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PubMedDate not supplied

HLA-DR/Dw matching by PCR fingerprinting: the origin of PCR fingerprints and further applications.

Polymerase chain reaction (PCR) fingerprinting, a new method for the rapid matching of HLA-Dr/Dw allotypes, involves the visual comparison of polymorphic HLA-DRB gene second exon PCR products, resolved in non-denaturing polyacrylamide gels (Bidwell & Hui, 1990). We show here that the satellite DNA bands within PCR fingerprints originate by heteroduplex formation between heterologous DNAs co-amplified by a common PCR primer set. We also present two further applications of the technique which permit discrimination between unrelated HLA-DR/Dw allotypes with similar PCR fingerprints.

DNA Fingerprinting↗
PubMed2003

HLA class II diversity in seven Amerindian populations. Clues about the origins of the Aché.

The study of the HLA variability of Native American populations revealed several alleles specific to one or more of the Latin American indigenous populations. The analysis of Amerindian groups distributed all over the continent might inform about the area of origin and the dispersal of these alleles and shed light on the evolution of this remarkable polymorphism. Moreover, HLA alleles and haplotypes are excellent markers to understand the genetic relationships between populations. For these reasons, we characterized the HLA class II polymorphism in seven South American Amerindian populations and compared the results with those previously reported for other Amerindian groups. The Guarani-Kaiowá (n = 160) and Guarani-Nandeva (n = 87) were from the Brazilian state of Mato Grosso do Sul, the Guarani-M'byá (n = 93) and Kaingang (n = 235) from Paraná state, the Aché (n = 89) from eastern Paraguay, the Quechua (n = 44) from Andean Peru. From Amazonia, a heterogeneous group was analyzed (n = 45). The most frequent alleles and haplotypes are common also in other Amerindian populations. Each HLA-DRB1 allele was typically found in combination with just one DQA1-DQB1 haplotype, most likely as a result of some form of random genetic drift and reduced gene flow from non-Amerindians. The frequency distribution differed significantly among all populations, although differences were less pronounced between the Guarani subgroups. Marker alleles allowed an estimate of European and sub-Saharan African gene flow into these populations: Quechua 23%, Guarani-Nandeva 14%, Kaingang 7%, Guarani-M'byá 4%, Guarani-Kaiowá, Amazonia, and Aché 0%. Interestingly, the DRB1*1413 allele, previously found only among the Guarani-M'byá (frequency 15%), appeared in the Aché (8%). The relationship of the Aché to other Amerindian populations is unclear, and this finding reveals a link with the Guarani. On the basis of genetic distance and the HLA allele/haplotype set, we propose that the Aché are differentiated Tupi-Guarani group, most closely related to the Guarani-M'byá.

Alleles↗
PubMed1984

A new polymorphic determinant distinct from but expressed concomitantly with an HLA-Bw44 specificity.

A new antigenic determinant defined by a monoclonal antibody (6.7) is described which displays restricted expression being present only on the cells of the immunizing donor and his father and not on a panel of over one hundred unrelated HLA-typed cells. The determinant segregated with the HLA haplotypes of the immunizing donor's family and was shown by immunochemical and capping studies to be located on a subpopulation of HLA molecules. Further capping and antibody-blocking studies using HLA-typing alloantisera revealed that the 6.7-reactive determinant was located on the same molecules that expressed the HLA-Bw44 specificity but was a separate epitope to the polymorphic HLA specificity.

Animals↗
PubMed1997

Idiopathic and secondary membranous nephropathy and polymorphism at TAP1 and HLA-DMA loci.

