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PubMed2006

[HLA-DM gene polymorphism in Cantonese with condyloma acuminata].

OBJECTIVE: To study the polymorphism of HLA-DM gene in Cantonese patients with condyloma acuminata(CA) and determine the susceptible genetic factors of CA. METHODS: DMA and DMB typing was performed in 98 Cantonese patients with CA and 93 healthy controls using restriction fragment length polymorphism method. RESULTS: The gene frequencies of DMA*0101 and DMB*0101 were significantly higher in the patients than in the controls (P<0.05 and P<0.01, respectively), and gene frequency of DMA*0102 was lower in patients than in the controls (P<0.01). Genotype frequencies of HLA-DM showed no significant difference between CA patients and the controls (P>0.05). CONCLUSION: DMA*0101 and DMB*0101 alleles may be the susceptibility genes or closely linked to the susceptibility gene in Cantonese patients with CA.

Adolescent↗
PubMed2006

Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function.

Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand-receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR-HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.

Female↗
PubMed1991

HLA complement markers in Italian narcoleptic patients with special emphasis on BfF subtyping.

Thirty narcoleptic patients (29 out of 30 of Mediterranean origin) were studied for HLA polymorphisms (only 24 were investigated for HLA class III). We found that these patients are characterized by DR2, DQW2 phenotype (p less than 0.0001) as those of Anglo-Saxon origin so far studied and by the complotype: BfS, C4A3, C4B1. Just 1 of 7 BfF patients has the Fb subtype detected by isoelectric focusing technique (p = 0.007). The only patient of Black origin (his mother is Eritrean) is completely different from other patients (DR3,5; DQW2,W3; C4A4,4; C4B1,2), supporting the hypothesis that it is not the DR2, DQW1 phenotype per se involved in this syndrome. Subdividing the subjects according to different clinical features, we cannot demonstrate genetic heterogeneity.

Adolescent↗
PubMed2005

Association of clinical features with HLA in chronic pulmonary thromboembolism.

The aetiology of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown and may be heterogeneous, because there are several ethnic differences in the clinical characteristics of CTEPH. Female predominance and a higher ratio of chronic to acute pulmonary thromboembolism have been reported in Japan as compared with the USA. Because such ethnic differences may be controlled by genetic factors, the current study investigated HLA polymorphisms in Japanese patients with CTEPH. HLA typing by serological and/or DNA typing methods was performed (for HLA-A, B, DPB1, DRB1) in 80 patients and 678 controls, and the association of clinical characteristics with HLA alleles was studied. The frequencies of HLA-B*5201 (40 versus 24%) and DPB1*0202 (19 versus 6%) were significantly higher in the patients. HLA-B*5201 positive patients showed a significant female predominance. Total pulmonary vascular resistance and mixed venous oxygen tension were better in the HLA-B*5201 positive patients. In contrast, cardiac index and gas exchange parameters were worse in the HLA-DPB1*0202 positive patients. In the patients carrying HLA-B*5201 and/or -DPB1*0202, the frequency of deep vein thrombosis was significantly lower than the other patients. These observations suggested that both the susceptibility and clinical characteristics of chronic thromboembolic pulmonary hypertension were controlled in part by the HLA-B and -DPB1 loci.

Adult↗
PubMed1986

Highly polymorphic products of both HLA-DR and HLA-DQ genes contribute to the polymorphism of the HLA-DRw13 haplotype.

We studied the polymorphisms of HLA-DR and HLA-DQ products from HLA-DRw13 haplotypes by analyzing the restriction of influenza A-specific cloned T cells from an HLA-DRw13,DQw1,Dw19 homozygous individual. The results show that some functional epitopes, which can be borne by either HLA-DR or HLA-DQ molecules, are strictly correlated with the HLA-Dw19 subtype of HLA-DRw13. This clearly indicates that both HLA-DR and HLA-DQ products contribute to the HLA-Dw19 subdivision of HLA-DRw13. At least two different restricting epitopes are borne by DR products: one is correlated with the HLA-DRw13 serologically defined specificity, which includes Dw19 and Dw18 haplotypes; the other is correlated with the only HLA-Dw19 subtype of HLA-DRw13. Restricting epitopes borne by DQ molecules have been found on Dw19 cells only. DQ-restricted clones were unable to react with DQw1 APC of any other haplotypes tested, including DR1, DR2-long, DR2-short, and DRw14, demonstrating a high degree of functional polymorphism among the serologically defined DQw1 specificities.

