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At least 1,207 records · Page 67Linked to original sources
PubMed1999

HLA-B27 subtypes and HLA class II alleles in Japanese patients with anterior uveitis.

PURPOSE: Some patients with anterior uveitis (AU) have ankylosing spondylitis (AS) and are HLA-B27 class I-positive. The purpose of this study was to investigate whether there are differences in HLA at the allele level among each group of patients with AU. METHODS: Seventy-three patients with AU were studied. They were classified into three groups: 31 with AS-associated AU, 14 with HLA-B27-associated AU, and 28 with idiopathic AU. Three control groups without AU were used: 138 random subjects, 33 HLA-B27-positive healthy subjects, and 19 HLA-B27-positive patients with AS. DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-single-strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism. HLA-B27 subtype was determined by PCR-SSCP. RESULTS: There was no difference in the frequency of any class I antigen except HLA-B27 among the patients studied. The frequencies of HLA-DR12 in AS-associated AU and HLA-DR1 in HLA-B27-associated AU showed an increase. In HLA-B27-associated AU, DRB1*0101 and DQB1*0501 were increased compared with HLA-B27-positive control subjects. When HLA-B27 subtype distribution was compared among the groups, the proportion of B*2704 was significantly lower in HLA-B27-associated AU (P = 0.037), however, such a difference was not present in AS-associated groups. CONCLUSIONS: These results indicated that B*2704 seemed to be less susceptible to AU compared with B*2705 in Japanese subjects. The increase of HLA-DR12 and HLA-DR1 in AU may be caused by linkage disequilibrium with B*2704 and B*2705, respectively.

Adult↗
PubMed2000

HLA-B27 and immunogenetics of spondyloarthropathies.

The arthritogenic peptide hypothesis has inspired research aimed at defining the peptide-presenting properties of HLA-B27 subtypes and their relation to ankylosing spondylitis. Various studies have shed new light on the influence of HLA-B27 polymorphism in modulating peptide binding and T-cell antigen presentation. Moreover, multiple factors along the antigen processing-loading pathway, including tapasin, contribute to shaping the HLA-B27 repertoire. Other studies have revealed significant peptide-binding similarities between HLA-B27 and subtypes of HLA-B39, supporting a role of this antigen in spondyloarthropathy. A putative pathogenetic role of the HLA-B27 heavy chain, initially suggested from studies in transgenic mice, is claimed on the basis of novel, yet circumstantial, evidence concerning an apparently unusual capacity of the heavy chain to form stable homodimers or misfold after biosynthesis. Finally, it appears that arthritogenic infections might downregulate HLA-B27 expression, favoring bacterial survival. The specificity and mechanism of this phenomenon are yet to be defined.

Alleles↗
PubMed1988

Polymorphism and complexity of HLA-DR: evidence for intra-HLA-DR region crossing-over events.

HLA-DR molecules were isolated from HLA-DR3, -5, and -w6 positive homozygous B-cell lines by immunoprecipitation with monoclonal antibodies and analyzed by gel electrophoretic techniques. DNA isolated from the same cell lines was digested with the restriction enzyme Taq I and hybridized with a DR beta full-length cDNA probe. We demonstrated that certain DR beta I alleles are found in combination with different DR beta III alleles as defined by Southern blotting, protein chemistry, a functional assay using purified protein derivative-specific T-cell lines, and, in one case, also alloreactive T-cell reagents. Our results indicate that within the family of HLA-DRw52-associated haplotypes DR beta chain genes may have been transferred from one haplotype to another. The implications of these findings are discussed.

Alleles↗
PubMed1991

Aspartic acid at position 57 of the HLA-DQ beta chain is protective against future development of insulin-dependent (type 1) diabetes mellitus.

Insulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQ beta chain. In all other subjects studied, the immunogenetic marker that confers "dominant resistance", aspartic acid at codon 57, was found. On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Adult↗
PubMed2007

Mapping of susceptibility and protective loci for acute GVHD in unrelated HLA-matched bone marrow transplantation donors and recipients using 155 microsatellite markers on chromosome 22.

