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At least 19 recordsLinked to original sources
PubMed1992

Susceptibility to primary biliary cirrhosis is associated with the HLA-DR8-DQB1*0402 haplotype.

In studies to date seeking associations between human leukocyte antigens (HLA) and primary biliary cirrhosis, no class I association but several different class II associations have been described. The aims of this study were to reassess the DR associations in primary biliary cirrhosis and to examine for the first time the role of DQB. DRB genotypes were determined on standard Taq1 restriction-fragment-length polymorphism analysis in 159 white northern European patients with the disease and 162 racially matched local controls. Polymerase chain reaction gene amplification and sequence-specific oligonucleotide analysis were used to determine DQB genotypes in 89 patients and 181 controls. An increased frequency of human leukocyte antigen DR8 was observed in the patient group (11% vs 4%; relative risk = 3.3; p < 0.01). Although we saw an increased frequency of the DQB1*0402 allele (11% vs. 3%; relative risk = 3.5; p < 0.025), this was not significant after correction for multiple testing. The strongest association was with the two-locus haplotype DR8-DQB1*0402 (11% vs. 2.2%; relative risk 5.5; p < 0.001). The DRB data reported here confirm the findings of previous studies, although the described association with DR8 is considerably weaker. The weak genetic contribution of human leukocyte antigen in the susceptibility to primary biliary cirrhosis is in contrast to its role in other autoimmune liver diseases.

Adult↗
PubMed1992

Nucleotide sequences of the HLA-DRw12 and DRw8 B1 chains from an Australian aborigine.

To gain a more detailed understanding of the molecular structure of the HLA genes in Australian aborigines, the polymorphic first-domain sequences of the DR B alleles were determined in an aborigine who was tissue typed as HLA-DRw8 and a probable DRw12; DRw52; DQw1,7. Both peripheral blood leukocytes and a lymphoblastoid cell line were reactive with the majority of DRw12-specific sera, but also with half of the DRw11-specific sera. With the use of primers specific for the conserved regions flanking the first domain, the polymerase chain reaction technique was used to amplify first-strand synthesis products prepared from the cell line. Two distinct DRB1 sequences were obtained. One was virtually identical to the reported DRw8,Dw8.3 sequence present in an Asian haplotype, differing only by a single silent nucleotide substitution at the third position of codon 36 (A to G). A second DRB allele was closely related to two recently published and nearly identical sequences for DRw12, with amino acid differences at positions 67 and 85 of the first domain. DRB RFLP studies on this cell line using the Taq I restriction enzyme indicated bands previously described for the DRw8 and DRw12 haplotypes.

Amino Acid Sequence↗
PubMed1992

Association between IgE response against Bet v I, the major allergen of birch pollen, and HLA-DRB alleles.

The association of the human IgE response against Bet v I, the major allergen of birch pollen, and the HLA-DR and DQ phenotype was studied. Birch pollen allergic patients showed a typical case history, positive skin-prick test, and positive RAST with birch pollen extracts. They were divided into two groups. Group I (n = 37) consisted of individuals generating IgE antibodies that selectively reacted with Bet v I. Their serum IgE did not react with minor allergens from birch pollen as tested by immunoblot analysis, nor did they show a response against allergens from a panel of grass and other tree pollen or perennial allergens from animals and fungi as determined by skin-prick test. Patients belonging to group II (n = 34) possessed IgE reacting with Bet v I plus one or more additional allergens. The control group consisted of 637 healthy blood donors. Comparison of the frequencies of RFLP-defined HLA-DR and DQ alleles in patients and the control group revealed that the distribution of DRB3 alleles in group I patients differed significantly from that in the control group: A higher frequency of the DRw52a/c alleles in comparison to the control group (pcorr less than 0.02) was observed. In addition, alleles defined by nucleotide sequences coding for the amino acid sequence tyrosine-phenylalanine-histidine at positions 30-32 of the beta chain of DR molecules were found with a higher frequency in patient group I (pcorr less than 0.02), too. These alleles comprise DRw52a/c and some DRB1 alleles.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Familial IgA nephropathy: a study of HLA class II allogenotypes in a Chinese kindred.

We have studied the restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II DQ, DR pattern of a Chinese family with IgA nephropathy (IgAN). The three affected and one apparently unaffected sibling shared the same DR and DQ pattern. The subjects were homozygous for DRw12, DQw7, DQ alpha 1b. The DQw7 allele was further confirmed by polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) probing. This study confirms that IgAN can run in a family and is consistent with the possible immunopathogenetic effects of MHC class II antigens on IgAN.