Antigen-Presenting Cells↗
PubMed1999

Little evidence of HLA-G mRNA polymorphism in Caucasian or Afro-Caribbean populations.

HLA-G is a nonclassical class I MHC molecule of unknown function expressed on human trophoblast. The level of polymorphism at the HLA-G locus is of considerable importance, since the paternally inherited gene product is exposed to the maternal immune system during pregnancy. However, previous studies of HLA-G polymorphism using genomic DNA samples have produced conflicting results. Our aim was to investigate polymorphism in trophoblast HLA-G mRNA from pregnancies in ten Caucasian and twelve Afro-Caribbean women by RT-PCR. A similar PCR protocol was also applied to umbilical cord blood genomic DNA from two Caucasian and two Afro-Caribbean neonates. Caucasian cDNA yielded only two different sequences: G*01011, and one containing a previously reported synonymous substitution. Afro-Caribbean samples yielded these sequences as well as one previously reported conservative (leucine-to-isoleucine) substitution. PCR amplification from genomic DNA samples from both populations using previously published primer pairs generated sequences containing multiple substitutions, many of which were nonsynonymous. More than two sequences were produced from genomic DNA from each individual. In contrast, amplification from the same genomic DNA using new primers complementary to exons of the HLA-G gene yielded the same few sequences generated from cDNA. These results suggest that polymorphism at the HLA-G locus is extremely limited in Caucasian and Afro-Caribbean populations. This suggests that spurious polymorphism has been reported in African Americans due to the use of intron-complementary PCR primers on genomic DNA samples. The monomorphic nature of HLA-G may allow trophoblast to carry out the immunological functions of class I-bearing tissues without compromising successful pregnancy.

Africa↗
PubMed2005

Understanding how combinations of HLA and KIR genes influence disease.

Combinations of HLA and killer cell immunoglobulin-like receptor (KIR) genes have been associated with diseases as diverse as autoimmunity, viral infections, reproductive failure, and now cancer. Much as early observations of disease associations with HLA polymorphism preceded a detailed knowledge of HLA recognition by T cell receptors, the recently reported disease associations with HLA-KIR gene combinations beg for a better understanding of the underlying mechanisms.

Genes, MHC Class I↗
PubMed1997

HLA-G gene polymorphism segregation within CEPH reference families.

HLA-G, a nonclassical HLA class I antigen, presents tissue-restricted expression on human trophoblasts and may play an important role in immune tolerance of mother-versus-fetus. In this work we have demonstrated extensive HLA-G genomic polymorphism within three CEPH reference families, by PCR-SSCP analysis and direct sequencing. Among six unrelated parents we assigned eight HLA-G alleles, seven of which are new. We observed the segregation of HLA-G alleles of heterozygous parents among their offspring that matched the segregation of the HLA class I haplotypes. Only one of the mutations observed was found to be nonsynonymous indicating low polymorphism of the HLA-G molecule.

Alleles↗
PubMed1999

Human papillomavirus type 16 E6 variants in cervical carcinoma: relationship to host genetic factors and clinical parameters.

