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PubMed1997

HLA-A typing: comparison between serology, the amplification refractory mutation system with polymerase chain reaction and sequencing.

In this study we typed HLA-A polymorphisms by a new sequence-based typing (SBT) method, which involved one PCR reaction and four sequencing reactions covering exon 2 and exon 3. This method allowed complete identification of all known HLA-A alleles and revealed the presence of a new allele, named HLA-A*2608. We also introduced sequencing of exon 4 for some samples in order to discriminate the allelic pairs that are identical in exon 2 and 3, thus improving SBT resolution. Finally, we compared the results obtained by SBT with data obtained by serological typing and the amplification refractory mutation system (ARMS-PCR). Together, our results suggest that the SBT here described provides an optimal HLA-A typing technique that may be useful in selecting donor-recipient pairs in bone marrow transplantation between unrelated individuals.

Adult↗

PubMed1998

Sequence of four new HLA-Cw alleles: a possible role of interallelic recombination.

In order to extend our current understanding of HLA-C polymorphism, four new alleles have been cloned and sequenced: Cw*1801 in a donor of mixed origin, Cw*02024 in a Senegalese individual, Cw*1205 and Cw*1604 in European Caucasoid blood donors. HLA-Cw*1801, which most likely results from an interallelic recombination between Cw*0704 and 0401 alleles, was not associated with B*8101, but with either B*4403 or B18. The Cw*02024 allele differs from Cw*02022 by a silent mutation in exon 3. Both Cw*1801 and Cw*02024 appear to be rather frequent in populations of African origin but have not yet been detected in Caucasoids. HLA-Cw*1604 differs from Cw*1601 by two nucleotides at codon 156 leading to a Gln to Trp substitution. This new Cw16 subtype was subsequently identified in three additional unrelated families, all of South-European origin, and presented an unusual association with B*4402 in all cases. HLA-Cw*1205 is a composite allele with the alpha1 domain of Cw*1602 and the alpha2 domain of Cw*1203. It appears to be rare, at least in European Caucasoids. Three of these four alleles may have resulted from gene conversion-like or interallelic recombination events.

Alleles↗

PubMed1995

Chimpanzee MHC class I A locus alleles are related to only one of the six families of human A locus alleles.

There are nearly 50 alleles at the highly polymorphic HLA-A class I locus that fall into six distinct families. To determine the allelic repertoire and the mechanism of generation of diversity of the A locus in primates we have analyzed A locus alleles from 28 apparently unrelated chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). We have, therefore, compared the sequences of 19 HLA-A homologues from chimpanzees and bonobos to 42 HLA-A sequences. HLA-A homologues were well preserved in chimpanzees and bonobos with very few new substitutions present in the A locus alleles of both species of chimpanzee. Surprisingly, all chimpanzees and bonobos expressed A locus alleles related to only one of the six families of human HLA-A alleles. This suggests that the common ancestor of these two species either passed through a genetic bottleneck or that selection has favored the maintenance of the HLA-A1, -A3, -A11 family in chimpanzees.

Alleles↗

PubMed1997

Polymorphism of exon 3 of the HLA-G gene.

HLA-G is a non-classical MHC class I gene with a limited tissue distribution. The most pronounced expression is detected in the cytotrophoblast of first trimester placenta. It is possible to detect mRNA for HLA-G in preimplantation blastocysts where expression is correlated with a high cleavage rate of embryos. HLA-G seems to play an important role in the feto-maternal relationship. The polymorphism of the HLA-G locus is not fully clarified. One study has shown extensive nucleotide sequence variation in the exon 3 (alpha-2 domain) in healthy African Americans. A few studies in other populations have only revealed a limited polymorphism. We investigated the polymorphism of the exon 3 of HLA-G by means of Polymerase Chain Reaction (PCR)-Single Strand Conformation Polymorphism (SSCP)- and DNA sequencing analysis in a Danish population. We detected four single-base substitutions in exon 3 compared to the sequence of HLA-6.0 (G*01011); one of these has not been reported before. We also found a deletion of the first base of codon 130 or the third of codon 129 in a heterozygous individual. This study, together with previous results, suggests that the polymorphism of exon 3 of the HLA-G gene in Caucasians is limited, in contrast to that observed in Americans originating from Africa. Implications of this discrepancy and the detected deletion in relation to certain disorders of pregnancy are discussed.