In a previous study on the effects of TAP1 and TAP2 gene polymorphism in kidney allograft recipients, we found no association between graft outcome and recipient/donor TAP1 and TAP2 allele polymorphism or compatibility, but we observed a surprising increased frequency of the TAP1*0201 allele among kidney recipients. This increase was restricted to patients with glomerulopathy. We now report on a larger cohort of 178 patients with membranous nephropathy who were typed for their HLA-DPB1, -DRB1, -DMA, -DMB, LMP2, LMP, TAP1 and TAP2 genes compared with 100 random ethnically matched and healthy unrelated individuals used as controls. The results show a significant increased frequency of two markers in membranous nephropathy patients as compared with controls: firstly the previously recognized increase in HLA-DR3 (59% vs 18%: Pc < 1 x 10(-9), RR = 6.6), secondly a new association with two TAP1 amino acid variants displaying respectively a valine in amino acid position 333 (TAP1-Val-333) and consequently a glycine in position 637 (TAP1Gly-637) due to its strong linkage disequilibrium with Val-333. No linkage disequilibrium was found between TAP1-Val-333 and HLA-DR3. Moreover, we also noticed a decrease of the DMA*0102 phenotype in membranous nephropathy patients. The other HLA-DPB, -DMB, LMP2, LMP7 and TAP2 phenotype frequencies were roughly similar between patients and controls. These results show that the TAP1-Val-333 like HLA-DR3 phenotype is positively associated with membranous nephropathy and that these two risk factors are not cumulative in membranous nephropathy pathophysiology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

HLA class II alpha chain gene polymorphisms in patients with insulin-dependent diabetes mellitus, dermatitis herpetiformis, and celiac disease.

We have investigated DNA polymorphism of the class II alpha chain genes in HLA typed patients with insulin dependent diabetes mellitus (IDDM; n = 79), celiac disease (CD; n = 46), dermatitis herpetiformis (DH; n = 53), and controls (n = 86). Preferential allelic associations of HLA genes and gene products have thus been constructed for susceptibility to these diseases. DR alpha and DQ alpha gene polymorphisms indicated heterogeneity of HLA DR3, DRw6, and DR7, and HLA DR2 and DRw6, respectively. In DR7 positive CD patients a 3.8-kilobase (kb) DR alpha fragment, which correlated with DQw3, was found in only 11% of patients compared with 45% of corresponding controls (P less than 0.05). An increased frequency of a DX alpha genotype UU in all three diseases was found (IDDM 59%, DH 45%, CD 48%, compared to 21% in controls, P less than 0.001), which is not explained solely by the increased frequencies of DR3-DX alpha U. We therefore conclude part of the genetic susceptibility for these three conditions is encoded by genes within the DQ-DX subregion.

Celiac Disease↗
PubMed1986

HLA-DR2-associated Dw subtypes correlate with RFLP clusters: most DR2 IDDM patients belong to one of these clusters.

Two variants of the serologically defined HLA-DR2 specificity have been reported: DR2 long and DR2 short. Distinct HLA-DR2-associated Dw subtypes have been described at the cellular level. In the Israeli population, DR2 individuals may be grouped into three clusters: DR2/Dw2, DR2/Dw12, and DR2/Dw"AZH". A new approach for the study of the polymorphism of HLA class II genes is to investigate restriction endonuclease fragments obtained from genomic DNA with specific class II cDNA probes. Previous analysis of DQ beta restriction endonuclease fragments subdivided the DR2 haplotypes into two subsets: a DQR1-positive subset and a DQR2.6-positive subset. These two subsets behave in the population as alleles that split HLA DQw1. In the present study, we have analyzed class II DQ alpha, DQ beta, and DR beta restriction fragment length polymorphism (RFLP) in HLA-DR2/Dw-typed healthy, unrelated Israeli individuals, as well as in 11 French HLA-DR2 insulin-dependent diabetes mellitus (IDDM) patients and 11 French DR-matched controls. Three DQ beta allelic clusters (DQR2.6, DQR1, and DQR12) were observed among the DR2 haplotypes and clearly correlated with Dw2, Dw"AZH", and Dw12, respectively. The vast majority of the DR2 IDDM patients (9 out of 11) fit into the DQR1 cluster which correlates with Dw"AZH", while only two patients (2 out of 11) belong to the DQR2.6 cluster (Dw2-like). In contrast, among 11 DR-matched healthy controls, 9 belonged to the DQR2.6 cluster and only 2 belonged to the DQR1 cluster. These studies establish the correlation between the DR2-associated Dw subtypes with specific RFLPs, and indicate that the frequency of the DQR1 subset which correlates with Dw"AZH" is increased in DR2 IDDM patients.

