Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HLA-B*2702 is an ankylosing spondylitis-associated allotype that differs from the more common B*2705 at residues 77, 80, and 81, in the peptide-binding site. The diversity and fine specificity of alloreactive cytolytic T-lymphocyte (CTL) raised against B*2702 were analyzed at the clonal level. Significant crossreaction with B*2705 and B*2709 indicated that the three subtypes share numerous T-cell epitopes. However, some epitopes shared by B*2702 and B*2705 were lost in B*2709, which correlates with weaker association of this subtype to disease. Clonal specificities were donor-dependent, indicating that allo-immunogenicity is variable among individuals. Anti-B*2702 CTL were little affected by single mutations mimicking B*2702/B*2705 polymorphism, but the double mutant at positions 77 and 81 was recognized worse than B*2705, suggesting a compensatory effect of residue 80. Thus, HLA-B27 polymorphism modulated alloreactivity through cooperative and compensatory effects on T-cell epitope structure. Comparison of B*2705- and B*2702-bound peptide repertoires revealed that they overlapped by 73% and 81%, respectively. This was larger than B*2702/B*2705 cross-reaction, indicating that HLA-B27 allospecificity is only partially determined by the nature of peptide repertoires. The large sharing of natural ligands and T-cell epitopes is consistent with a pathogenetic role of B*2702 and B*2705 in spondyloarthritis based on antigen presentation.
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PMID:Large sharing of T-cell epitopes and natural ligands between HLA-B27 subtypes (B*2702 and B*2705) associated with spondyloarthritis. 1192 85

HLA-B27 is strongly associated with spondyloarthropathies, including ankylosing spondylitis and reactive arthritis. The latter disease is triggered by various Gram-negative bacteria. A dodecamer derived from the intracytoplasmic tail of HLA-B27 was a natural ligand of three disease-associated subtypes (B*2702, B*2704, and B*2705) but not of two (B*2706 and B*2709), weakly or not associated to spondyloarthropathy. This peptide was strikingly homologous to protein sequences from arthritogenic bacteria, particularly to a region of the DNA primase from Chlamydia trachomatis. A synthetic peptide with this bacterial sequence bound in vitro disease-associated subtypes equally as the natural B27-derived ligand. The chlamydial peptide was generated by the 20 S proteasome from a synthetic 28-mer with the sequence of the corresponding region of the bacterial DNA primase. Molecular modeling suggested that the B27-derived and chlamydial peptides adopt very similar conformations in complex with B*2705. The results demonstrate that an HLA-B27-derived peptide mimicking arthritogenic bacterial sequences is a natural ligand of disease-associated HLA-B27 subtypes and suggest that the homologous chlamydial peptide might be presented by HLA-B27 on Chlamydia-infected cells.
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PMID:Molecular mimicry of an HLA-B27-derived ligand of arthritis-linked subtypes with chlamydial proteins. 1212 5

The presence of HLA-B27 in patients affected with ankylosing spondylitis (AS) was well established prior to the advent of DNA typing of various genes within the major histocompatibility complex (MHC) in humans. However, molecular typing of the MHC genes revealed that B27 comprises a motley assortment of alleles, some of which are strongly positively associated with the disease and some of which are negatively associated with the disease. B*2706 was reported to have a negative association with AS in the Thai population and in Chinese Singaporeans. We report here our finding of an absence of B*2706 in 184 Taiwanese AS patients.
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PMID:Low frequency of HLA-B*2706 in Taiwanese patients with ankylosing spondylitis. 1235 55

There is substantial evidence strongly favouring a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis (AS) and related spondyloarthropathies (SpA), although the underlying molecular basis has yet to be identified. HLA-B27 itself is a serologic specificity that encompasses 26 different alleles that encode 24 different subtypes - HLA-B*2701 to B*2725, with the exclusion of B*2722. [The B*2722 allele was deleted as an official WHO allele in April 2002, with a note that the reference cell has been shown to have the same sequence as B*2706. Thus, from now on, with this deletion of B*2722, there will be a "hole" among the HLA-B*2701 to B*2725 group of alleles]. The 24 HLA-B27 alleles (subtypes) seem to have evolved from the most widespread subtype, B*2705. Two B27 alleles have been reported to lack association with AS: B*2706 among Southeast Asian populations, and B*2709 among Sardinians. The distinction between the disease-associated subtypes and those that are not disease-associated may provide some clues to the actual role of HLA-B27 in disease pathogenesis. Genetic family studies in populations of European descent indicate that HLA-B27 contributes only 16 % of the total genetic risk for the disease. The genes in the Major Histocompatibility Complex (MHC) as a whole, that includes HLA-B27, account for about half of the genetic susceptibility for AS. This clearly indicates the presence of additional disease predisposing genes in the MHC region on chromosome 6, and genome-wide studies have identified many areas of interest on other chromosomes that may contain additional disease predisposing genes. Additional studies emanating from the recent mapping of the human genome is expected to lead to better understanding of the genetic basis of these and other rheumatic diseases. Genetic counselling and the use of HLA-B27 typing as an aid to diagnosis are also reviewed.
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PMID:Genetic aspects of ankylosing spondylitis. 1240 34