Alleles↗

PubMedDate not supplied

Analysis of the HLA-DR gene locus by temperature gradient gel electrophoresis and its application for the rapid selection of unrelated bone marrow donors.

The human leucocyte antigen (HLA) class II compatibility of bone marrow donor and recipient is an essential prerequisite for the prevention of severe graft versus host disease and therefore for the successful outcome of bone marrow transplantation. In this study an efficient protocol was developed for the rapid analysis of the polymorphic HLA-DR gene locus, based on DNA-polymerase chain reaction (PCR) amplification of the variable exon II of the HLA class II DR genes and subsequent temperature gradient gel electrophoresis (TGGE). Computer-assisted melting map calculations were carried out to determine the melting behavior of the different HLA-DR fragments. Despite the high variability of the DR alleles on the nucleotide sequence level the calculations revealed a common melting domain structure of the different HLA-DR fragments, which was experimentally confirmed by perpendicular TGGE. On parallel TGGE, all samples were separated under the same electrophoretical conditions using a single PCR fragment without GC-clamp. TGGE was applied for the analysis of the DR alleles of numerous bone marrow receipt pairs and compared to the corresponding serological and DNA typing results. The TGGE patterns were found to be different for all samples with different HLA-DR typing results. Identical homoduplex and heteroduplex patterns occurred only in the case of complete genotypic HLA-DR identity as determined by direct sequencing of PCR products.

Alleles↗

PubMed1995

HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy.

CD is a gluten-sensitive enteropathy, strongly associated with expression of the DQA1*0501, DQB1*0201 genotype. CD patients have an increased risk of malignancy, particularly EATCL. However, it is controversial as to whether adults with EATCL represent a subgroup of patients with CD or should be regarded as a distinct entity. To investigate the genetic relationship between CD and EATCL, HLA class II DRB1, DQA1, and DQB1 typing of peripheral blood, frozen or paraffin-embedded biopsy tissue obtained from Caucasian patients with CD (n = 91) or EATCL (n = 47) was performed by PCR-SSOP typing. Genotype frequencies were compared with those observed in 151 unrelated control individuals. A total of 83 (91%) of 91 CD patients were of DQA1*0501, DQB1*0201 genotype (pc < 10(-6), RR = 522.2), compared with 40 (93%) of 43 EATCL patients (pc < 10(-6), RR = 44.2) with amplifiable DNA versus 35 (23%) of 151 controls. DRB1*03 frequencies were also elevated in both patient groups (79 of 91 in CD [87%; pc < 10(-6), RR = 24.5] and 38 of 40 in EATCL [95%; pc < 10(-6), RR = 70.7]) compared with controls (32 of 151, 21%). These results confirm previous studies of HLA associations in CD and also suggest that EATCL arises in individuals with the DQA1*0501, DQB1*0201 CD-predisposing genotype. However, the frequency of DRB1*03,04 heterozygotes was significantly increased in the EATCL group (16 of 40, 40%) compared with both control individuals (3 of 151, 2%; pc < 10(-6), RR = 32.9) and uncomplicated CD patients (6 of 91, 7%; pc = 0.04, RR = 9.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2000

A disulfide-linked natural killer cell receptor dimer has higher affinity for HLA-C than wild-type monomer.

Inhibitory receptors on the surface of natural killer (NK) cells recognize specific MHC class I molecules on target cells and prevent the target cell lysis by NK cells. The killer cell immunoglobulin-related receptors (KIR), KIR2D, found in human, specifically interact with polymorphic HLA-C molecules. The crystal structure of the inhibitory receptor, KIR2DL1, revealed a relationship to the hematopoietic receptor family, suggesting that the signaling mechanism of KIR2D molecules may resemble that of the hematopoietic receptors, and involve KIR2D dimerization. We have engineered a disulfide-linked dimer of KIR2DL1 by introducing a free cysteine at the C-terminal stem region of the receptor. The disulfide-linked KIR2DL1 dimer binds to HLA-Cw4 at a molar ratio of one dimer to one HLA-Cw4 molecule. Furthermore, the covalently-linked KIR2DL1 dimer binds more tightly to HLA-Cw4 than the wild-type monomer, suggesting the occurrence of a second binding event that increases the overall affinity of KIR dimer for HLA-C.