DNA Restriction Enzymes↗
PubMed1994

Study of the possible association of HLA class II, CD4, and CD3 polymorphisms with schizophrenia.

In the present study the HLA-DRB and DPB1 alleles as well as CD4 and CD3 polymorphisms were tested in 100 Belgian schizophrenic patients and 204 controls. Our results indicate a significant negative association of the DPB1 0101 allele with schizophrenia (relative risk [RR] = 0.27). Furthermore a significant positive and negative association could be noticed for the CD4*A4 allele and CD4*A7/A8 genotype, respectively (RR 1.79 and 0.47, respectively). These findings suggest that some contribution of HLA class II and CD4 genes to an autoimmune-like pathogenesis in schizophrenia might exist.

Adolescent↗
PubMed1989

Epitope mapping of an HLA-DR-specific monoclonal antibody produced by using human-mouse transfectant cells.

A polymorphic HLA-DR mAb, TAL15.1, was produced against L cells transfected with DR alpha- and beta-chain cDNA from a cell line homozygous for HLA-DRw8. This antibody reacted with DRw8 plus all other DR types except DR3 and DRw52. DR3 and DRw52 differ uniquely from other other DR antigens at position 77 in the beta 1-domain of their beta-chains where there is asparagine instead of threonine. In Western blots the antibody reacted with DR alpha/beta-dimer but not with free alpha- or beta-chains. Two-dimensional gel analysis of a DRw11, DRw52 cell line showed that TAL15.1 immunoprecipitated the DR products. Although it also coprecipitated the DQ beta chain products, flow microfluorimetric analysis with various transfectant cell lines showed that TAL15.1 failed to bind the DQ or DP products tested. We conclude that TAL15.1 is a DR-specific polymorphic antibody whose activity correlates with a specific residue. It has already proved to be a valuable reagent for distinguishing DR3 homozygotes from DR3, DRw6 heterozygotes, which have in the past been difficult to separate.

Amino Acid Sequence↗
PubMed1995

A rare neutral polymorphism in 21-hydroxylase genes as HLA haplotype marker. Evidence for strong founder effect in the Finnish population.

The usefulness of rare neutral gene polymorphisms as an HLA haplotype marker and as a probe for founder effect in small populations was tested by determining the frequency and MHC associations of an NcoI polymorphism in the P450c21 genes in the Finnish population. In the general population, 13% (9 of 70) of samples had the NcoI site. A very strong association with the HLA-B62, Bf*F, C4A*3, C4B*Q0, DRB1*13, DQA1*0103, DQB1*0603 alleles was observed. P450c21A and P450c21B gene-specific amplifications mapped the polymorphic site to both P450c21A pseudogene and P450c21B functional gene of this haplotype in all cases. The majority of haplotypes with the NcoI cutting site found in this population may thus have derived from a single ancestral haplotype. The HLA homozygous cell lines with the NcoI site showed heterogeneous HLA associations. Our results suggest that in small populations the variety of MHC haplotypes may be surprisingly low and rare polymorphisms can serve as informative markers.

Base Sequence↗
PubMed1988

An HLA-A2 population variant with structural polymorphism in the alpha 3 region.

