frequency of DPB1*0101 allele increased in the control than in the IDC group. The frequency of HLA-DPB1*0601 allele was significantly higher in IDC patients with positive autoantibody against ADP/ATP carrier of myocardial mitochondria in contrast to those with negative autoantibody. We conclude that HLA-DR4, -DR15, -DPB1*0601 alleles confers susceptibility to, while DPB1*0101 allele confers protection from IDC among individuals of northern Chinese Han nationality. The glutamate at position 69 in the second exon of DPB1*0601, as a key residue for special conformation of HLA-DP, may confer predisposition to IDC. HLA-DR and -DP alleles polymorphisms may serve as genetic markers for IDC and be involved in the regulation of the immune specific response to auto or exterior anti-myocardium antibodies.

Alleles↗

PubMed1988

HLA class I and H ferritin gene polymorphisms in normal subjects and patients with haemochromatosis.

The gene for idiopathic haemochromatosis is located on the short arm of chromosome 6 within 1 cM of the HLA-A locus. In this region there are many HLA class I genes, and there may also be a gene for the 'H' subunit of ferritin. Both HLA class I and H ferritin genes are therefore candidates for the abnormal gene in idiopathic haemochromatosis. In 15 unrelated patients the frequency of HLA-A3 was 80% compared with 24% for 600 unrelated individuals from South Wales. The most common haplotype involved is probably HLA-A3, B7. DNA was prepared from leucocytes from 12 of these patients and from 85 normal subjects. After digestion with Taq1, electrophoresis, and Southern blotting, class I sequences were detected by hybridisation to an HLA class I probe (pHLA-A). Of the 34 restriction fragments detected, 22 were polymorphic. Particular fragments correlated with the presence of HLA-A antigens A1, 2, 3, 10, 11, w19, and 28, but there was little correlation with B antigens. Restriction fragment patterns specific for haemochromatosis were not found with TaqI or during less extensive studies with other restriction enzymes. No differences in restriction fragment patterns were found between four patients and four normal subjects apparently homozygous for HLA-A3 and B7. Examination of Southern blotting patterns for genomic DNA from patients and normal subjects with a panel of 12 restriction enzymes and a probe for the H ferritin gene (pDBR-2) revealed no polymorphisms associated with either idiopathic haemochromatosis or particular HLA phenotypes. These studies provide no support for either HLA class I genes or the H ferritin gene as candidates for the haemochromatosis gene.

DNA Restriction Enzymes↗

PubMed2004

HLA class II and class I polymorphism in Venezuelan patients with myasthenia gravis.

Oligotyping performed among ethnically mixed Venezuelan patients with myasthenia gravis (MG) and controls has revealed positive associations of HLA class I A*31, B*08, B*39, B*40, C*15, C*17, and class II DRB1*09 and negative associations of DQB1*06 and DQA1*02 with the disease. Sequential removal of human leukocyte antigen B (HLA-B) alleles when relative predispositional effects (RPEs) were looked for demonstrated that B*08 is the allele group with the largest contribution in the overall MG patients followed by B*39 and B*40. Several specificities (A*31, B*08, C*17, DRB1*03, DQA1*05, and DQB1*02) indicated increased frequencies among patients with thymic hyperplasia versus patients without hyperplasia or controls. Tests to identify alleles with the strongest association to MG in our patients detected DRB1*13 and B*38 as possible predisposing secondarily associated alleles in patients with hyperplasia. The associations observed disappear after Bonferoni correction of probability values and have been described in patients of Caucasian and/or Oriental ethnic background. Thus, our results reflect the heterogeneity of our population and of the patients tested and suggest a limited influence of several HLA genes in this heterogeneous disease or that these might be only markers of nearby non-HLA genes responsible for the susceptibility or resistance effect.

Adult↗

PubMed1992

Identification of residues involved in polymorphic antibody binding epitopes on HLA-DR molecules.

Based on previous studies it was predicted that amino acids 4 or 25 of the DR4 beta 1 and DR7 beta 1 chains are involved in polymorphic antibody binding epitopes on DR4 or DR7 molecules. These predictions were tested by analyzing monoclonal antibody (mAb) binding to transfectants expressing mutant DR4 beta 1 or DR7 beta 1 chains with single amino acid substitutions at positions 4 or 25. Antibody binding to transfectants expressing additional DR4/7 beta 1 hybrids was also analyzed to assess further the contributions of four segments of the DR4 beta 1 or DR7 beta 1 chains: amino acids 1-20, 21-40, 41-97, and the beta 2 domain. Single amino acid substitutions at positions 4 and 25 of the DR4 beta 1 chain or DR7 beta 1 chain eliminate binding of several mAb to DR4 or DR7 molecules, documenting that these residues are involved in antibody epitopes. However, the data with the hybrid DR4/7 beta 1 chains indicate that some of these epitopes require contributions from both segments 1-20 and 21-40 of these DR beta chains, whereas other epitopes can be generated by placing the appropriate segment in the context of the other DR beta chain. In addition, the data with other mAb indicate that their epitopes are determined primarily by sequences within the 41-97 segment or in the beta 2 domain.