The human leukocyte antigen (HLA) alleles HLA-B*2704 and HLA-B*2706 show an ethnically restricted distribution and are differentially associated with ankylosing spondylitis, with HLA-B*2706 lacking association with this autoimmune disease. However, the products of the two alleles differ by only two amino acids, at heavy-chain residues 114 (His in HLA-B*2704; Asp in HLA-B*2706) and 116 (Asp in HLA-B*2704; Tyr in HLA-B*2706). Both residues could be involved in contacting amino acids of a bound peptide, suggesting that peptides presented by these subtypes play a role in disease pathogenesis. Two HLA-B*2706-peptide complexes were crystallized using the hanging-drop vapour-diffusion method with PEG as precipitant. Data sets were collected to resolutions of 2.70 A (viral peptide pLMP2, RRRWRRLTV; space group P2(1)2(1)2(1)) and 1.83 A (self-peptide pVIPR, RRKWRRWHL; space group P2(1)). Using HLA-B*2705 complexed with the pGR peptide (RRRWHRWRL) as a search model, unambiguous molecular-replacement solutions were found for both HLA-B*2706 complexes.
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PMID:X-ray diffraction analysis of crystals from the human major histocompatibility antigen HLA-B*2706 in complex with a viral peptide and with a self-peptide. 1651 Dec 45

The association of HLA-B27 with ankylosing spondylitis accounts for nearly 40% of the total disease risk. However, fewer than 5% of B27-positive individuals in the general population become affected. Genomewide scans suggest that other major histocompatibility complex genes further heighten this risk, although linkage disequilibrium with HLA-B27 has confounded their precise identification. Over 31 variants of HLA-B27 have been identified to date, which have evolved from the original B27 allele (B*2705) along three geographic lines. HLA-B*2705 and B*2702 are the primary subtypes in Caucasians with spondylitis, and B*2704 and B*2707 are the primary subtypes in Asians. HLA-B*2706 and B*2709 are not disease associated. There are four theories of how HLA-27 causes spondyloarthritis: (1) HLA-B27 presents a bacterially derived 'arthritogenic peptide' (not yet identified); (2) misfolding or homodimerization of HLA-B27 heavy chains results in a pro-inflammatory response; (3) HLA-B27-positive individuals have deficient intracellular killing of arthritogenic organisms; and (4) HLA-B27 itself, due to sequence homology with bacterial proteins, becomes autoantigenic.
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PMID:Major histocompatibility genes and ankylosing spondylitis. 1677 85

HLA-B*2707 is associated with ankylosing spondylitis in most populations. Like the non-associated allotypes B*2706 and B*2709, it lacks Asp116 and shows preference for peptides with nonpolar C-terminal residues. The relationships between the peptide specificity of B*2707 and those of the disease-associated B*2705 and the non-associated subtypes were analyzed by determining the overlap between the corresponding peptide repertoires, the sequence of shared and differential ligands, and by comparing allospecific T cell epitopes with peptide sharing. The B*2707-bound repertoire was as different from that of B*2705 as from those of B*2706, B*2709, or the two latter subtypes from each other. Differences between B*2707 and B*2705 were based on their C-terminal residue specificity and a subtle modulation at other positions. Differential usage of secondary anchor residues explained the disparity between the B*2707-, B*2706-, and B*2709-bound repertoires. Similar differences in residue usage were found between B*2707 and both B*2704 and B*2706, as expected from the high peptide overlap between the two latter subtypes. T cell cross-reaction paralleled peptide sharing, suggesting that many shared ligands conserve their alloantigenic features on distinct subtypes. Our results indicate that association of HLA-B27 subtypes with ankylosing spondylitis does not correlate with higher peptide sharing among disease-associated subtypes or with obvious peptide motifs.
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PMID:B*2707 differs in peptide specificity from B*2705 and B*2704 as much as from HLA-B27 subtypes not associated to spondyloarthritis. 1678 53