The HLA-A2 antigen expressed by donor OZB can be distinguished from the main HLA-A2.1 subtype by isoelectric focusing - it is one charge unit more acidic - and by some alloreactive T-cell clones but not by cytolytic T lymphocyte lines. The structure of variant OZB has been examined by comparative peptide mapping with A2.1 and radiochemical sequence analysis. The two molecules were found to differ in a single tryptic peptide from the alpha 3 region, spanning residues 220-243. The amino acid sequence of this peptide from variant OZB revealed that there was only one amino acid change of Glu instead of Ala at position 236, a hitherto invariant residue in class I HLA antigens. All previously characterized HLA or H-2 natural variants have structural changes restricted to the alpha 1 and/or alpha 2 domains. Thus, variant OZB is unique in that (1) it has one amino acid change in alpha 3 and (2) it has no changes in alpha 1 and alpha 2. The only detected substitution of this variant may be accounted for by a single base change at the DNA level, suggesting that it might have resulted from a point mutation in the A2.1 gene. The structural features of variant OZB open a novel way to examine the influence of polymorphism in alpha 3 on cytolytic T-cell recognition of naturally occurring class I antigens.

Amino Acid Sequence↗
PubMed1996

HLA-DPB1 mismatch at position 69 is associated with high helper T lymphocyte precursor frequencies in unrelated bone marrow transplant pairs.

HLA incompatibility between bone marrow recipient and unrelated donor pairs is often associated with severe acute graft-versus-host disease following bone marrow transplantation. Due to the extensive polymorphism of HLA genes, finding genotypically identical pairs is a difficult challenge. Therefore, it is crucial to single out the relevance of each HLA gene and, within each sequence, the polymorphic positions that induce a T-cell response. Among HLA class II genes, the relevance of HLA-DPB1 in inducing graft-versus-host disease is still controversial. In this study, we selected 37 bone marrow transplant pairs on the basis of HLA class I A and B identity as determined by isoelectric focusing and of class II identity as determined by serology and by low-resolution genomic typing. We analyzed them for the possible relationship between frequency of cytotoxic T lymphocyte and helper T lymphocyte precursors (CTLp and HTLp, respectively) and genomically determined class II mismatches. Seventeen pairs had high numbers of both CTLp and HTLp. They were not further considered because of the difficulty in determining whether the T-cell response was induced by class I or class II mismatches. Of the remaining pairs with low CTLp and high HTLp, six had disparities at HLA-DRB1 and HLA-DPB1 genes, and 14 differed only at the HLA-DPB1 locus. Among the latter pairs, we found a correlation between HLA-DPB1 mismatches and HTLp frequency, thus suggesting that disparity at this locus influences the alloreactive T-cell response. When the HTLp frequency was correlated with each single mismatch found in the 14 pairs, it appeared that the nature of the amino acid at position beta69 played a relevant role in inducing alloreactivity.

Bone Marrow Transplantation↗
PubMed1997

[Sequence of HLA-DQA1 promoter region in the Han people].

Polymorphism of HLA-DQA1 promoter region (QAP) in the Han people has been identified. The results revealed a number of differences, some of which are in the critical class II boxes, and generally conserved in HLA-DQA1 promoter region. The major differences occurred in the X box, Y box and S box. Within the X box, the Hans carry a A at position -111, instead of a G, and a G or a A can be present at position -98. Within the S box, the Hans carry a G at position -131. Within the Y box, position -71 is a A rather than a G. Some single base substitutions have been detected from IDDM patients at the 5'-flanking region of the S box and between X box and Y box. Particularly, the insertion of CCA bases has been identified at the position between -157 and -158 in a IDDM patient. These data suggest that the polymorphism of HLA-DQA1 promoter region may play a role in susceptibility to IDDM.

Adult↗
PubMed2003

Impact of HLA-C on acute rejection in liver transplantation.

