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PubMed1988

HLA-DR expression by adrenocortical cells of the zona reticularis: structural and allotypic characterization.

We previously reported that human adrenocortical cells in the zona reticularis of normal glands express antigenic determinants recognized by HLA-DR monoclonal antibodies (MoAbs). In the present study, it is shown that these adrenocortical HLA-DR determinants are present on glycoproteins having similar structural characteristics, regarding subunit composition and molecular weight, to those of HLA-DR molecules present on immunocomponent cells. Furthermore, adrenocortical HLA-DR molecules include serologically-defined genetically-appropriate allotypic specificities, detectable by immunostainings with both HLA-DR human alloantisera and MoAbs against polymorphic HLA-DR determinants. The finding of a normal expression of HLA-DR antigens by these highly differentiated and biosynthetically active endocrine cells gives support to the notion that MHC class II molecules may perform biological functions in addition to those related to the immune response.

Adrenal Cortex↗

PubMed1992

Alloantisera can detect some of the variants of HLA DRw13 identified by oligotyping.

Oligotyping has revealed a considerable polymorphism of HLA DRw13; so far, 5 alleles coded by DRB1 have been identified. An even greater number of haplotypes are apparent when considering the association of DRw13 with alleles coded by DRB3 and DQB1. Serology can now define some of these variants which had formerly escaped detection. We have tested by serology and by oligoprobes 66 genotyped Caucasoid cells comprising the known DR and DQ alleles. Among the 28 DRw6 cells, 10 different haplotype patterns were selected, of which 8 concern DRw13 and 2 DRw14. Four variants of DRw13 were represented: DRB1 *1301, *1302, *1303 and *1305 associated with usual and with uncommon alleles belonging to DRB3 and to DQB1. We have centered our analysis on 19 sera of the XIth Workshop defining DRw6. Two sera (639, 826) were noteworthy since they reacted with certain subtypes of DRw13 and with DRB1 *1102, *1103 only, the other DR specificities remaining negative.

Amino Acid Sequence↗

PubMed2006

HLA and MICA associations with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive tumour arising from the epithelial lining of the upper aerodigestive tract. The precise mechanisms involved in the pathogenesis of HNSCC have not been elucidated. Previous studies observed aberrant HLA expression patterns on HNSCC tumour cells and this study focused on the allelic polymorphism of HLA genes and the MHC class I chain related gene A (MICA) and HNSCC. We investigated whether associations with HLA and/or MIC alleles or haplotypes are involved in the pathogenesis of HNSCC and could explain the observed HLA expression patterns. Patients and controls were typed for HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 with sequence specific priming (SSP), supplemented with sequencing based typing (SBT). MICA allelic polymorphism was included and MICA allele assignment was based upon the combination of high resolution SBT of exons 2-4 in combination with repeat analysis and nucleotide polymorphism of exon 5. HLA-B *35 (p=0.014, OR=0.31) and HLA-B *40 (p=0.013, OR=2.9) were significantly associated in respectively the metastasized patients and the oral cavity patients. In addition, the HLA-B *40-DRB1 *13 haplotype (p=0.016, OR=4.1) was more often observed in the oral cavity patient group. The biological significance of the prevalence of specific HLA haplotypes in patients with oral cavity HNSCC and metastasizing HNSCC requires further investigation.

Alleles↗

PubMed2004

High prevalence of coeliac disease in siblings of children with type 1 diabetes.

UNLABELLED: Coeliac disease has been shown to occur more frequently among first-degree relatives of diabetic patients than in the general population. Our objective was to assess the prevalence of endomysium antibodies (EMA) in non-diabetic siblings of Czech diabetic children and to evaluate the effects of HLA-DQ polymorphisms in determining the genetic susceptibility to coeliac disease (CD) in these subjects. We investigated 240 siblings of diabetic children from 213 families (125 males and 115 females, aged 12.6+/-4.9 years, mean +/- SD). All subjects were tested for the total IgA level to exclude IgA deficiency, and for endomysium IgA to disclose CD. In five IgA-deficient subjects, anti-gliadin IgG was used instead. Small bowel biopsy was offered to subjects with confirmed positive EMA. The HLA-DQA1, -DQB1 genotypes were determined using PCR-SSP. Positive EMA were found in 9/240 (3.8%) subjects (three males, six females). The biopsy confirmed CD in six children, two had a normal mucosal finding and one refused the biopsy. The HLA-DQ2 polymorphism was more frequent among siblings with EMA (seven of nine) than in siblings without EMA (33%), corrected P = 0.031. CONCLUSION: The 3.8% frequency of coeliac disease found in siblings of diabetic children is close to the 4.3% found previously in Czech children with type 1 diabetes mellitus and is substantially higher than the rate in the healthy children population.

