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PubMed1995

An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients.

Fifty-two British and 29 Greek idiopathic membranous nephropathy (IMN) patients were analysed for DRB, DQA1, DQB1 and DPB1 gene polymorphism using second exon amplification and sequence-specific oligonucleotides (SSO). In addition 100 British and 92 Greek controls were analysed. A highly significant increased frequency of the DRB1*0301 allele was found in IMN patients from Britain (80%), when compared to controls (27%, OR 10.6, P = 0.000004). A lower frequency of DRB1*0301 was observed in Greek IMN patients (33%), but this was just significant before correction, when compared to Greek controls (15%, OR 3, P = 0.02). The DRB3 allele most often associated with DRB1*0301 was DRB3*0101 (OR 4.2, P = 0.00025) in British patients and DRB3*0201/2 (OR 11, P = 0.006) in Greek patients. In Greek IMN patients a decrease in DR16 was found (OR 0.08, P = 0.004), and the overall incidence of DR2 was significantly lowered when both sets of IMN patients were combined (OR 0.21, chi 2 17.6, P = 0.00013). The incidence of DQA1*0501 was raised in both Greek (96% vs. 66%, OR 9.7, chi 2 6.9, P = 0.009) and British IMN (85% vs. 45%, OR 7.4, chi 2 20, P = 0.00007) patients. This gives some support to a proposal for a major role for this allele in IMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1982

Recognition of a polymorphic monocyte antigen in HLA.

The serological recognition of 'new' gene products of the HLA system can be accomplished by selecting sera with strong leucocyte antibodies and testing these against a panel of cells obtained from donors which are compatible for the known HLA antigens with the antibody producer. This approach, which we termed the HLA-CAP approach (compatible with antibody producer), was essential in the recognition of what is now called the HLA-DR locus and of non HLA-linked T-cell subgroups. Using the same technique, we have defined here several sera recognizing a structure on monocytes similar to one of the alleles of the HLA-linked PL3 or secondary B-cell (SB) system, so far only recognized by cellular techniques.

Adult↗
PubMed1999

Pregnancy, HLA allogeneic challenge, and implications for AIDS etiology.

Because of the large HLA genetic polymorphism, a human fetus usually has several paternal HLA antigens allogeneic to its mother. The maternal gamma-immunoglobulin (IgG) antibody response to fetal HLA alloantigens is noncytotoxic and associated with local suppression of maternal cell-mediated immunity (CMI) at the maternal-fetal interface. When mother and fetus are syngeneic for most HLA antigens, an increased risk exists for a maternal anti-placental cytotoxic CMI responses, compromising fetal survival. Local suppression of maternal CMI by an anti-HLA IgG response may have evolved to protect the fetoplacental unit from a maternal CMI cytotoxic reaction against expressed developmental neoantigens. A negative aspect of this adaptive response is that infectious organisms bearing HLA-homologous alloantigens (e.g. human immunodeficiency virus type 1, HIV-1) may generate a systemic IgG response suppressing CMI. Findings are reviewed suggesting this is an etiologic factor in the acquired immune deficiency syndrome (AIDS).

Acquired Immunodeficiency Syndrome↗
PubMed1990

An HLA class II region restriction fragment length polymorphism (RFLP) in patients with dermatitis herpetiformis: association with HLA-DP phenotype.