Adult↗
PubMed1992

Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E.

Superantigens are thought to make external contacts with major histocompatibility complex (MHC) class II molecules and with the V beta portion of a T cell antigen receptor (TCR), thereby stimulating entire families of T cells. The precise mapping of superantigen binding sites on class II molecules may provide valuable information on how TCR and MHC molecules interact. Two bacterial superantigens, staphylococcal enterotoxins A and E (SEA/SEE) bind well to most HLA-DR alleles, but poorly to HLA-DRw53. The sequences responsible for this binding were localized to the putative alpha helix of the DR beta chain by measuring toxin binding to a panel of chimeric class II molecules expressed on transfected cells. Binding of SEA/SEE to the DRw14 (Dw9) molecule suggested that the conserved histidine 81 in the beta chain of most DR molecules was important, whereas the tyrosine 81 in the DRw53 beta chain was detrimental for high-affinity binding. To prove this, reciprocal point mutations were introduced in the DR1 and DRw53 beta chains. Mutation of histidine 81 in the DR1 beta chain to tyrosine reduced SEA/SEE binding, but did not prevent recognition of two DR1-restricted peptides by six of eight antigen-specific T cell lines. Conversely, introduction to histidine at position 81 in the DRw53 beta chain restored normal levels of SEA/SEE binding. These data suggest that a binding site of SEA and SEE lies on the outer face of the beta chain alpha helix, pointing away from the antigen-binding groove.

Amino Acid Sequence↗
PubMed1992

A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201.

This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named "Sardinian haplotype" because of its frequency (12-15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of "Sardinian haplotype" was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p less than 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.

Adult↗
PubMed1992

Studies of the HLA class II alleles involved in human responses to ragweed allergens Ambrosia artemisiifolia V (Ra5S) and Ambrosia trifida V (Ra5G)

Previous studies have associated skin test sensitivity and specific IgE response to Ambrosia artemisiifolia V (Amb a V) with HLA-DR2, and to Ambrosia trifida V (Amb t V) with HLA-DRw52 haplotypes in atopic individuals. Using HLA class II typing by restriction fragment length polymorphism (RFLP) analysis with DRB, DQB and DQA DNA probes to define the HLA-D alleles, we have demonstrated the association of the DQw6 in 16 out of 16 (100%) Amb a V-responsive individuals, compared to 3 out of 18 (17%) ragweed-sensitive but Amb a V-nonresponsive individuals (p = 5.7 x 10(-6), RR greater than 75). We suggest that the DQw6 association with Amb a V sensitivity may be a reflection of an association with the DQA*0102 allele. This suggests an association of a particular HLA class II allele with an immune response to a well-characterized antigen (Amb a V). The HLA-DRw52 haplotypes in the Amb t V-sensitive individuals are not of one particular subtype. The HLA-DRw52 association with Amb t V sensitivity may reside in homologous DRB1 alleles linked on HLA-DRw52-bearing haplotypes.

Alleles↗
PubMed1992

Studies of RFLP-inferred HLA-DR-DQ haplotypes in Danish women with recurrent fetal losses.

Results of HLA-DR and -DQ typing by RFLP in 152 unrelated women with at least 3 unexplained fetal losses were compared with those of 210 normal controls. The overall distribution of DR-DQ phenotypes did not differ significantly between patients and controls. In a subgroup of 59 patients having had at least 4 fetal losses, a significantly higher number of patients than controls were DRw17,DQw2-positive (RR = 2.9, pcorrected less than 0.02). DR-DQ haplotypes which carry DQB1 alleles encoding an amino acid other than aspartic acid at codon 57 in the second exon (non-Asp57 haplotypes) have been reported to confer susceptibility to several immunologically-mediated diseases. We found that the total frequency of non-Asp57 haplotypes (other than DR7,DQw2 which has unique features) was significantly increased in patients (50.0%) compared with controls (39.3%) (p less than 0.005). In the total group of patients and in the group with at least 4 fetal losses, 22.4% and 32.2% respectively were homozygous non-Asp57/non-Asp57 compared with 13.3% among controls (RR = 1.9, p less than 0.025 and RR = 3.1, p less than 0.001, respectively). The results suggest that DRw17,DQw2 confers susceptibility to suffer recurrent fetal losses. However, it is possible that the HLA-associated susceptibility may be primarily conferred by DQ molecules lacking aspartic acid at codon 57 in the DQ beta chain.