Dimerization↗

PubMed1998

Absence of imprinting of HLA class Ia genes leads to co-expression of biparental alleles on term human trophoblast cells upon IFN-gamma induction.

Human trophoblast cells have developed various efficient regulatory mechanisms to prevent cell surface expression of the classical HLA-A, -B, and (but not always) -C class I molecules. This allows them to escape maternal alloimmune attack during pregnancy. However, recent results have demonstrated that such a lack of expression could be reversed in villous cytotrophoblast cells purified from term placenta by in vitro IFN-gamma treatment. In this context, we investigated whether both maternal and paternal HLA class Ia antigens were co-dominantly expressed in such trophoblast cells. Using polymerase chain reaction sequence-specific primers for HLA-A and HLA-C alleles, we detected transcripts of both paternal and maternal origins, showing that these genes were not affected by genomic imprinting, at least in term placenta. After in vitro IFN-gamma treatment, the polymorphic HLA-A and HLA-B antigens of both parental origins become detectable at the cell surface, as assessed by flow cytometry and/or complement-dependent microtoxicity test. Appearance of paternal antigens on trophoblast cells upon IFN-gamma induction raises the question of the in vivo biological consequences of this phenomena, in term of materno-fetal tolerance and in particular of a potential allogeneic cytotoxic immune response.

Alleles↗

PubMed1991

Nonresponsiveness to an immunodominant Epstein-Barr virus-encoded cytotoxic T-lymphocyte epitope in nuclear antigen 3A: implications for vaccine strategies.

An immunodominant Epstein-Barr virus (EBV)-encoded cytotoxic T lymphocyte (CTL) epitope has been mapped to the EBV nuclear antigen 3A. The epitope, represented by the peptide sequence AWNAGFLRGRAYGLD (hereafter termed AWNA), is restricted through the HLA-B8 allele and is expressed by type A but not type B-infected transformants. Herein, we show that EBV-specific memory CTLs from an HLA-B8+ healthy virus carrier, JS, did not respond in vitro to AWNA, even though that individual's endogenously infected transformants processed and presented the natural equivalent of this peptide to AWNA-specific CTLs from another B8+ individual. Instead, an epitope, represented by the peptide sequence QLSDTPLIPLTIFVGENTGV, was the dominant EBV-specific CTL epitope in donor JS. This epitope mapped to EBV nuclear antigen 2A, was restricted by an HLA-A2 subtype, and specifically associated with type A strains of EBV. No AWNA-specific CTL precursors were detected by limiting dilution analysis of peripheral blood mononuclear cells from donor JS whereas the precursor frequency of AWNA-specific CTLs from a responder donor, LC, was estimated at 1:4500. The presentation in vivo of an immunogenic epitope-HLA antigen complex is clearly insufficient to guarantee an effective memory CTL response to that foreign epitope. Thus, vaccination strategies based on peptides inducing CTL responses may need to take into account not only the polymorphism of HLA antigens but also possible allelic variation in the repertoires of T-cell receptors.

Amino Acid Sequence↗

PubMed2001

Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism.

KIR3DL1 and KIR3DL2 are NK cell receptors for polymorphic HLA-B and -A determinants. The proportion of NK cells that bind anti-KIR3DL1-specific Ab DX9 and their level of binding vary between individuals. To determine whether these differences are due to KIR polymorphism, we assessed KIR3D gene diversity in unrelated individuals and families. Both KIR3DL1 and KIR3DL2 are highly polymorphic genes, with KIR3DS1 segregating like an allele of KIR3DL1. A KIR haplotype lacking KIR3DL1 and KIR3DS1 was defined. The two KIR3DL1 alleles of a heterozygous donor were expressed by different, but overlapping, subsets of NK cell clones. Sequence variation in KIR3DL1 and KIR3DL2 appear distinct; recombination is more evident in KIR3DL1, and point mutation is more evident in KIR3DL2. The KIR3DL1 genotype correlates well with levels of DX9 binding by NK cells, but not with the frequency of DX9-binding cells. Different KIR3DL1 alleles determine high, low, and no binding of DX9 Ab. Consequently, heterozygotes for high and low binding KIR3DL1 alleles have distinct subpopulations of NK cells that bind DX9 at high and low levels, giving characteristic bimodal distributions in flow cytometry. The Z27 Ab gave binding patterns similar to those of DX9. Four KIR3DL1 alleles producing high DX9 binding phenotypes were distinguished from four alleles producing low or no binding phenotypes by substitution at one or more of four positions in the encoded protein: 182 and 283 in the extracellular Ig-like domains, 320 in the transmembrane region, and 373 in the cytoplasmic tail.