Dermatitis herpetiformis (DH) is characterized in part by an associated gluten-sensitive enteropathy (GSE), and a strong association with the HLA antigens HLA-A1, -B8, -DR3, and -DQw2, essentially identical to that seen in patients with isolated GSE (celiac disease). A 4.0-kb RsaI RFLP has been identified using a DQ beta-chain cDNA and localized to the HLA-DP beta-chain region. This RFLP has been found more frequently in patients with isolated GSE than in normal HLA matched controls. We have analyzed genomic DNA from 24 patients with DH and 15 HLA-matched controls to determine if this 4.0-kb RsaI RFLP was present in patients with DH. Twenty-one of 24 (87%) of patients with DH were found to have this RFLP as compared to 7 of 10 (70%) HLA-DR3, -DQw2 matched control subjects (p = 0.23). Thus, the 4.0-kb RsaI RFLP detected in patients with isolated GSE is also present in patients with DH; however, its frequency in DH patients does not differ significantly from that of HLA matched controls. Family studies of patients with DH revealed that although the 4.0-kb RsaI RFLP segregated with the HLA-A1, -B8, -DR3, -DQw2 haplotype in one family, it did not segregate with this disease-associated haplotype in two other families. In both patient and control populations, this RFLP was associated with HLA-DPw1 or -DPw3 phenotypes; 25 of 26 (96%) HLA-DPw1 or -DPw3 subjects were found to have this RFLP compared to only 1 of 6 (17%) who did not express HLA-DPw1 or -DPw3 (pc = 0.0009). These population and family data suggest that this 4.0-kb RsaI RFLP is primarily associated with the HLA-DPw1, -DPw3 phenotype, rather than the clinical manifestations of DH. These data further document that the strongest association of DH with HLA antigens remains with HLA-DQw2 and HLA-DR3 antigens.

Cell Line↗
PubMed1985

The monoclonal antibody AC1.59 defines a new polymorphic determinant on HLA-DR molecules.

2-dimensional gel electrophoresis analysis and sequential immunoprecipitation studies have shown that the monoclonal antibody (MoAb) AC1.59 recognizes a gene product of the HLA-DR locus. The determinant defined by the MoAb AC-1.59 has an unusual distribution on HLA-DR allospecificities, since it is expressed by HLA-DR1, DRw8, DRw9 antigens and by subtypes of HLA-DRw6 and HLA-DR4 antigens. In the latter allospecificity the expression of the MoAb AC1.59 defined determinant correlates with the cellularly defined HLA-Dw4 alloantigen. The present investigation provides evidence of serological heterogeneity within HLA-DR alloantigens. Furthermore these results suggest that monoclonal antibodies can sharpen the discriminatory power of serological assays to dissect the heterogeneity and complexity of HLA-DR alloantigens.

Antibodies, Monoclonal↗
PubMed1998

Impact of the MHC-encoded HLA-DMA, DMB, and LMP2 gene polymorphisms on kidney graft outcome.

We previously studied the relationship between TAP1 and TAP2 gene polymorphism and compatibility in kidney graft outcome and reported that the currently described TAP1 and TAP2 gene polymorphisms did not influence the incidence of acute rejection episodes. In this study, we report on the effect of polymorphism and matching of HLA-DMA, -DMB, and LMP2 genes on kidney graft outcome. This study was performed on 102 selected kidney recipients who experienced two or more acute rejection episodes (rejection group) during follow up and who were compared to a group of 150 patients who never had rejection (non rejection group). Although a significant effect of HLA-DR matching was observed between these two groups, our data suggest that matching for all the new genes located in the HLA class II region (TAP1, TAP2, LMP2, HLA-DMA and -DMB) does not influence the kidney graft outcome. However, a significant increase (pc < 0.05) of DMA*0102 allele was observed in the recipients of the rejection group as compared to those of the non rejection group. This effect was not due to a linkage disequilibrium between DMA and HLA-DR loci and suggests that this specific HLA-DMA allele could play a role in the indirect pathway of class II presentation of donor antigens.

Adult↗
PubMed1998

Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region.

The human major histocompatibility complex (MHC) class I region is believed to contain a large number of disease-related loci for diseases such as Behçet's disease and psoriasis vulgaris. Although many novel genes have recently been identified in this region, it still appears to be difficult to relate any of these new genes to MHC class I-associated diseases as causative genetic factors. During the course of large-scale genomic sequencing of the human MHC class I region, we identified 262 microsatellite sequences with dinucleotide to pentanucleotide repeats around the HLA-B, -C and HLA-E genes. Of these, 26 microsatellites were investigated for repeat polymorphism using 60 HLA homozygous B-cell lines and 60 healthy random individuals. The average number of alleles at these microsatellite loci was 9.6 with a PIC (polymorphism content value) of 0.69. These new polymorphic microsatellite markers will probably be very useful for precise mapping of disease-related genes within the HLA class I region in linkage analysis. Moreover, they will provide a powerful tool to study recombination events in this region, which contributes to haplotypic diversification.

