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PubMed1994

HLA class II DNA typing and subsequent transplantation of an aplastic anemia patient using hair follicles as a DNA source.

Identification of HLA-DR, DQ and DP alleles at the DNA level is an important tool for bone marrow transplantation (BMT). We recently encountered an aplastic anemia patient for whom the ability of molecular HLA typing to utilize alternative sources of DNA proved to be fundamental for her treatment. After repeated failures to obtain HLA typing using peripheral blood, HLA-DR and DQ alleles were identified by molecular techniques utilizing two hairs as a source of DNA, ultimately resulting in successful BMT from a sibling donor. This case clearly illustrates the potential of DNA methodologies for HLA typing in patients whose condition precludes the use of more traditional methods.

Adult↗
PubMed1996

Investigation of the association of major histocompatibility complex genes, including HLA class I, class II and TAP genes, with clinical forms of Crohn's disease.

The aim of this study was to determine immunogenetic markers of susceptibility in Crohn's disease (CD), taking the different features of the clinical course of the disease into account. HLA class I, HLA class II and TAP transporter gene polymorphisms were studied using DNA typing methods. Gene and antigen frequencies were analysed and compared in a group of 102 CD patients and 200 unrelated healthy controls from the same area. Analysis of the whole CD patient population revealed no definite association with either HLA or TAP gene alleles, with the exception of an association with DRB1*1302 (Pc < 0.05). However, when clinical subgroups of patients were considered, specific associations with some genetic markers were found. The most definitive results involved a genetic association in the group of patients who did not respond to glucocorticoid therapy. This group was characterized by a high frequency of HLA-DRB1*04 (P < 0.05). Conversely, a positive association with the TAP2-A allele was found in cortico-responder patients (Pc < 0.03). Furthermore, analysis of the distribution of HLA class II alleles in relation to the presence of extra-intestinal manifestations revealed an association with the DQB1*0501 or *0503 suballele of DQ5 (P < 0.05). Finally, patients with lesions in the small bowel were more frequently HLA DRB1*07 (P < 0.05). The present study supports the concept of clinical heterogeneity in Crohn's disease associated with a background of genetic heterogeneity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

In vitro proliferative responses and antibody titers specific to human acetylcholine receptor synthetic peptides in patients with myasthenia gravis and relation to HLA class II genes.

To investigate which parts of the acetylcholine receptor are involved in the initiation and development of myasthenia gravis (MG), peptides representing different sequences of the human acetylcholine receptor alpha-subunit were synthesized. These peptides were tested for their ability to stimulate T cells of myasthenic patients and healthy control patients in proliferation assays and to bind to sera antibodies. Three of eight peptides discriminated significantly between the two groups in the proliferation assay, as well as in their ability to bind to serum antibodies. HLA-DR3 and DR5 were associated with proliferative responses to specific AChR peptides in the group of myasthenics. Acetylcholine receptor epitopes that might play a specific role in myasthenia gravis thus were demonstrated.

Amino Acid Sequence↗
PubMed1995

HLA class II genotyping: two assay systems compared.

In the last few years, a variety of DNA-based human leukocyte antigen (HLA) typing methods have emerged, revealing the extreme polymorphism of HLA genes. This polymorphism makes it difficult for a clinical laboratory to establish the best HLA typing strategy. In this study we have compared two techniques for performing HLA-DRB typing: a commercial rapid assay based on the polymerase chain reaction (PCR) followed by reverse dot-blot hybridization of the PCR products (the Inno-LiPA assay), and a method based on PCR followed by restriction fragment length polymorphism analysis. We found that both methods provide reliable results with a high rate of concordance (97%) and that Inno-LiPA is convenient for large-scale routine typing. However, if a high-resolution allelic typing is required, each method lacks accuracy but using them in association improves the accuracy of the results.

Alleles↗
PubMed1986

[Analysis of HLA-class II antigen mRNAs on T lymphoblasts].