Despite matching donors and recipients for the human leukocyte antigens (HLAs) expressed by the major histocompatibility genomic region of the short arm of chromosome 6, several recipients still develop acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT). This is possibly due to non-HLA gene polymorphisms, such as minor histocompatibility antigens (mHas) and genes coding for cytokines. However, a detailed genetic background for aGVHD has not yet been established. To find novel susceptibility and/or protective loci for aGVHD, a whole genome-wide association study of donors and recipients needs to be performed. As the first step to such a study, we retrospectively analyzed polymorphisms of 155 microsatellite markers spread across the long arm of chromosome 22 in 70 pairs of HLA-matched unrelated BMT donors and recipients. We performed individual typing and then compared the markers' allele frequencies (1) between all the aGVHD (grades III and IV GVHD) and GVHD-free (grade 0 GVHD) groups in donors and recipients and (2) between the aGVHD and aGVHD-free groups in donor/recipient pairs that were matched and mismatched for the microsatellite marker's allele. Screening of the microsatellite markers revealed five loci with a significant difference between the aGVHD and GVHD-free groups and revealed eight loci on chromosome 22, where the microsatellite allele mismatched markers were associated with aGVHD. This screening analysis suggests that several aGVHD-associated susceptible and protective loci exist on chromosome 22, which may encompass novel gene regions that need to be elucidated for their role in aGVHD.

Acute Disease↗
PubMed1986

[Human T lymphocyte clones: a new approach for studying relations between the major histocompatibility complex and pathology].

Human T cell clones specific of, or restricted by, HLA molecules allow the definition of HLA molecule polymorphism. The advantages of this technical approach are: the definition of a functional polymorphism on the one hand, and the monospecificity of this definition of the other hand. Therefore human T cell clones are unique tools for defining functional epitopes borne by HLA molecules and playing a role in disease associated with HLA.

Clone Cells↗
PubMed2001

High-resolution sequence-based typing strategy for HLA-DQA1 using SSP-PCR and subsequent genotyping analysis with novel spreadsheet program.

We present a new sequence-based typing (SBT) strategy for the polymorphic HLA-DQA1 locus that is based on sequence-specific primer - polymerase chain reaction (SSP-PCR) amplification from genomic DNA. This method allows high-resolution genotyping in the second exon of the DQA1 gene. This gene presents a unique situation in which half of the known alleles contain an inframe three base pair deletion of codon 56. This deletion confounds direct SBT methodologies of heterozygous individuals containing both a deletion and nondeletion allele. The primary HLA haplotype associated with type 1 diabetes susceptibility is DR3/DR4. The DQA1 genotype for these two haplotypes are DQA1 *0501, a non-deletion allele and *0301, a deletion allele, thus creating a situation that cannot be resolved using a direct sequencing approach. Our group-specific SBT strategy isolates the deletion alleles from the nondeletion alleles, allowing them to be resolved by direct sequencing. Additionally, we present a novel spreadsheet program that accurately assigns the genotype of both homozygous and heterozygous persons.

Alleles↗
PubMed1991

Immunogenetics of the HLA system.

The study of the HLA system was primarily initiated to understand the basis for the histocompatibility between recipients and tissue donors. HLA typing methods are being continuously improved and biochemical and molecular typing, in particular, are expected to provide precise typing of the HLA system. Conventional HLA typing methods can define antigen specificities, while biochemical and molecular methods will provide direct allele typing that is based on the actual sequence polymorphism. The precise tissue typing will definitely improve the outcome of transplantation. Structural studies have revealed the highly polymorphic nature of the HLA system and given insight to understanding the molecular basis of the HLA polymorphism. One big immunological puzzle remaining to be answered is how T-cell receptor molecules recognize peptide antigen in conjunction with the HLA molecule. The crystallization of the T-cell receptor molecule, an experiment currently underway, will eventually reveal the structural basis of the trimolecular interaction.

Animals↗
PubMed2001

Plasma tumor necrosis factor alpha levels and the -238*A promoter polymorphism in patients with antiphospholipid syndrome.

OBJECTIVES: To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFalpha in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNFalpha and disease. PATIENTS AND METHOD: We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFalpha levels were determined in plasma from 35 patients' and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. RESULTS: TNFalpha levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p <0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306.5], p <0.0001). CONCLUSIONS: Raised plasma TNFalpha levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFalpha may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNF genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.

Adolescent↗
PubMed2004

The distribution of polymorphic Alu insertions within the MHC class I HLA-B7 and HLA-B57 haplotypes.