Cell Line↗
PubMed1992

DPB1 polymorphism in rheumatoid arthritis: evidence of an association with allele DPB1 0401.

HLA-DP polymorphism was examined in 71 rheumatoid arthritis patients and 148 controls, using dot-blot analysis with 14 synthetic oligonucleotide probes specific for the variable region of the DPB1 second exon. The DPB1 0401 allele was found to be significantly more frequent in RA patients than in controls (77.46% vs 55.40%, p less than 0.002, pc less than 0.03, relative risk value: 2.74). An association between DPB1 0401 and seropositivity for rhumatoid factors was also observed: 44 of the 55 seropositive RA patients were DPB1 0401 (p less than 0.001). Analyzing the HLA DPB1 alleles frequencies in 57 HLA-DR-typed RA patients did not show any linkage between the DPB1 0401 and the DR4 specificities. Furthermore, the DPB1 0401 homozygous frequency was increased in DR4-negative RA patients. Our findings suggest an independent role of the DPB1 0401 allele in the genetic susceptibility to RA.

Adult↗
PubMed1993

Analysis of HLA-A/B recombinant families with new polymorphic markers.

The MHC in humans is a much studied region of the genome, the genes of which display a high rate of polymorphism and a high rate of linkage disequilibrium. Four families in which intra-class-I recombination has occurred have been analyzed with six polymorphic markers between HLA-A and -B in order to determine the full haplotypes of the whole families and to localize the points of crossover. The previously proposed order of the markers was confirmed by recombination mapping. In one family, the crossover was shown to have occurred in the 20-kb stretch of DNA bounded by the two markers (P3B and P5) between which no evidence of linkage disequilibrium was found, a region which constitutes of only about 1% of the distance between HLA-A and HLA-B. Although supportive of the suggestion of a hot spot of recombination in this region, based on the apparent lack of linkage disequilibrium between the markers P3B and P5, more such families need to be tested in order to confirm or refute this hypothesis.

Crossing Over, Genetic↗
PubMed1986

Use of nonisotopic M13 probes for genetic analysis: application to HLA class II loci.

Previously, DNA polymorphisms in the HLA gene cluster have been analyzed using radioactive probes in Southern blot experiments; the restriction fragment length polymorphisms (RFLPs) revealed by this analysis are capable of subdividing HLA serological types. Here, we report the use of DNA probes labeled with biotinylated psoralen to provide nonisotopic detection of HLA class II RFLP patterns. These biotinylated probes contain cDNA sequences encoding the alpha and beta chains of DP, DQ, and DR HLA class II genes as inserts in M13 vectors. The recombinant M13 molecules are partially double-stranded with single-stranded HLA cDNA regions and contain biotinylated psoralen covalently linked to duplex DNA by UV irradiation. Following hybridization, the presence of biotinylated probe bound to target DNA is detected using a streptavidin-horseradish peroxidase conjugate, which converts the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue precipitate in less than 1 hr. The probe and detection system described here can detect single-copy genes in less than 0.5 microgram of total human DNA on Southern blots and generates the same specific RFLP patterns as do probes labeled with 32P by nick-translation. These biotinylated HLA class II probes have been applied to tissue typing for bone marrow transplantation and the study of insulin-dependent diabetes susceptibility, revealing in each case relevant polymorphisms not detected by serologic typing.

Biotin↗
PubMed2005

[Microarray DNA chip in analyzing the association between HLA-DRB and advanced hepatosplenic schistosomiasis].