The expression of human class II antigens on T lineage cells was analysed at the mRNA and the protein levels. Alpha- and beta-chains of class II antigens were identified on phytoheamagglutinin (PHA)-activated T lymphoblasts by two-dimensional polyacrylamide gel electrophoresis analysis. It was, however, not clear whether their spots represent HLA-DR, DQ or -DP antigen. Northern blot analysis using cDNA probes for alpha- and beta-chains of DR, DQ, and DP antigens revealed that mRNAs for all the class II antigen components were detected in PHA-activated T lymphoblasts. Among six T lymphoblastoid cell lines studied (Molt 4, RPMI 8402, CCRF-CEM, TALL 1, HSB 2 and MT-2), only MT-2, a human T cell leukemia virus-1 producing line, expressed class II antigen molecules and their mRNAs. The rest of the lines did not express class II antigens either at the protein level or at the mRNA level. However, Southern hybridization showed that these cell lines retained DQ beta-chain gene at the DNA level.

Antibodies, Monoclonal↗
PubMed1988

HLA class II allelic variation and susceptibility to pemphigus vulgaris.

The autoimmune dermatologic disease pemphigus vulgaris (PV) is associated with the HLA serotypes DR4 and DRw6. Susceptibility to PV could be conferred either by sequences shared between the DR4 and DRw6 haplotypes or by different sequences in these haplotypes. We have examined the distribution of DR and DQ beta-chain and DQ alpha-chain alleles in PV patients and in control subjects by hybridization with oligonucleotide probes and sequence analysis of in vitro amplified DNA. Ninety percent (34/38) of the DR4 haplotypes in patients contain a specific DR beta I sequence present in 36% (16 of 44) of DR4 controls (P = 0.001). This sequence is also found in DRw6 haplotypes. However, it is present in only 25% (6 of 24) of DRw6 patients. The results of our analysis indicate that predisposition to PV is conferred by different sequences in DR4 and DRw6 haplotypes. The DR4 susceptibility is highly associated with the Dw10 DR beta I allele, implicating the polymorphic residues in the third hypervariable region. The DRw6 susceptibility is strongly associated with a rare DQ beta allele (DQB1.3). This allele differs from a common DQ beta allele (DQB1.1) only by a valine----aspartic acid substitution at position 57.

Alleles↗
PubMed1992

HLA class II frequencies in celiac disease patients in the west of Ireland.

Restriction fragment length polymorphism analysis, using a single restriction enzyme TaqI-multiple-probe system for HLA-DRB1-DQB1 and -DQA1, was used to determine HLA-DR and -DQ frequencies in 56 unrelated celiac patients and 47 unrelated controls from the west of Ireland. In addition, HLA-DPB1 allelic frequencies were determined in the same group of patients and controls by using the technique of enzymatic DNA amplification of the polymorphic second exon of HLA-DPB1 genes in conjunction with sequence-specific oligonucleotide probing. The results suggest that HLA-DQ rather than HLA-DR is more important in conferring susceptibility to celiac disease. Furthermore, no association between HLA-DP and celiac disease was found in this study.

Adolescent↗
PubMed1992

HLA class II alleles associated with celiac disease susceptibility in a southern European population.

Susceptibility to celiac disease in Northern Europe is associated with the human leukocyte antigens (HLA) B8, DR3 and DQ2, which exist together on an extended haplotype. The strong predominance of this haplotype within the Northern European celiac populations, together with the linkage disequilibrium which occurs between these loci, does not allow identification of the gene(s) primarily associated with disease susceptibility. Studies from Southern Europe using both serology and examination of restriction fragment length polymorphisms (RFLP) have demonstrated associations with DR3, DR7 and DQ2, suggesting that the DQ locus is primarily involved. We investigated 43 celiac patients and 41 healthy controls from Rome, Italy, using sequence-specific oligonucleotide (SSO) probes, in conjunction with gene amplification by the polymerase chain reaction (PCR), to determine alleles at the DRB, DQA1, DQB1 and DPB1 loci: 19% of celiac patients possessed the alleles DRB1*0301 DRB3*0101, 33% DRB1*0301 DRB3*0201 and 33% of celiac patients were heterozygous for DRB1*1101-1201/DRB1*0701. The strongest association with celiac disease susceptibility was the combination of alleles DQA1*0501 DQB1*0201 (91% celiac patients vs. 12% controls; p = 0.000002). There was no additional susceptibility associated with alleles at the DPB locus. This study confirms the hypothesis that susceptibility is associated with a particular combination of DQ alleles and the ethnic variation in DR frequencies is secondary to linkage disequilibrium with these DQ alleles.