Adolescent↗

PubMed2000

HLA and other host factors in transfusion-acquired HIV-1 infection.

The host and viral factors that underlie infection with HIV-1 vary considerably with some individuals progressing to AIDS within 3 to 5 years after infection, whereas others remain clinically asymptomatic for over 10 years. Host factors that may contribute to disease progression include HLA and allelic variants of the chemokine receptors CCR5 and CCR2, which have been shown to influence both long-term survival and rapid progression. In this study, we have examined the contribution of HLA and polymorphisms in CCR5 and CCR2 to long-term survival in transfusion-acquired HIV-1-infected individuals. We have found a higher number of HLA-A32 and -A25 alleles but a lower number of the HLA-B8 allele in the study group compared with the frequencies seen in the HIV-1-negative Australian caucasian population. However, there was no apparent contribution by allelic variants of CCR5 and CCR2 to long-term survival and the combined influence of HLA and CCR polymorphisms could not be evaluated in this relatively small (n = 20) group of study subjects. The results of this work support a role for HLA in long-term nonprogression though the presence in the Sydney Blood bank Cohort of nef-defective HIV-1 may confound associations between certain HLA alleles and long-term survival in the face of infection with HIV-1.

Adult↗

PubMed1999

Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism.

We analyzed the origin of allelic diversity at the class II HLA-DRB1 locus, using a complex microsatellite located in intron 2, close to the polymorphic second exon. A phylogenetic analysis of human, gorilla, and chimpanzee DRB1 sequences indicated that the structure of the microsatellite has evolved, primarily by point mutations, from a putative ancestral (GT)x(GA)y-complex-dinucleotide repeat. In all contemporary DRB1 allelic lineages, with the exception of the human *04 and the gorilla *08 lineages, the (GA)y repeat is interrupted, often by a G-->C substitution. In general, the length of the 3' (GA)y repeat correlates with the allelic lineage and thus evolves more slowly than a middle (GA)z repeat, whose length correlates with specific alleles within the lineage. Comparison of the microsatellite sequence from 30 human DRB1 alleles showed the longer 5' (GT)x to be more variable than the shorter middle (GA)z and 3' (GA)y repeats. Analysis of multiple samples with the same exon sequence, derived from different continents, showed that the 5' (GT)x repeat evolves more rapidly than the middle (GA)z and the 3' (GA)y repeats, which is consistent with findings of a higher mutation rate for longer tracts. The microsatellite-repeat-length variation was used to trace the origin of new DRB1 alleles, such as the new *08 alleles found in the Cayapa people of Ecuador and the Ticuna people of Brazil.

Alleles↗

PubMed2006

[Distribution of HLA-A, -B allele and haplotype polymorphism in the Tu nationality of Hubei province in China].

OBJECTIVE: To investigate the genetic diversity in Chinese populations. And HLA-A, -B alleles and haplotypes of 190 unrelated healthy individuals of Tu nationality from Wufeng county Hubei province were identified for the associated studies of HLA gene polymorphism and disease. METHODS: The high-resolution typing methods--sequence-based typing(SBT) was used to define the most polymorphism of exons 2 and 3 of the HLA-A, -B locus alleles. The allele and haplotype frequencies were calculated by maximum likelihood estimation with Arlequin software. RESULTS: HLA-A, -B alleles were found to be in Hardy-Weinberg equilibrium(P>0.05). A total of 26 HLA-A and 41 HLA-B alleles were detected. The most frequent alleles were A*0201(0.16053), A*110101(0.14737), A*24020101(0.14211), B*4001(0.14737), B*4601(0.13947), followed by A*0207(0.08947), A*0206(0.08158), B*1301(0.07632), B*5801(0.08947), B*1501(0.09737). The frequencies of following alleles to be A*330301(0.05526), B*1502(0.05526), B*3501(0.05263) were all higher than 0.05. The extensive HLA-A-B haplotypes were observed, and the most common haplotypes were A*0202-B*4001(0.04196), A*0201-B*4601(0.03625). CONCLUSION: In the present study, we first analyzed the HLA-A, B gene typing with SBT, all of these results will be the basic and reference data for Tu race, and also will have the applications available to trace the population migration, clinical organ transplantation, disease-associated study, HLA genetic feature and forensic identification.

Alleles↗

PubMed1994

Role of the polymorphic residues in HLA-DR molecules in allele-specific binding of peptide ligands.