Abortion, Habitual↗
PubMed1992

Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.

DNA sequence analysis of class II HLA from Caucasian and black patients with type 1 (insulin-dependent) diabetes mellitus has suggested that aspartic acid at position 57 (Asp 57) of the DQ beta chain provides protection against insulin-dependent diabetes mellitus (IDDM). In contrast, most Japanese patients with IDDM have Asp 57-positive alleles. To determine the reason for the differences and to localize the HLA-linked diabetogenic gene in Japanese, we studied the DQA1 and DQB1 genes of Japanese patients with IDDM and control subjects by the polymerase chain reaction in combination with restriction fragment length polymorphism analysis. Associations of DQA1*0301 and DQB1*0303 with IDDM were observed. DQA1*01 was associated negatively with IDDM. The HLA-DR9 haplotype, which is associated positively with IDDM in Japanese, was associated with DQA1*0301 and DQB1*0303, indicating that the Japanese DR9 haplotype is the same as that in caucasians but different from that in blacks. Of the loci on Japanese DR9 haplotypes, the DQA1*0301 allele showed the highest association with IDDM. DQB1*0303 was also positively associated with IDDM. Since DQB1*0303 is identical to DQB1*0302 except that it contains Asp 57, the data suggests that an Asp 57-positive allele confers susceptibility to IDDM when the whole molecule of the DQ beta chain is similar to other susceptible DQ beta chains. DQA1*0301 appears to be a marker of IDDM in all these populations: Japanese, caucasian, and black.

Adult↗
PubMed1992

[Research on myasthenia gravis in children with HLA supratype].

38 cases of MG Children's patients were typed for HLA-I, II and III antigens. It shows that MG significantly associated with HLA-A2, Bw46 and DRw9. Their relative risk were 3.60, 8.18. 4.60, Pc < 0.05 or 0.001 respectively. The association with C4 and Bf were not found. Aw19 is seemed as a protection factor of this disease. These results are similar with the research on Chinese MG patients in Hong Kong but are quite different with those of caucasian data.

Asian People↗
PubMed1992

[HLA-DR gene frequencies in IgA nephropathy patients obtained by oligonucleotide genotyping].

HLA-DR alleles of 255 healthy northern Chinese donors and 30 IgA nephropathy (IgAN) patients were determined by using a set of 30 different sequence specific oligonucleotide (SSO) probes directed to various DRB alleles. We found that SSO typing gave high gene frequencies for the alleles DR2, DR7 and DR 9 in the northern Chinese Han donors, while we obtained significantly high gene frequency for DRw12 in IgAN, especially in those with massive proteinuria and recurrent gross hematuria, indicating that those who have DRw12 may form a high risk population of IgAN.

Adult↗
PubMed1992

HLA-D-region genomic DNA restriction fragments in DRw15 (DR2) familial narcolepsy.

Restriction fragment length polymorphism (RFLP) associated with the three human lenkocyte antigen (HLA)-D-region gene-specific cDNA probes (gene-specific DQ alpha, DQ beta and DP beta) was evaluated in two Caucasian families from southwestern Ontario, each with two confirmed narcoleptic siblings. The special feature of the two families is that the affected members are not necessarily DRw15 (previously DR2) positive. In family 1, of the two affected sibs one is DRw15 positive, whereas in family 2 all members including the two affected sibs are DRw15 negative. There is no association between narcolepsy and HLA haplotype in the two families. Further, the polymorphic DNA band patterns generated by a number of restriction enzymes do not show a relationship with the presence or absence of narcolepsy. The probe-specific DNA and patterns however do follow the HLA haplotypes associated with the DQ and DR loci. These results suggest that in DRw15-negative narcolepsy, the DNA patterns are not informative with respect to diagnosing or predicting the presence of narcolepsy. Further, such results argue for genetic heterogeneity in narcolepsy, and the role of DRw15 in the development of the disease could at best be viewed as contributory and not essential.

DNA↗
PubMed1992

Investigation of the mode of inheritance of insulin-dependent diabetes mellitus in Japanese subjects.