Adolescent↗
PubMed1991

DNA typing for class II HLA antigens with allele-specific or group-specific amplification. IV. Typing for alleles of the HLA-DR2 group.

In this study we present an approach for the definition of the alleles belonging to the HLA-DR2 group by DNA typing with oligonucleotide probes. Following methodology similar to that we used previously for the definition of other HLA-DR subsets, we have now developed primers for DR2-DRB1 and DR2-DRB5 amplification, and probes for the identification of sequences that distinguish the subtypes of this group of genes. The method used defines all the previously described alleles at both DR2-associated DRB loci. In addition, we have identified a variant of DRB1-DR2-Dw2. This new allele has been called DRB1*15.3. It is different from DRB1*1501 in codon 30, where it carries histidine instead of tyrosine. Eight different haplotype combinations of DRB5, DRB1, and DQB1 were identified within the DR2 group and their occurrence in four normal panels of different ethnic origin has been described. Haplotypes containing DRB1*15.3 occurred most frequently in black panel members in whom it was associated with either DQB1*0602 or DQB1*0501. Two unusual haplotypes were observed: one containing elements of DR2-Dw21 (DQB1*0502) and of DR2-Dw22 (DRB1*1602) and one containing elements of Dw21 (DRB1*1601, DQB1*0502) and Dw2 (DRB5*0101). The methods described permit simple and rapid determination of the alleles of the HLA-DR2 group and should be useful for population studies and for investigation of DR2-associated diseases.

Alleles↗
PubMed2003

Heterozygosity or homozygosity for 2 HLA class II haplotypes predict favorable outcomes for renal cell carcinoma treated with cytokine therapy.

PURPOSE: Durable responses to cytokine therapy occur in a small subset of patients with renal cell carcinoma. We determined if a common HLA genotype existed among these patients which might be associated with response and survival. MATERIALS AND METHODS: The study population consisted of 80 patients with metastatic renal cell carcinoma who had received cytokine therapy. DNA obtained from these patients was used for high resolution typing of HLA A, B, C, DRB1, DQA1 and DQB1 alleles. RESULTS: The class II alleles from patients with prolonged disease-free survival were predominantly composed of haplotype DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501/DQA1*0102/DQB1*0602. The frequency of heterozygosity or homozygosity for these alleles was significantly greater in the good outcome group of patients than in those whose disease progressed during therapy. Heterozygosity or homozygosity at these loci was also associated with significant prolongation of survival. CONCLUSIONS: We conclude that heterozygosity or homozygosity for the class II haplotypes DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501/DQA1*0102/DQB1*0602 is associated with durable response and survival in patients with metastatic renal cell carcinoma treated with cytokine therapy.

Adult↗
PubMed1990

HLA class II (DR, DQ) in Japanese patients with type 1 diabetes mellitus.

DNA restriction fragment length polymorphism (RFLP) typing of HLA-DR and DQ alleles of 60 Japanese type 1 (insulin dependent) diabetic patients and 115 controls was performed. RFLP typing of DRB1 showed increased frequency of DR9 and decreased frequencies of DR2 and DRW6 among patients compared to controls. In the RFLP typing of BamHI-digested DNA to DQ beta probe (BamHI-DQB1), the incidence of the 10.26 kb fragment, which represents either DQW4, DQW8 or DQW9, was markedly elevated in the patients, whereas the incidence of DQW6 was reduced. The predicted DR-DQ haplotype study revealed that DR4-DQW4 or DQW8, DRW8-DQW4 or DQW8 and DR9-DQW9 may contribute to susceptibility to type 1 diabetes. When serological typing of the 13 DRW8 patients was performed, all the 11 DRW8 patients carrying DQW4 or DQW8 (BamHI-10.26 kb) were positive for DQW3. These results indicated that the HLA-DQ locus may play an important role in the development of type 1 diabetes in the Japanese as well as other ethnic groups and that the DRW8-DQW8 haplotype may predispose to the disease in Japan.