Amino Acids↗

PubMed1996

World distribution of HLA alleles and implications for disease.

The high level of polymorphism of the HLA system makes it useful for the study of diversity in different populations. However, its relationships with disease susceptibility, resistance and progression impose selective pressure on population frequencies that must be taken into consideration. These relationships allow useful studies on the genetic susceptibility to disease, which can be studied further and may provide us with another tool with which to examine the history of populations.

Alleles↗

PubMed2005

Emerging new alleles suggest high diversity of HLA-C locus.

Human leukocyte antigen (HLA)-C has only recently emerged as an important transplantation antigen and as a receptor for natural killer cells. Over the last few years, sequence-based typing (SBT) revealed the true diversity of HLA-C locus; however, the frequency at which new alleles are detected still remains high. During routine SBT of 3500 samples for the National Marrow Donor Program, we have identified 20 new HLA-C alleles reported in this article in 26 individuals. New variants have been characterized by direct sequencing of polymerase chain reaction product obtained by allele-specific amplification of potential new alleles. Most of the new alleles carry coding substitutions of residues located within the antigen-binding groove. The substitutions are predominantly located in the alpha2-helix which is consistent with the unique to HLA-C conservation of alpha1-helix. Seven new alleles, or 35%, have been identified in African Americans, two of them in three and four individuals each, suggesting that these alleles may not be rare. This observation reflects the fact that the minority groups, previously under-represented in the HLA research pools subjected to SBT, now begin to emerge as a main source of new HLA-C alleles. This study further confirms that HLA-C locus is at least as polymorphic as HLA-A and HLA-B.

Alleles↗

PubMed1990

[Use of monoclonal antibodies in HLA immunology].

The author gives an account of the classification and use of HLA monoclonal antibodies. In experimental work the author demonstrates the contribution of investigations of the expressivity of histocompatible antigens class I and II and their changes in sound and tumourous tissues. In clinical practice they are important in particular in transplantology--cleaning of bone marrow, follow up of the GvH reaction, monitoring of patients. HLA monoclonal antibodies serve to reveal the polymorphism in the HLA sphere and the follow up of general biological laws.

Antibodies, Monoclonal↗

PubMed2000

The association of HLA-DM genes with rheumatoid arthritis in Eastern France.

In this study, the polymorphisms of the HLA DMA and DMB genes in patients with rheumatoid arthritis (RA) were examined.DMA and DMB typing was performed in 120 white RA patients from eastern France and 100 healthy controls, using PCR-SSO (sequence specific oligonucleotide probes) method for DMA determination and PCR-RFLP (restriction fragment length polymorphism) method for DMB typing. All patients and controls had been HLA DRB1* genotyped.DMA*0103 was found significantly increased in RA patients (RA vs. controls: 18.3% vs. 4%) (p(corr) = 0.004; OR: 5.39; CI: 1.67-19.23). A decreased frequency of DMA*0102 was also observed in the RA group (RA vs. controls: 18.3% vs. 31%), but not significantly. There were no differences in the prevalence of DMB alleles between RA and controls. The patients and the controls were then stratified according to the expression of the HLA DRB1* RA-linked alleles (DRB1*01 and *04) and this allowed us to find no linkage disequilibrium between DMA*0103 and DRB1*01 or *04 alleles. Finally, most DMA*0103 patients were positive for rheumatoid factors and had extraarticular involvement such as subcutaneous nodules. Thus, our results suggest that DMA*0103 could be an additional genetic factor for RA susceptibility in French whites.

Adolescent↗

PubMed2001

[The study on human leucocyte antigen DQ region genes polymorphism in unexplained habitual abortion patients].

OBJECTIVE: To investigate whether human leucocyte antigen DQ (HLA-DQ) genes polymorphism are related to the susceptibility to unexplained habitual abortion. METHODS: HLA-DQA1 and HLA-DQB1 gene typings are performed by polymerase chain reaction-restrictive fragment length polymorphism(PCR-RFLP) technique in 32 cases of unexplained habitual abortion and 54 women with normal pregnancy history. RESULTS: In unexplained habitual abortion group, the frequency of DQB1 * 0604, 0605 allele is increased significantly compared with that of controls(12.5% and 2.8%, P < 0.05) and the frequency of DQB1 * 0501, 0502 allele is decreased significantly (3.1% and 11.1%, P < 0.05). The frequency of DQA1 alleles do not differ significantly between two groups. Furthermore, the frequency of DQA1 * 01/DQB1 * 0604,0605 haplotype in patients is significantly increased than that of controls (12.5% and 2.8%, P < 0.05). CONCLUSION: The results suggest that DQB1 * 0604,0605 allele and DQA1 * 01/DQB1 * 0604,0605 haplotype may be a susceptible gene and haplotype of unexplained habitual abortion, while DQB1 * 0501,0502 allele may be a protective factor for habitual abortion.

Abortion, Habitual↗