Analysis of peptide binding to a set of HLA-DR alleles has allowed the proteins to be segregated into functional subsets, depending on the amino acids at positions 57 and 86 of the beta-chain. DR proteins with glycine at 86 beta and aspartic acid at 57 beta bound a simplified peptide with significantly lower IC50 values than alleles that did not have this combination of amino acids. The size of the amino acid at 86 beta seemed to modify the steric requirements for the single most important side chain of the peptide. Within each of the four subgroups, other polymorphic amino acids define allele-specific binding requirements. These were explored by analyzing the ability of eight different DR alleles to bind 13 known T cell determinants. The side chains in the peptides that seemed to be responsible for allele specificity were determined by correlating their common structural features with complementary polymorphic residues in the binding site. The importance of these residues was tested by incorporating them into a polyalanine backbone, and was confirmed by the ability of these residues to transfer allele specificity to these simplified analogues. Even though polymorphic contacts affected peptide affinity, the majority of the free energy of binding in all cases arose from interactions with the peptide backbone and the single hydrophobic amino acid at the third position. These constraints seem to orient all peptides in a similar location, forcing them to adopt a closely related conformation in the binding site. The corresponding side chain in each peptide contacts the same pocket in the binding site, regardless of the allele. This apparent similarity should allow any DR allele to be analyzed by extrapolation from the DR1 crystal structure.

Alleles↗

PubMed1985

Haplotype study on C4 polymorphism in Japanese. Associations with MHC alleles, complotypes, and HLA-complement haplotypes.

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A,-B,-C,-DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2, 0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1. C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Alleles↗

PubMed1991

DNA sequence analysis and restriction fragment length polymorphism (RFLP) typing of the HLA-DQw2 alleles associated with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a blistering autoimmune skin disease associated with a 95-100% incidence of the HLA class II antigen HLA-DQw2. Although the precise role of this antigen in the pathogenesis of DH is unclear, one theory proposes that patients with DH possess a molecularly unique subtype of the HLA-DQw2 antigen that causes immune abnormalities eventuating in the clinical manifestations of DH. To test this hypothesis, we performed DNA sequence analysis on the highly polymorphic HLA-DQB1 and HLA-DQA1 loci of eight patients with dermatitis herpetiformis. All DQB1 alleles sequenced were identical to the previously described HLA-DQB*0201 allele from HLA-DQw2 normal subjects. In addition, DQA1 alleles sequenced were identical to those alleles previously associated with HLA-DQw2 (DQA*0201, DQA*0501). These data document that although HLA-DQw2 appears to be a necessary element in the pathogenesis of DH, the development of DH is not dependent on the presence of a unique HLA-DQw2 antigen. HLA-DQ allelic typing by restriction fragment length polymorphism analysis of PCR-amplified HLA-DQA1 and HLA-DQB1 fragments was also performed in ten patients with DH to determine the allelic distribution among both HLA-DR3 (eight patients) and non-DR3 (two patients) DH patients. At the HLA-DQ beta chain locus, all patients possessed the DQB1*0201 allele. At the HLA-DQ alpha chain locus, all HLA-DR3 patients and one non-DR3 patient displayed a pattern consistent with the DQA1*0501 allele, whereas one non-DR3 patient displayed a pattern consistent with the DQA1*0201 allele. These data document that patients with DH do not express a unique HLA-DQw2 heterodimer, that the HLA-DQw2 molecules present in patients with DH have no DNA sequence differences from those found in normal HLA-DQw2 subjects and therefore that susceptibility to DH is not due to a unique HLA-DQw2 molecule.

Alleles↗

PubMedDate not supplied

HLA-DR, DQ and DP typing using PCR amplification and immobilized probes.