OBJECTIVE: To explore possible associations between host polymorphism of HLA class II genotypes and advanced hepatosplenic schistosomiasis japonica. METHODS: 45 advanced schistosomiasis patients (experimental group) and 44 age- and sex-matched patients with chronic schistosomiasis (control group) from the same area were investigated for their HLA class II gene DRB genotypes by genotyping the alleles using microarray DNA chip. The correlation of allele frequencies to advanced hepatosplenic schistosomiasis was compared for the two groups. RESULTS: HLA-DRB1*04x exhibited markedly higher frequency in advanced patients than that in control group (P < 0.01, RR = 3.928). In contrast, the frequency of HLA-DRB1*15x in advanced patients was much lower when compared with that in control group (P < 0.01, RR = 0.050). Besides, the significant allele HLA-DRB1*15x displayed concurrence with allele DRB5*010x/020x. The linked gene haplotype DRB1*15x-DRB5*010x/020x showed significantly higher incidence in control group than in experimental group (P < 0.01). CONCLUSION: Allele HLA-DRB1*04x is positively, while HLA-DRB1*15x is negatively, correlated with advanced hepatosplenic schistosomiasis.

Adult↗
PubMed1999

HLA genes and haplotypes in Ryukyuans suggest recent gene flow to the Okinawa Islands.

Polymorphism of HLA genes was investigated in a population sample of Ryukyuans living on the main island of Okinawa (n = 197), in the southwestern islands of Japan. Serological typing was applied to class I loci (HLA-A, -B, and -C) and to HLA-DRB1; nucleotide sequence-level typing was performed using PCR microtiter plate hybridization and PCR single-strand conformation polymorphism methods. Ryukyuans showed a higher frequency of DRB1*0405 and lower frequencies of DRB1*1502 and DRB1*1302 compared with Hondo Japanese living on main islands. Principal components and phylogenetic analyses of 12 East Asian populations, including Ryukyuans, were performed based on the allele frequencies of HLA-A, -B, and -DRB1. In the principal components analysis 3 Japanese populations (Ryukyuans, Hondo Japanese, and Ainu) formed a cluster and showed the highest affinity to 2 Korean populations. In the phylogenetic tree Ryukyuans and Ainu were neighbors, but the genetic distance between them was larger than the distances between Ryukyuans and Hondo Japanese and between Ryukyuans and Korean populations. The geographic cline of the predominant haplotype in Ryukyuans, A*24-B*54-DRB1*0405, suggests that an ancestral population possessing A*24-B*54-DRB1*0405 moved into the Okinawa Islands after the divergence of Ryukyuans from the Ainu. Such a recent gene flow, probably from South China to the Okinawa Islands, is considered the major cause of difference in genetic characteristics between Ryukyuans and the Ainu.

Adult↗
PubMed1998

HLA-DR and -DQ gene polymorphism in Latvian patients with insulin-dependent diabetes mellitus.

Latvian insulin-dependent diabetes mellitus (IDDM) patients (n=101) and healthy controls (n=111) were analyzed for HLA-DR and DQ polymorphism. DR3-DQ2 and DR4-DQ8 were positively associated and DR15-DQ6, DR13-DQ6, DR1-DQ5 and DQ7 negatively associated with the disease. The incidence of IDDM in Latvia is very low (6.5 per 100,000) compared to Sweden (24.4 per 100,000), even though Latvia is close to Sweden. The reasons for the decreased incidence are not clear. When the negatively associated DQ were taken together in the healthy controls, more than 75% of the healthy controls were positive for one of the four negatively associated DQ molecules. The excess frequency of the negatively associated DQ molecules in the general population could explain the lower incidence of IDDM in Latvia. Association of HLA-DR and DQ genes with autoantibody markers shows DR3, but not DQ2, to be increased in GAD65 antibody-positive compared to antibody-negative patients. This association was not observed with ICA512 antibodies.

Adolescent↗
PubMed1998

HLA-DQA1 and HLA-DQB1 alleles and haplotypes in two Brazilian Indian tribes: evidence of conservative evolution of HLA-DQ.