This study was to investigate the frequency of HLA-B27 and its subtypes in the Han population of Hunan province, southern China. One hundred and sixty-nine healthy unrelated donors were tested for HLA-B27 by polymerase chain reaction-sequence-specific primer (PCR-SSP). One hundred and twenty-eight B27-positive spondyloarthropathy patients and 18 B27-positive healthy controls were subtyped using the high-resolution PCR-SSP. The phenotype frequency of human leukocyte antigen (HLA)-B27 was found to be 2.36% in healthy population. Five B27 alleles were identified: B*2704, B*2705, B*2706, B*2707, and B*2724. No significant difference was found in the distribution of HLA-B27 subtypes between the patients and controls studied. Notably, B*2724 was observed in a juvenile patient with ankylosing spondylitis. This subtype has not been previously reported in Chinese ankylosing spondylitis (AS) patients and other ethnic groups.
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PMID:Diversity of human leukocyte antigen-B27 alleles in Han population of Hunan province, southern China. 1686 86

B*2704 is strongly associated to ankylosing spondylitis in Asian populations. It differs from the main HLA-B27 allotype, B*2705, in three amino acid changes. We analyzed the influence of tapasin, TAP, and immunoproteasome induction on maturation, surface expression, and T cell allorecognition of B*2704 and compared some of these features with B*2705 and B*2706, allotypes not associated to disease. In the tapasin-deficient .220 cell line, this chaperone significantly influenced the extent of folding of B*2704 and B*2705, but not their egress from the endoplasmic reticulum. In contrast, B*2706 showed faster folding and no accumulation in the endoplasmic reticulum in the absence of tapasin. Surface expression of B*2704 was more tapasin dependent than B*2705. However, expression of free H chain decreased in the presence of this chaperone for B*2705 but not B*2704, suggesting that more suboptimal ligands were loaded on B*2705 in the absence of tapasin. Despite its influence on surface expression, tapasin had little effect on allorecognition of B*2704. Both surface expression and T cell recognition of B*2704 were critically dependent on TAP, as established with TAP-deficient and TAP-proficient T2 cells. Both immunoproteasome and surface levels of B*2704 were induced by IFN-gamma, but this had little effect on allorecognition. Thus, except for the differential effects of tapasin on surface expression, the tapasin, TAP, and immunoproteasome dependency of B*2704 for maturation, surface expression, and T cell recognition are similar to B*2705, indicating that basic immunological features are shared by the two major HLA-B27 allotypes associated to ankylosing spondylitis in human populations.
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PMID:HLA-B*2704, an allotype associated with ankylosing spondylitis, is critically dependent on transporter associated with antigen processing and relatively independent of tapasin and immunoproteasome for maturation, surface expression, and T cell recognition: relationship to B*2705 and B*2706. 1708 17

The aim of the present study was to analyze haplotypic associations of two the most common HLA-B*27 subtypes (B*2702 and *2705) in the Croatian population. One hundred and eleven unrelated HLA-B*27 positive individuals were included. None of them had any sign of ankylosing spondylitis. The total number of analyzed haplotypic associations was 112 because one individual was homozygous for HLA-B*27. HLA-B*27 alleles as well as HLA-A and DRB1 specificities were tested by PCR-SSP method. Among seven different HLA-B*27 alleles observed among our individuals, B*2705 was the most frequent (61.6%), followed by B*2702 (30.4%), while the frequency of all other observed alleles (B*2701, B*2703, B*2704, B*2708 and B*2714) was less than 2.0%. HLA-A*02 was the most frequent specificity at HLA-A locus in both groups of haplotypic associations (B*2702 and B*2705) and no difference in distribution of HLA-A genes was observed between two groups. Analysis of HLA-B*2702 haplotypic associations showed the high frequency of DRB1*16 (44.2%) in comparison to B*2705 haplotypic associations (4.0%) with significant P value (P<0.00001). HLA-DRB1*01 demonstrated significantly higher presence among 69 B*2705 haplotypic associations compared to 34 B*2702 haplotypic associations (28.0% vs. 1.5%; P<0.00001).
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PMID:[Haplotipic associations of the two most common HLA-B*27 alleles in the Croatian population]. 1902 62


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