A simple, rapid, and precise method of typing HLA class II polymorphism would be valuable in the areas of disease susceptibility, tissue transplantation, individual identification and anthropological genetics. Here we describe a method of analysing class II sequence polymorphism based on polymerase chain reaction (PCR) amplification and hybridization with oligonucleotide probes. One valuable property of sequence-based HLA typing strategies, like oligonucleotide probe hybridization, is that they reveal how and where two alleles differ, not simply that they can be operationally distinguished. The nature and location of HLA polymorphisms appears to be critical in disease association studies and are likely to be important in tissue typing for transplantation. New alleles at the DRB1, DPB1 and DQB1 loci are likely to be identified as this technology is applied to more and more samples, particularly in non-Caucasian ethnic groups. A new allele is uncovered as an unusual pattern of probe binding and then confirmed by sequencing. This pattern is observed because class II polymorphism is localized to specific regions and virtually all 'new' alleles have polymorphisms in the region of probe binding. Obviously, any new allele with a new polymorphic sequence in a region for which typing probes are not available would not be revealed by oligonucleotide typing. With the PCR primers and probes described here, 7 DQA1 alleles, 15 DQB1 alleles, 18 DPB1 alleles, and 32 DRB1 alleles are distinguished. Additional primers and/or probes can, of course, increase the allelic discrimination of oligonucleotide dot blot typing. These horseradish peroxidase (HRP)-labelled oligonucleotide probes are stable (greater than 2 years when stored at 4 degrees C) and the typing system is simple and robust. Over 500 samples from the CEPH pedigrees (unpublished data; A. B. Begovich, et al., manuscript in preparation) and greater than 1000 unrelated samples have been typed by this procedure. Although this dot blot/oligonucleotide hybridization procedure is a powerful and precise method of HLA class II typing, the complexity of the procedure increases as the number of probes required for analysis increases. The reverse dot blot method, based on an array of immobilized probes, allows the typing of individual samples in one single hybridization reaction. In this approach, a panel of unlabelled oligonucleotides are immobilized to a nylon membrane. The PCR product is labelled during the amplification reaction by using biotinylated primers and hybridized to the membrane. The presence of bound PCR product specifically hybridized to a given probe is detected using streptavidin-HRP conjugates and either chromogenic or chemiluminescent substrates.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMedDate not supplied

[Genes, polymorphism and function of the HLA gene region].

Great biological significance of the HLA complex and its impact on practical medicine impels researchers to study it, the result of which is an annual expansion of our knowledge on the system. The polymorphism of the HLA complex has increased--altogether 664 alleles are officially recognised. The genetic defect leading to the bare lymphocyte syndrome was elucidated, too--the mutations in genes coding transcription factors RFX5 and CIITA are responsible for. Also the role of HLA-DM antigens in the exogenous pathway of antigen presentation was elucidated. They are principle molecules which dislodge CLIP from the groove of HLA class II molecules leaving it free to accommodate more suitable immunogenic peptide. It was also discovered that HLA class I antigens are target structures for NK-cells. NK-cell receptors recognising them transduce negative signals switching their cytotoxic activity off. (Fig. 8, Tab. 1, Ref. 34.)

Alleles↗

PubMed1988

Functional polymorphism of each of the two HLA-DR beta chain loci demonstrated with antigen-specific DR3- and DRw52-restricted T cell clones.

HLA-DR3- and HLA-DRw52-associated functional polymorphism was investigated with selected tetanus toxoid (TT)-specific T cell clones. We have shown earlier that HLA-DR antigens are encoded by two distinct loci, DR beta I and DR beta III. The alloantigenic determinant(s) defined by the serological HLA-DR3 specificity map to the former, while the supratypic HLA-DRw52 determinants map to DR beta III. Furthermore, we have recently recognized by DNA sequencing three alleles of HLA-DRw52 at locus DR beta III, referred to as 52 a, b, and c. Our objective was to correlate the pattern of T cell restriction with the gene products of individual DR beta chain loci and with the three newly described alleles of locus DR beta III. Among the selected T cell clones, 5 reacted exclusively when TT was presented by HLA-DR3+ APCs (TT-DR3-APC). In contrast, two T cell clones were stimulated by TT-DRw52-APC. More specifically, these two T cell clones (Clones 10 and 16) were stimulated by different subsets of TT-DRw52-APC. Clone 16 responded to some DR3 and TT-DRw6-APC, while clone 10 was stimulated by other TT-DR3 and TT-DRw6, and all TT-DR5-APC. This same pattern of DRw52 restriction was found in panel, as well as in family studies. Because this suggested a correlation with the pattern of DRw52 polymorphism observed earlier by DNA sequencing and oligonucleotide hybridization, the APC used in these experiments were typed for the 52 a, b, and c alleles of locus DR beta III by allele-specific oligonucleotide probes. This distribution overlapped exactly with the stimulation pattern defined by the T cell clones. Clone 16 responded to TT-52a-APC, clone 10 to TT-52b-APC, and both clones to a TT-52c-APC. The response of the T cell clones was inhibited differentially by mAbs to DR. Raising TT concentration, or increasing HLA-class II expression with INF-gamma both affected the magnitude of response of the TT-specific clones but did not modify their specificities. These results demonstrate that a restriction specificity can be attributed to the DR beta III locus and illustrate the functional relevance of the polymorphism observed at this locus. This is of special interest in view of the striking difference in the pattern of structural diversity among alleles of DR beta I and DR beta III.

Alleles↗

PubMed2006

TNFa-e microsatellite, HLA-DRB1 and -DQB1 alleles and haplotypes in Brazilian patients presenting recently diagnosed type 1 diabetes mellitus.