Alleles↗

PubMed1997

New diallelic markers in the HLA region of chromosome 6.

Diallelic polymorphisms have been identified in the HLA-H gene and the ZNF192 gene located about 2 megabases centromeric to HLA-H. The three polymorphic sites in HLA-H together with the two hemochromatosis mutations in this gene give rise to 8 different haplotypes. The three polymorphic sites in ZNF192 give rise to 4 different haplotypes. The haplotypes in HLA-H are in complete linkage disequilibrium with the two common mutations in that gene, 845A (C282Y) and 187G (H63D). The 845A mutation is in weak linkage disequilibrium with the ZNF192 polymorphisms and the 187G mutation appears to be in equilibrium with this polymorphism. The 187G mutation therefore appears to be the older of the two HLA-H mutations.

Alleles↗

PubMed1998

HLA and T-cell receptor gene polymorphisms in Guillain-Barré syndrome.

OBJECTIVE: We examined a possible involvement of genetic factors influencing the development of Guillain-Barré syndrome (GBS). METHODS: We studied T-cell receptor (TCR), alpha-chain constant (AC), and beta-chain variable (BV) gene polymorphisms using microsatellite markers and serologic HLA class I antigens, HLA-DRB1, and HLA-DQB1 alleles in 81 Japanese patients with GBS and 87 controls. RESULTS: There were no significant differences in these genetic markers between GBS patients and controls. Subgrouping of GBS patients according to recent Campylobacter jejuni infection, the presence of anti-GM1 antibody in the sera, or their combinations also failed to reveal significant associations with these genetic markers. There was, however, a tendency for an increased frequency of HLA-DRB1*0803 in the C. jejuni + GM1 + GBS group, when compared with controls. CONCLUSIONS: The data suggest that the roles of TCRAC, T-cell receptor beta-chain variable (TCRBV), HLA class I or class II in the development of GBS are not critical, and further research is necessary to clarify other genes encoded within the HLA region for genetic susceptibility to GBS.

Campylobacter Infections↗

PubMed2001

HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility.

BACKGROUND AND AIMS: Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided. METHODS: We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease. RESULTS: There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease. CONCLUSIONS: These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.

Case-Control Studies↗

PubMed1992

HLA and disease.

Many human diseases are associated with HLA class I, class II and class III antigens. It appears that the class III antigen disease associations can be explained by a direct defect operating at the level of either the class III gene or its gene product. The mechanism underlying class I and class II antigen disease associations is at present unknown. In this review we have considered thirty diseases which have been ranked according to their relative risk as defined by the frequency of a given HLA antigen in patient and control populations. The chronic inflammatory disorder, ankylosing spondylitis and its association with HLA B27 has been used as a model to study the HLA linked diseases. We have suggested that the disease may be caused by the Gram-negative microorganism Klebsiella which has antigenic similarity to HLA B27. It is proposed that some antibodies made against Klebsiella bind to HLA B27, thereby acting as autoantibodies leading to the pathological sequelae of chronic inflammatory arthritis. This is the crosstolerance hypothesis or molecular mimicry model and it has been compared to the receptor model. It is further suggested that the crosstolerance hypothesis can be utilised as a general theory to explain the association of other diseases with the class I and class II antigens, and offer a possible explanation for the polymorphism of HLA.

Antigen-Presenting Cells↗

PubMed1989

The DR3(w18),DQw4 haplotype differs from DR3(w17),DQw2 haplotypes at multiple class II loci.