Infection with human papillomavirus type 16 (HPV-16) confers a high risk for the development of cervical neoplasia. Variants of this virus may interact differentially with host genetic factors, possibly altering the disease course. Thus, HPV-16 E6 variants may differ in their ability to degrade p53 whereas the polymorphic p53 alleles may provide more or less susceptible substrates for the viral oncogene product. Also, E6 variants may differ in immunogenicity by generating different peptides for presentation by polymorphic HLA molecules to specific T cells. This study examines HPV-16 E6 sequence variation in cervical carcinomas from the UK and its relationship to polymorphism of HLA and p53 and to clinical parameters. Sequence analysis of the HPV-16 E6 ORF from 77 tumour biopsies detected the viral prototype sequence in 38% of cases. The most common variation detected was a T to G transition at base pair 350, resulting in an amino acid change from a leucine to a valine. Overall, the frequencies of 350T and 350G sequences were similar (49. 4% and 50.6% respectively). Other mutations of lower frequencies were detected together with and independently of 350G. HPV-16 E6 sequence variation at base pair 350 did not correlate with HLA genotype or clinical outcome. There was no difference in the distribution of p53 proline and arginine alleles between HPV-16-positive cervical carcinoma patients and local controls, and no influence on clinical outcome; however, there was a trend for an increased frequency of p53 arginine homozygotes among the 350T carcinoma patients.

Adult↗
PubMed1989

Histocompatibility antigens in primary and metastatic squamous cell carcinoma of the larynx.

A series of 38 primary laryngeal and hypopharyngeal tumours, 15 lymph-node metastases and normal tissue were evaluated in frozen sections for the expression of MHC class I and II antigens, using monomorphic monoclonal antibodies (MAbs) to HLA-ABC, beta 2-microglobulin, DR, DP, DQ, HLA-B and polymorphic HLA-ABC antigens. Normal distant mucosa of larynx reacted to anti-class I antibodies but not to anti-class II. In 9 primary tumours (23.7%) HLA class I antigens were not observed. The remaining 29 showed a strong reaction to not observed. The remaining 29 showed a strong reaction to anti-HLA-ABC (heavy chain) and anti-beta 2-microglobulin, although in 3 cases out of 29 no staining was observed with anti-HLA-B locus-specific MAbs. These selective losses were confirmed using the corresponding anti-HLA polymorphic MAbs. For HLA class II molecules, only DR was observed in 3 of 38 cases. Defective HLA class I expression statistically correlates with high scores according to Jakobsson's criteria for histopathological tumour grading. Loss of HLA-ABC antigens was most frequent among the cases with poor differentiation (6/8 cases). On the contrary, class II antigen expression was correlated with a well differentiated pattern and a more favourable prognosis (p less than 0.001). We have found differences in HLA class I expression when comparing primary tumours and autologous metastases (3/9 cases). Immunoprecipitation and SDS-PAGE of class I antigens, Northern and Southern blot analyses of MHC class I genes were performed. We have not detected class I gene rearrangement using HLA coding and locus-specific non-coding probes. However, we have found a class I transcription defect that corresponds with a class-I-negative phenotype.

Antibodies, Monoclonal↗
PubMed1999

Distribution of HLA gene and haplotype frequencies in Taiwan: a comparative study among Min-nan, Hakka, Aborigines and Mainland Chinese.

A total of 8,497 blood samples were typed for HLA-A, B, DR and DQ. Of these, 7,137 Min-nan, 714 Hakka, 535 Mainland Chinese (152 from North China, 211 from Middle China, and 172 from South China) and 111 Aborigines were randomly selected from Tzu Chi Taiwan Marrow Donor Registry (TCTMDR). Differences in HLA gene and antigen frequencies have been observed between various ethnic groups of the Chinese population in Taiwan. The phylogenic tree shows Taiwan Aborigines and Javanese cluster together; Min-nan shares a common cluster with Hakka, Southern Hans and Thai; and Northern Hans shares a cluster with Middle Hans. The separation between Northern/Middle and Southern Chinese Hans support the idea that Northern and Southern Chinese have different genetic background. Aborigines appeared to be quite distinct in the distribution of a majority of the class I and class II antigens. High frequency of HLA-A24 (60.4%) and relatively restricted HLA polymorphisms are noted in Aborigines. The HLA haplotypes with high frequency in Aborigines included A24-B60-DRB1*04, A24-B60-DRB1*14, A24-B48-DRB1*04, and A24-B48-DRB1*14, which are different from the other ethnic groups. Although the phylogenic tree separates Aborigines and Han Chinese populations, 4 out of 20 most common HLA-A, -B, and -DR haplotypes presented in both Aborigines and Han Chinese may reflect an ancient common origin or intermixture between early settlers of Han Chinese and Taiwan Aborigines. The results in this study are essentially a summary of the observed gene/haplotype frequencies and differences among various ethnic groups in Taiwan.