Alleles↗
PubMed1995

Maternal HLA class II allogenotypes are markers for the predisposition to fetal losses in families of women with unexplained recurrent fetal loss.

The HLA allogenotypes DR1/Br, DR3 and DR10 (entitled risk HLA markers) have been reported as being genetic markers for the predisposition to experience unexplained recurrent fetal losses. The aim of the study was to determine whether the putative risk HLA markers might also be markers for the risk of pregnancy loss in sisters and wives of brothers of women with unexplained recurrent fetal losses. Information concerning pregnancy outcomes among the relatives of 146 consecutive women with unexplained recurrent fetal losses was collected. Ninety-five of the full sisters, 69 of the full brothers and 50 of the wives of the brothers were HLA typed. Sisters who had experienced at least one previous pregnancy loss (affected women) shared more HLA haplotypes with the proband than unaffected sisters, when the proband was positive for the risk markers (P = 0.02). More affected than unaffected sisters and brothers' wives were positive for the risk markers (P < 0.005 and P < 0.03; respectively). The lowest estimate of the odds ratio for experiencing pregnancy loss among sisters and brothers' wives who were positive compared with those negative for the risk markers was 3.5 (95% credible interval = 1.9-5.8). It is concluded that maternal DR1/Br, DR3 and DR10 allogenotypes seem to be genetic markers for the risk of pregnancy loss among relatives of women with unexplained recurrent fetal losses. The pattern of inheritance suggests a polygenic mode of inheritance with alleles linked to the risk HLA markers interacting with non-HLA linked genes expressed on the fetus or the trophoblast.

Abortion, Habitual↗
PubMed1995

The role of HLA class II antigens in the induction of cytotoxic T lymphocytes.

Investigation of pairs of unrelated persons mismatched for a particular HLA-DQB1 or -DPB1 gene on the induction of cytotoxic T lymphocytes (CTL) revealed that HLA-DQ and HLA-DP antigens provided a slight proliferative stimulus which was, however, sufficient for the generation of CTL. Monomorphic anti-DQ and anti-DP monoclonal antibodies abrogated the induction of cytotoxic response. The results indicate that the HLA-DQ and HLA-DP antigens play a similar role to HLA-DR specificities in clinical bone marrow transplantation.

Female↗
PubMed2005

Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris.

Early studies of genetic susceptibility to pemphigus vulgaris (PV) showed associations between human leukocyte antigen (HLA) DR4 and DR6 and disease. The emergence of DNA sequencing techniques has implicated numerous DRB1 and DQB1 loci in various populations, leading to confusion regarding which exact alleles confer susceptibility. The strong linkage disequilibrium among DR and DQ HLA alleles further complicates the investigation of the true susceptibility loci. In this study, we report genotyping data for the largest sampling of North American Caucasian non-Jewish and Ashkenazi Jewish PV patients studied to date and compare our data with other population studies. To pinpoint true susceptibility, alleles among overrepresented sequences, we applied a step-wise reductionist analysis through (1) determination of the degree of linkage disequilibrium (LD) between purportedly associated alleles, (2) haplotype frequencies comparisons, and (3) primary sequence comparisons of disease-associated versus non-disease-associated alleles to identify crucial differences in amino acid residues in putative peptide binding pockets. Collectively, our data provide extended support for the hypothesis that the HLA associations in Caucasian PV patients map to DRB1*0402 and DQB1*0503 alone. Further structure-function studies will be required to define the exact mechanisms of HLA-mediated control of susceptibility and resistance to disease.

Adult↗