Nucleotide sequence polymorphism of the HLA-DQA1 and HLA-DQB1 class II genes was analyzed in the Kaingang and Guarani Amerindians from southern Brazil using PCR sequence-specific oligonucleotide typing methods. Four different DQA1-DQB1 haplotypes were found: DQA1*0401-DQB1*0402 (associated with DRB1*0802, DRB1*08041, and DRB1*0807), DQA1*0501-DQB1*0301 (associated with DRB1*1602, DRB1*1413, and DRB1*1402), DQA1*03-DQB1*0302 (associated with DRB1*0404 and DRB1*0411), and DQA1*03-DQB1*03032 (associated with DRB1*09012). These HLA-DQA1 and HLA-DQB1 alleles and haplotypes are common in many other populations of all major ethnic groups. Alleles and haplotypes introduced into the populations by post-Columbian admixture were seen at low frequency both in the Kaingang (3.2%) and in the Guarani (3.8%). No novel HLA-DQA1 and HLA-DQB1 alleles have thus far been identified in Amerindians. This differs from previous results for HLA-DRB1, another class II locus presenting novel alleles (i.e., alleles not found in other ethnic groups and probably generated after migration of paleo-Indians to the Americas) in the Guarani and in other South American Indian populations. The distribution of the HLA-DQ alleles and haplotypes in Amerindians indicates a weaker diversifying selective pressure on the HLA-DQ genes compared with HLA-DRB1 and HLA-B. The more conservative evolution of HLA-DQA1 and HLA-DQB1 compared with HLA-DRB1 is strong evidence of (still not well-defined) functional differences of these class II genes.

Alleles↗
PubMed1993

HLA-DR and -DQ genotyping by PCR-SSO in Shanghai Chinese.

The polymorphism of HLA class II (HLA-DRB1, -DQA1 and -DQB1) were investigated in 89 Shanghai Han Chinese using polymerase-chain reaction amplification and oligonucleotide (PCR-SSO) typing. Of the 43 DRB1 alleles tested, 24 were observed. DRB1*0901 (16.85%), *0803 (9.55%), *1202 (9.55%) and *1501 (12.92%) were most frequent and account for the high frequencies of DR9, DR8, DR5 and DR2 specificities in this population. The alleles DRB1*0101, *0102 and *1001 had very low frequencies. Among the 8 DQA1 and 13 DQB1 alleles tested, only DQA1*0401 and DQB1*0402 were absent. DQA1*0301, and DQB1*0301 and *0303 were among the most common alleles of the two loci respectively. Unusual DRB1-DQA1-DQB1 haplotypes were observed and a DRB1 "new" allele was suggested.

Alleles↗
PubMed1995

RG1, a new murine monoclonal antibody recognizing a "supertypic" determinant on HLA-A molecules.

Monomorphic and polymorphic anti-HLA monoclonal antibodies (mAb) are valuable reagents for assessment of the structural and functional importance of different class I determinants. We have generated a new mAb, RG1, reacting with an epitope variably expressed on normal and leukemic hematopoietic cells of different lineages. Immunoprecipitation of the RG1 antigen disclosed a bimolecular complex characteristic of class I proteins. The RG1 epitope was expressed on an HLA-A2 transfected cell line but not on cells transfected with HLA-E, -F or -G molecules. MAb reactivity with reference B-lymphoblastoid cell lines and HLA typing of RG1 reactive and unreactive cells demonstrated that the epitope was expressed in conjunction with defined HLA-A molecules. Cells expressing HLA-A2, -A24(9) and -A68(28) proteins were brightly stained with RG1 whereas mAb binding to HLA-A1, -A11 and a split of A3 molecules was significantly lower. In contrast, the RG1 epitope was apparently not expressed on HLA-A23(9), -A25(10), -A26(10), -A29(19), -A30(19), -A31(19), -A32(19), -A33(19) and some HLA-A3 molecules. Based on class I alpha sequence data, these results suggest that the RG1 epitope is localized to a region of the alpha 2 helix accessible to the T cell receptor for antigen on cytotoxic T lymphocytes. Lys in position 144 and His in position 151 are apparently critical for RG1 binding.

Amino Acid Sequence↗