There are five polymorphic Alu insertion (POALIN) loci within the major histocompatibility complex (MHC) class I region that have been strongly associated with HLA class I alleles, such as HLA-A1, HLA-A2 and HLA-B57. In order to assess the variability and frequency of POALIN distribution within two common HLA-B haplotypes, we detected the presence of the MHC class I POALIN by PCR in a panel of 15 individuals with HLA-B57 and 47 homozygous individuals with 7.1 AH (HLA-B7, -Cw7, -A3) obtained from the Australian Bone Marrow Donor Registry, and also from four families (25 individuals) containing the HLA-B57 allele. Only two of the 47 HLA-B7 genotypes had a detectable POALIN, whereas all of the HLA-B57 genotypes had at least one or more POALINs present, confirming that certain MHC class I haplotypes are relatively POALIN-free and others are POALIN-enriched. Six distinct HLA-B57 haplotypes, based on differences at the HLA-A locus and three of five POALIN loci, were identified that appear to have evolved by different mechanisms, including either by shuffling different combinations of conserved alpha and beta blocks or by recombination events involving two or more previously generated HLA-B57 haplotypes.

Alleles↗
PubMed2003

Polymorphism in clinical immunology - From HLA typing to immunogenetic profiling.

The pathology of humans, in contrast to that of inbred laboratory animals faces the challenge of diversity addressed in genetic terms as polymorphism. Thus, unsurprisingly, treatment modalities that successfully can be applied to carefully-selected pre-clinical models only sporadically succeed in the clinical arena. Indeed, pre-fabricated experimental models purposefully avoid the basic essence of human pathology: the uncontrollable complexity of disease heterogeneity and the intrinsic diversity of human beings. Far from pontificating on this obvious point, this review presents emerging evidence that the study of complex system such as the cytokine network is further complicated by inter-individual differences dictated by increasingly recognized polymorphisms. Polymorphism appears widespread among genes of the immune system possibly resulting from an evolutionary adaptation of the organism facing an ever evolving environment. We will refer to this high variability of immune-related genes as immune polymorphism. In this review we will briefly highlight the possible clinical relevance of immune polymorphism and suggest a change in the approach to the study of human pathology, from the targeted study of individual systems to a broader view of the organism as a whole through immunogenetic profiling.

Journal Article↗
PubMed2001

Polymorphisms in the tumor necrosis factor (TNF) genes are associated with susceptibility to effects of ultraviolet-B radiation on induction of contact hypersensitivity.

We investigated the allelic distributions of single nucleotide polymorphisms (SNPs) of the TNFA, TNFB and IKBL genes, 3 microsatellites within the tumor necrosis factor (TNF) region of HLA locus, and the HLA phenotypes as well as the TLR4 gene in Chromosome 9 in 26 healthy Caucasian volunteers. These individuals were also assessed as ultraviolet B (UVB)-susceptible (S) or UVB-resistant (R). Our results identified 12 UVB-S and 14 UVB-R individuals. Attempts to correlate particular HLA-A, -B, -C, and -DR antigens with the UVB phenotypes failed. Similarly, attempts to correlate SNP at the NcoI-RFLP within intron 1 of the TNFB, IKBL and TLR4 gene with UVB phenotypes also failed. However, microsatellite analyses of TNFa, TNFc, and TNFd markers revealed a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of 5 SNPs of the TNFA promoter region revealed a significant increase in the frequency of the allele B of the TNFA gene (TNFApB) representing the nucleotide A at position -863 and C at position -1031 (P=0.015). Since it is known that TNFa2 and TNFApB is a high TNF-alpha responder, whereas TNFd3 is a TNF-alpha low responder, we propose that the TNF region of HLA contains polymorphic genes that confer susceptibility and resistance to the deleterious effects of UVB radiation on the induction of contact hypersensitivity. This proposal is consistent with previous reports that a unique microsatellite region of the Tnfa gene in mice contains alleles that dictate the UVB-dependent phenotypes in mice, and implicate TNF-alpha as the primary mediator of the immune-damaging effects of UVB radiation.

Adaptor Proteins, Signal Transducing↗
PubMed1989

An allelic cluster of DQ alpha restriction fragments is associated with multiple sclerosis: evidence that a second haplotype may influence disease susceptibility.