Previous studies have shown that insulin-dependent diabetes mellitus is positively associated with HLA-DR4 and HLA-DR9 in Japanese populations. It was proposed that susceptibility to the disease is determined by a single HLA allele associated with both DR4 and DR9. DR genotypes in a Japanese population with insulin-dependent diabetes mellitus were determined by DRB/DQB RFLP analysis. A single disease-susceptibility-allele model was tested by the antigen-genotype-frequency-among-patients method. Recessive and additive inheritance of a single susceptibility allele were rejected. The DR9-associated disease-susceptibility allele in Japanese subjects is distinct from both the DR3- and DR4-associated susceptibility alleles in white Caucasians. The data suggest further complexity in the inheritance of HLA-associated susceptibility to insulin-dependent diabetes mellitus.

Adult↗
PubMed1992

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.

OBJECTIVE: In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS: We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS: DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION: Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.

Amino Acid Sequence↗
PubMed1992

HLA-DR and DQ matching by DNA restriction fragment length polymorphism methods and the outcome of mixed lymphocyte reaction tests in unrelated bone marrow donor searches. The IMUST Study.

The use of DNA restriction fragment length polymorphism (DNA-RFLP) typing for HLA-DR and DQ genes was assessed in 96 patients who were HLA-A,B and DR matched by serology with one or more potential unrelated marrow donors (UD). Two hundred recipient-donor pairs from 10 transplant centres in the UK were studied. DNA-RFLP revealed serological errors in HLA-DR typing and identified additional recipient-donor mismatches. Of the 200 allegedly serologically matched pairs, 55 (28%) were mismatched for HLA-DR and/or DQ by DNA-RFLP typing. Of the 200 pairs, 68 (34%) mixed lymphocyte reactions (MLR) were negative and 132 (66%) positive. There was a significant correlation between DNA-RFLP defined mismatch and MLR positivity. However quantitative studies revealed no trend towards increasing MLR relative response index (RRI) with cumulative RFLP defined mismatch (i.e. for DR plus DQ compared with DR or DQ alone). RFLP matching for HLA-DR and DQ failed to predict a negative MLR. The RRI in the graft-versus-host direction was greater in RFLP matched pairs who carried HLA-DR4 than in matched pairs lacking DR4, suggesting that failure of RFLP to characterize DR4 subtypes was one reason why routine prediction of a negative MLR was not possible. Despite these limitations we have shown that DNA-RFLP is a reliable method for HLA-DR, DQ typing in routine UD searches in diverse clinical centres. By reducing the number of UD tested in MLR, RFLP typing can substantially reduce the work involved in donor selection.

Bone Marrow Transplantation↗
PubMed1992

About DR beta-restriction fragment length polymorphism (RFLP) analysis in kidney transplantation in connection with a paediatric patient.

A retrospective analysis of the HLA-DR antigens was performed at the DR beta DNA locus by the means of restriction fragment length polymorphism (RFLP) in the case of a two-times kidney transplanted paediatric patient and in 16 adult kidney donor recipient pairs in order to prove the importance of DNA molecular analysis in those cases where the serological identification is poor. The child and her grafts (first from her mother, the second from a cadaver donor) carried the DRw6 antigen which serologically can very poorly be defined. According to DR serotyping before transplantation both the child and the cadaver kidney proved to be DR5, 6, while the DNA analysis revealed mismatches; the child possessed the two subtypes: 13b1 and 14a of the DRw6 antigen only and none of the DR5, the cadaver kidney proved to belong to the DR4 antigen group instead of DR5, and furthermore to a different subtype of the DRw6 (13a3) than the recipient. The DNA analysis of other 16 adult donor-recipient pairs also underlined the importance of the DR beta RFLP analysis in cases where the transplantation antigens could be poorly defined.

Adult↗
PubMed1992

Oligonucleotide genotyping of HLA polymorphism on microtitre plates.

Molecular analysis of mutations and polymorphisms that are of medical importance requires both accuracy and simplicity. In organ transplantation there is a need for an HLA typing procedure that combines the remarkable accuracy of oligonucleotide genotyping with the simplicity of conventional serological typing. We describe a simple semiautomated method of HLA class II typing consisting of an oligonucleotide hybridisation assay done on microtitre plates followed by automatic colorimetric reading. Individual HLA-DR generic typing for 30 DR specificities, including subtypes of DR1, DR2, DR13, DR14, and DR52, is done on a single plate. The entire typing assay can be completed in less than 4 hours. The procedure has been validated on more than a thousand haplotypes in prospective DR typing of kidney transplant patients, leukaemic patients, and their potential donors. The simplicity of this assay makes it suitable for routine laboratory use. It can be applied to genetic testing in general, including the testing of patients with multiple mutations.

Base Sequence↗