The polymorphism of HLA class II molecules in man is particularly evident when comparisons between population groups are made. This study describes a DR3 haplotype commonly present in the American black population. Unlike the Northern European population, in which almost all DR3 individuals are DQw2, approximately 50% of DR3-positive American blacks express a DQw4 allelic product. This study characterizes the DR subregion of that haplotype. cDNA sequence analysis has revealed a DR beta gene which differs at several positions from previously described DR3 beta 1 genes. It is postulated that a gene-conversion-like event with a DRw52 beta gene as donor has generated some of these differences. The haplotype carries a DRw52a allele as defined by oligonucleotide hybridization studies. DNA restriction fragment analysis using a family and several unrelated individuals has allowed us to identify DR alpha and beta fragments associated with the DR3(w18),DQw4 haplotype. The most striking observation is that the DR3(w18),DQw4 haplotype differs from DR3(w17),DQw2 haplotypes at multiple class II loci. Several genetic mechanisms including reciprocal recombination, gene conversion, and point mutation were involved in generating the differences between these haplotypes. Once established, the DR3(w18),DQw4 haplotype appears to be relatively stable in the population.

Amino Acid Sequence↗

PubMed1997

Differential expression of HLA-DQA1 alleles associated with promoter polymorphism.

The promoter regions of DQA1 alleles are polymorphic, with some of the nucleotide sequence polymorphisms being located within X and Y motifs essential for the regulation of HLA class II gene transcription. In the present study, we demonstrate that polymorphisms in the promoter regions of three DQA1 alleles influence constitutive and inducible transcription of reporter gene constructs in epithelial, B-, and T-cell lines. Promoter strength in transient transfection assays generally followed a pattern of DQA1(*)03011>DQA1(*)0101>DQA1(*)05011, and was not affected by the endogenous HLA haplotype of the recipient cells. TNFalpha significantly activated the DQA1(*)05011 promoter, but had little effect on the DQA1(*)03011 promoter. Mutagenesis of the X and Y motifs of DQA1(*)03011 and DQA1(*)05011 demonstrated that nucleotide sequence polymorphisms in the Y element had the greatest effect on the promoter strength and differential TNFalpha inducibility. The finding that alleles of the DQA1 gene differ in promoter strength and responsiveness to TNFalpha suggests a mechanism for the association of certain alleles of this gene with susceptibility to autoimmune disease.

Alleles↗

PubMed1988

DQw3 variants defined by cloned alloreactive T cells.

The polymorphism of HLA class II molecules expressing the serologically defined alloantigen DQw3 was studied using cloned proliferative T lymphocytes. Two clones, IG9 and IC3, were selectively primed against DQw3-associated determinants and tested against a panel of 92 HLA-D homozygous cells. Both clones were specific for DQw3, but each showed a distinct response pattern. Clone IG9 recognized a DQw3-associated determinant expressed on a subset of DR4 and DR5 haplotypes and on all DRw6, 7, w8, and w9 haplotypes tested. In contrast, clone IC3 recognized a distinct DQw3-associated determinant expressed only on a subset of DR4 haplotypes. In monoclonal antibody inhibition experiments, anti-DQ, but not anti-DR or anti-DP antibodies, blocked reactivity of both clones IG9 and IC3, further demonstrating that the determinants defined by these clones are associated with DQ molecules. In DNA hybridization studies using a DQ beta probe, a correlation was observed between restriction site polymorphisms in the DQ beta gene, designated DQw"3.1" and "3.2," and the expression of the T-cell-defined IG9 and IC3 determinants. It is, thus, possible to demonstrate by cloned T-cell reactivity functionally relevant recognition sites on DQw3+ molecules that are associated with structural polymorphisms defined by molecular and genomic analysis.

Antibodies, Monoclonal↗

PubMed1989

HLA-DO-related restriction fragment length polymorphisms in rheumatoid arthritis: evidence for a link with disease expression.

Eighty-three patients with rheumatoid arthritis (RA) were investigated for HLA-DQ and DR locus restriction fragment length polymorphisms (RFLP). Of the 83 patients, 61 (73%) possessed the DR4 allele and within this group we have investigated the relative frequencies of two DQ beta gene variants of DQw3, DQw7 and DQw8, one of which we had previously found to be raised in Felty's syndrome. This analysis revealed a significantly higher frequency of DQw7 containing haplotypes in DR4 positive rheumatoid patients (64%) than in DR-matched healthy controls (42%). Furthermore, the distribution of DQw7 was biased towards those patients with greater disability indicated by the HAQ score, more systemic disease and higher titres of rheumatoid factor, suggesting that DQw7 may contribute to disease expression.

Arthritis, Rheumatoid↗