Extensive analysis of restriction fragment length polymorphism using HLA class II and T-cell receptor gene probes has been carried out in an attempt to identify genetic markers more strongly associated with multiple sclerosis than the classically defined antigens DR2, Dw2, and DQw1. The use of DNA pooled from groups of patients and controls from northeast Scotland enabled the screening of 14 restriction endonucleases with five HLA-D region probes (DP alpha, DP beta, DQ alpha, DQ beta, DR beta) and two T-cell antigen receptor probes. Restriction fragment length polymorphisms which discriminated between multiple sclerosis and control pools were identified with four restriction enzymes: Msp1 (DQ alpha), BamH1, Bgl11, and Taq1 (DQ beta). No discriminatory polymorphism was seen with any of the other enzyme/probe combinations. Subsequent Southern blot analysis of individual DNA samples was carried out using these enzymes and probes in two independently conducted studies, in Northern Ireland and northeast Scotland. Following Msp1-digestion and hybridization to DQ alpha, a 3.25-kb fragment was observed in 31% of Scottish patients but in only 4% of controls from the same population. Furthermore, when only DR2-positive individuals were analyzed, there was a significant excess of this fragment in patients from both Scotland (28, or 2.9%) and Northern Ireland (20, or 3.4%). Although the DQ alpha gene characterized by this fragment remains to be determined, this fragment exhibits apparent allelism to DQw1. Therefore, these data raise the possibility that two different DQ alleles, one on each haplotype, may jointly contribute to disease susceptibility.

Alleles↗
PubMed1996

HLA class I and II polymorphisms and trachomatous scarring in a Chlamydia trachomatis-endemic population.

Immune responses to Chlamydia trachomatis contribute to protection from infection and to immunopathologic disease. To test whether subjects' HLA class I (A, B, and Cw) or class II (DRbeta1 and DQbeta1) types influence risk of trachomatous scarring from chronic infection with C trachomatis, 153 cases and pair-matched controls in Gambia were studied. No HLA type was associated with protection from scarring, indicating that protective immune responses are not limited to only one or a few HLA-restricted epitopes in C. trachomatis antigens. One class I antigen, HLA-A28, was significantly more common among cases than controls (25.8% vs. 15.9%, respectively; McNemar's odds ratio [OR], 1.88; 95% confidence interval [CI] = 1.01-3.49; P = .046). In DNA subtyping of the A28 specificity, the A*6801 allele was equally common among cases and controls, but the A*6802 allele was significantly overrepresented among cases (McNemar's OR, 3.14; 95% CI = 1.32-7.44; P = .009). This association may be due to an immunopathologic HLA-A*6802-restricted cytotoxic T lymphocyte response.

Adolescent↗
PubMed1997

Genetic risk factors in inflammatory abdominal aortic aneurysms: polymorphic residue 70 in the HLA-DR B1 gene as a key genetic element.

PURPOSE: Evidence of a genetic predisposition to the development of inflammatory abdominal aortic aneurysms (AAAs) exists as a positive family history in 17% of patients. Familial clustering and other similarities between inflammatory AAAs and giant cell arteritis (GCA), which possesses a genetic risk determinant mapped to the HLA-DR molecule, suggest a role of genetic risk factors in inflammatory AAAs. The purpose of this study was to explore whether patients with inflammatory AAAs express disease-relevant genes associated with the HLA-DR region on the short arm of chromosome 6. METHODS: Thirty-seven patients with histomorphologic findings of inflammatory AAA at operation were genotyped for the polymorphism of the HLA-DR B1 and HLA DQ B1 alleles and compared to ethnically matched, healthy control subjects (n = 90). RESULTS: Distribution of HLA-DR B1 alleles was nonrandom in patients with inflammatory AAAs versus control subjects. The HLA-DR B1 alleles B1*15 and B1*0404 were enriched in patients with inflammatory AAAs compared with control subjects (47% versus 27%, and 14% versus 3%; p < 0.05, respectively). Analysis of functionally relevant amino acid polymorphisms encoded by the HLA-DR B1 gene showed relevance at amino acid position 70. HLA-DR B1 alleles overrepresented in patients with inflammatory AAAs express a glutamine substitution at position 70, whereas alleles disfavored in the patient cohort express a negatively charged aspartic acid. Distribution of HLA-DQ B1 alleles were indistinguishable in patients and control subjects. CONCLUSION: These data indicate that a genetic risk determinant can be mapped to the HLA-DR B1 locus in patients with inflammatory AAAs. This association suggests a critical contribution of antigen binding in the pathogenesis of this disease.

Aged↗