TNF microsatellite and HLA class II polymorphisms were studied in 28 recently diagnosed Brazilian patients presenting type 1 diabetes mellitus (T1DM) and in 120 healthy controls. TNFa-e and HLA-DRB1/DQB1 alleles were identified using sets of sequence-specific primers. Compared to controls, the DRB1*03 and DQB1*02 allele groups, TNFa1 allele, and the TNFa4-b5-c1-d4-e3 and TNFa10-b5-c1-d4-e3 haplotypes were overrepresented in patients. TNF microsatellite together with HLA polymorphisms is associated with type 1 diabetes in Brazilian patients, corroborating the participation of the MHC genes in disease susceptibility.

Adolescent↗

PubMed2005

Selection of unrelated donors for hematopoietic cell transplantation.

Transplants from partially human leukocyte antigens (HLA)-incompatible relatives are associated with an increased risk of graft rejection, graft-versus-host disease (GVHD), and lower survival, which are correlated with the degree of disparity. For patients without an HLA-matched sibling, the preferred donors of hematopoietic cells remain HLA-compatible, unrelated volunteers. The hurdle for a wider application of hematopoietic cell transplantation is the enormous polymorphism of HLA genes that makes unrelated individuals unlikely to match randomly. The identification of functional HLA genes and their polymorphic alleles, the development of precise and effective tissue typing techniques, and the assembly of large volunteer registries worldwide that exceed 9 million HLA-typed individuals have made it feasible to transplant hematopoietic stem cells from well-matched, unrelated donors for most patients.

Graft Rejection↗

PubMed1986

The use of DNA polymorphisms demonstrated by means of the HLA system.

The advances reached by using DNA polymorphisms (restriction fragment length polymorphisms) in blood group serology are demonstrated by means of the HLA system. The potentialities for various applications (e.g. better definition of alloantigens, association with diseases, paternity testing, forensic medicine or genetic counselling) are mentioned.

DNA↗

PubMed1996

HLA class II DNA typing in Buerger's disease.

To analyze the genetic factors involved in the pathogenesis of Buerger's disease, the polymorphisms of HLA class II genes (HLA-DP, -DQ and -DRB) were investigated in 36 patients using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. HLA class I (B54 and B52) and HLA class II (DQ alleles) genes were also typed by polymerase chain reaction-sequence-specific oligonucleotide probe (PCR SSOP) method to confirm alleles. PCR-RFLP typing revealed that the frequencies of HLA class II genes, DRB1*0405, DQB1*0401, DQA1*03 and DPB1*0501, were significantly increased in the patients with Buerger's disease compared with the healthy controls. Further, DNA typing confirmed that HLA-B54 was associated with Buerger's disease. These results suggested that the haplotype of HLA-B54-DRB1*0405-DQB1*0401- DQA1*03-DPB1*0501 was associated with Buerger's disease in Japanese population.

Adult↗

PubMed2005

The HLA-G genotype is associated with IL-10 levels in activated PBMCs.

Human leukocyte antigen (HLA)-G is an MHC class Ib molecule that is expressed at the feto-maternal interface during pregnancy. However, recent results have also shown that it may have important functions as an immuno-modulatory factor in adult life. Differences in the pattern of alternative splicing and in the stability of HLA-G mRNA transcripts have been associated with HLA-G polymorphisms, especially a 14 bp deletion/insertion polymorphism in the 3' untranslated region of the HLA-G gene. We have investigated the secretion of HLA-G5/soluble HLA-G1 and interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated peripheral blood mononuclear lymphocytes (PBMCs) in relation to the HLA-G 14 bp genotype. No HLA-G5/sHLA-G1 could be detected in the non-activated control PBMC culture media, and there were no significant differences among the three HLA-G 14 bp genotypes regarding IL-10 concentrations. In LPS-activated PBMC cultures, no significant differences among the three HLA-G 14 bp genotypes regarding HLA-G5/sHLA-G1 concentrations were observed. However, this was in contrast to the IL-10 levels (P=0.0004, Kruskal-Wallis test). The +14/+14 bp PBMC samples expressed higher levels of IL-10 when compared to the -14/+14 bp genotype and the -14/-14 bp genotype. Interestingly, the IL-10 G/G polymorphism at position -1082 was more frequent in the +14/+14 bp genotype (P=0.024, chi2 test). These results support an autocrine loop between HLA-G5/sHLA-G1 and IL-10 expression in activated PBMCs, which may result in higher IL-10 levels in +14/+14 bp HLA-G genotypes.

3' Untranslated Regions↗