Asian People↗
PubMed1991

[Monoclonal antibodies and T-cell clones against HLA antigens: production and characterization].

The production and characterization of 21 monoclonal antibodies (MoAbs) resulting from the immunization of Balb/c mice with human lymphoblastoid cell lines is reported. Twelve MoAbs seem to be detecting an HLA polymorphic determinant. Four MoAbs are recognizing monomorphic Class I molecules and another MoAb detects HLA Class II molecules. These results were confirmed by ELISA, cytotoxicity, immunofluorescence and immunoprecipitation. Class and subclass of the MoAbs were assessed by Ouchterlony analysis. Twenty two T cell clones were additionally generated by limiting dilution of lymphocytes stimulated by allogeneic peripheral blood lymphocytes on mixed lymphocyte cultures. Five of these clones were characterized, testing each one for its ability to proliferate in response to a panel of lymphoblastoid cell lines. It was found that they detect the HLA-A9, A23, A29-31, Bw62 and DR7 specificities respectively. These results indicate that the generation of cellular monoclonal reagents is apparently more productive than the generation of murine MoAbs specific for polymorphic variants of HLA antigens.

Animals↗
PubMed2006

HLA class II polymorphisms in Spanish melanoma patients: homozygosity for HLA-DQA1 locus can be a potential melanoma risk factor.

BACKGROUND: The association of melanoma with HLA class II loci is under extensive debate. Different investigators have found discrepant results due to, at least in part, sample size, patient series heterogeneity, choice of control population and differences in the techniques employed for the detection of HLA antigens and alleles. OBJECTIVES: This study was designed to analyse the possible association of melanoma with HLA class II loci with regard to different clinic pathological factors and to investigate other risk factors for melanoma susceptibility, such as HLA homozygosity. PATIENTS AND METHODS: HLA-DRB1, -DQA1 and -DQB1 genotyping was performed for 117 eastern Spanish patients presenting with primary melanoma. RESULTS: Although there were no significant alterations in the phenotypic frequencies of HLA-DQA1, -DQB1 or -DRB1 alleles in any subgroup of patients when compared with controls, patients exhibited a statistically significant increase in HLA-DQA1 homozygosity rate. This DQA1 homozygosity-specific association was particularly dependent on some features in melanoma patients such as light hair colour, skin type I or II, early age at diagnosis, absence of atypical naevi, or abscence of atypical naevus syndrome phenotype (aetiological fractions about 10-20%). Analysis of homozygosity for single DQA1 alleles showed an increased homozygosity rate for DQA1*0505 and DQA1*0301 in comparison with controls. These DQA1 alleles are in strong linkage disequilibrium with DQB1*0301 in white populations, and DQB1*0301 homozygous individuals were significantly increased in red in or fair-haired patients (relative risk 5.65). CONCLUSIONS: Our results indicate that the contribution of HLA class II alleles to primary melanoma incidence is not significant in the Spanish population. However, homozygosity for the HLA-DQA1 locus (and, perhaps, for the HLA-DQB1*0301 allele) might be considered a potential risk factor for developing melanoma depending on the person's genetic background and, perhaps, on certain environmental conditions.

Adult↗
PubMed2004

Molecular typing of human leukocyte antigen and related polymorphisms following whole genome amplification.