Although liver transplants show a special tolerogenic behaviour, rejection remains an important problem that involves several immunological mechanisms, some of which are unknown. Our study sought to analyze the influence of HLA-C polymorphism on short-term liver graft acceptance by HLA-C genotyping of 100 orthotopic liver transplant recipient-donor pairs. Recipients were statified according to the occurrence of acute rejection. HLA-Cw*06 allele appeared to be underrepresented among recipients without versus those with acute rejection or those in control groups. With regard to HLA-C allelic compatibility, the frequency of acute rejection or those in episodes decreased with fewer HLA-C mismatches. These findings suggest the participation of HLA-C molecules in liver graft alloresponses, involving HLA-C genotyping, as well as compatibility.

Alleles↗
PubMed1998

Polymorphism and distribution of HLA-DR2 alleles and haplotypes in a Greek population.

HLA-DR2 serological subtyping has indicated that the DR16 serotype appears at a higher frequency relative to the DR15 serotype in the Greek population, differing from the distribution observed in most other Caucasian groups. In this study, we have analyzed by the PCR-SSP technique a DR2-positive group of unrelated Greek individuals selected from our normal control panel for the different DRB1, DRB5, DQB1 and DQA1 DR2-associated alleles present. Six of the 50 individuals analyzed were homozygous for DR2, contributing a total of 56 haplotypes for DR2. The observed frequencies of the DR2-related DRB1 alleles were as follows: 58.9% for the DRB1*1601, 7.1% for the DRB1*1602, 25.0% for the DRB1*1501 and 7.1 % for the DRB1*1502 allele. The rare allele DRB1*1605 was detected in one heterozygous sample and its presence was definitively established by DNA sequencing. The alleles *1503, *1504, *1505, *1603 and *1604 were not detected. Three DRB5 alleles were identified: DRB5*0202 (67.8%), DRB5*0101 (25.0%) and DRB5*0102 (7.1%). Ten different DRB1/DQB1/ DQA1 DR2-associated haplotypes were defined. The most frequently observed haplotype was DRB1*1601-DQB1*0502-DQA1*0102 (relative frequency=57%) followed by DRB1*1501-DQB1*0602-DQA1*0102 (relative frequency=14.3%). In conclusion, the refined analysis of the DR2-associated DRB1 alleles in the Greek population revealed the prevalence of the DRB1*1601 allele. The rare allele DRB1*1605 was demonstrated once. A considerable variety of different DR2-related DR/DQ haplotypes was detected and the overall haplotypic frequencies in the Greek population are distributed differently compared to those reported for most other Caucasian populations.

Alleles↗
PubMed1997

Hematopoietic stem cell transplants from unrelated donors.

Transplantation of hematopoietic stem cells is now well established as life-saving therapy for patients with several different genetic and acquired diseases. This has been possible largely because of the identification of HLA as the human major histocompatibility system and the application of new technologies for improving the accuracy of HLA typing and matching. Clinical advances including the development of more effective immune suppression therapy and improvements in supportive care have also been critically important. The lack of HLA-identical sibling donors for most patients and the extensive polymorphism of HLA genes have necessitated establishing very large registries of HLA-typed volunteers. With more than 3 million donors now available worldwide, the number of patients identifying HLA matches has increased substantially. Despite a higher incidence of graft-versus-host disease (GVHD), the results of unrelated donor transplants are favorable when performed under optimal conditions with a well-matched donor. In order to provide transplants for all patients, improved methods for GVHD prophylaxis are needed that will make it possible to safely perform transplants even across limited degrees of HLA disparity.

Animals↗
PubMed1985

Comparison of multiple HLA-A alleles at the DNA level by using Southern blotting and HLA-A-specific probes.

Numerous alleles of the HLA-A gene have been serologically identified. In this report we present a rapid and straightforward means to assess HLA-A polymorphism at the genomic level. Using 5' and 3' HLA-A-specific DNA probes and Southern blotting, we have placed the recognition sequences for five endonucleases relative to the coding regions of 15 HLA-A alleles. These data permit two interesting conclusions: four of the HLA-A alleles studied are associated with unique restriction fragments, and HLA-A alleles of a cross-reactive group are more closely related at the DNA level than are noncross-reactive alleles.

Alleles↗