Reliable, high-resolution genotyping of human leukocyte antigen (HLA) polymorphisms is often compromised by DNA samples of suboptimal quality or limited quantity. We tested the feasibility of molecular typing for variants at HLA and neighboring loci using whole genome amplification (WGA) strategy facilitated by the Phi29 DNA polymerase. With little (5-100 ng) starting genomic DNA of varying quality and source materials, WGA was deemed successful in 167 of 169 DNA from 47 cell lines, 100 European Americans, and 22 native Africans. The Phi29-processed DNA provided adequate templates for polymerase chain reaction (PCR)-based analyses of several HLA (A, B, C, DRB1, and DQB1) and related loci (HFE, MICA, and 10 microsatellites) in the 6p24.3-6p21.3 region, with PCR amplicons ranging from 92 to 2200 bp. Five different genotyping techniques resolved and confirmed 364 genotypes when both original and Phi29-processed DNA worked in PCRs. General population genetic analyses provided additional evidence that WGA may represent a reliable and simple approach to securing ample genomic DNA for typing HLA, MICA, and related variants.

Africa↗
PubMed1994

Molecular techniques for typing unrelated marrow donors: potential impact of molecular typing disparity on donor selection.

HLA matching between a bone marrow recipient and donor is one of the major factors influencing transplant success. However, it is not possible to locate an HLA-identical donor for about 70% of patients who might benefit from bone marrow transplantation (BMT). New molecular biological methods for detection of HLA polymorphism currently provide an opportunity to improve HLA matching of unrelated donors as well as a research tool to investigate the relationship between HLA disparity and transplant complications. These molecular HLA typing methods include sequence-specific amplification, hybridization with oligonucleotide probes, heteroduplex formation and direct nucleotide sequencing. Molecular HLA typing is being utilized to address questions regarding the extent of HLA disparity between two unrelated individuals and the effect of HLA disparity that is not detected using conventional HLA typing methods. Accumulating data suggest some HLA disparities may be tolerated while others are very immunogenic. Use of more precise HLA typing may contribute to the success of future transplants utilizing alternative donors. A better understanding of the relationship between HLA disparity and transplant complications may make it possible to relax the stringency of donor matching to make BMT available to larger numbers of patients.

Adult↗
PubMed1998

High resolution genetic typing of the class II HLA-DRB1 locus using group-specific amplification and SSO-hybridisation in microplates.

The HLA-DRB1 locus is one of the most polymorphic HLA class II loci and rapid and accurate typing of this polymorphism is important both in bone-marrow transplantation, analysis of disease association and in forensic medicine. The allelic variation at DRB1 is characterized by combinations of a limited number of amino-acid motifs, reducing the resolution of a typing strategy based on a single PCR and subsequent analysis of polymorphic motifs. In the present paper we describe a strategy for typing of DRB1 based on eight allele-specific PCRs followed by sandwich hybridization to immobilized probes in a microplate format. The combined approach results in a rapid typing system with very high resolution. Using a rapid DNA extraction protocol, a complete HLA-DRB1 typing can be performed in less than a day.

Alleles↗
PubMed1987

Genomic HLA-DQ beta polymorphism associated with insulin-dependent diabetes mellitus. Analysis of possible functional significance.

Twelve insulin-dependent diabetes mellitus (IDDM) patients and healthy controls, who all carried the serologically defined DR3 and DR4 antigens, were compared with respect to other HLA polymorphisms. No significant differences between patients and controls were found by typing for HLA-Dw determinants by homozygous cell typing, nor by studies of their genomic DR beta polymorphism using different restriction enzymes. In contrast, certain DR beta polymorphism using different restriction enzymes. In contrast, certain DR4-associated genomic DQ beta fragments had a significantly different distribution among the IDDM patients than among the controls. Furthermore, when the distribution of all DQ beta-specific fragments which demonstrated polymorphism in our material was taken into account, nine of the 12 DR3, 4 IDDM patients demonstrated a similar DQ beta polymorphism compared with only two out of the 12 DR3, 4 controls (P = 0.006; corrected P = 0.037). Cells from patients and controls who demonstrated this IDDM-associated DQ beta polymorphism stimulated each other significantly less in reciprocal MLC tests, compared with the responses seen when their cells were confronted with cells from the DR3, 4 individuals with other genomic DQ beta polymorphisms.

Adult↗