UNIPROT:P01889 - FACTA Search

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)

Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles carrying Bw4-I80 in trans position in the Spanish population (30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7% in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other hand, 3DL1 was decreased in patients compared with B27 controls (p < 0.0001 in the Spanish population and p < 0.003 in Azoreans). The presence of this allele in combination with Bw4-I80 had a protective effect against the development of AS in the Spanish population (19.7% in AS, 35.2% in B27 controls; p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1 in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes may modulate the development of AS. The susceptibility to AS could be determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes.
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PMID:Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations. 1680 19

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for spondyloarthritis (SpA), two polymorphisms (-238 and -308 positions) were analyzed in 229 patients with SpA (113 with ankylosing spondylitis [AS], 92 with undifferentiated SpA [U-SpA], 24 with reactive arthritis), and 169 ethnically matched healthy control subjects. The HLA-B alleles were detected by PCR-SSP technique and the TNF-alpha polymorphism by PCR-RFLP. In comparison with healthy control subjects, the frequencies of TNF-238 in SpA were similar. In contrast, the analysis of -308 polymorphism showed increased frequencies of the T2(A) allele in the whole SpA group (p < 0.05, pC = NS, OR = 1.83) as well as the T2(A) allele (pC < 0.05, OR = 2.4) and T1T2(AG) genotype (p < 0.05, pC = NS, OR = 2.25) in U-SpA patients. Comparison of B27-negative patients and healthy control subjects yielded similar results. There was no significant correlation between TNF genotypes and clinical data. The present study demonstrates that TNF-alpha -308 polymorphism appears to be associated with the genetic susceptibility U-SpA. The association seems independent of the susceptibility conferred by the HLA-B27 in this group of patients.
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PMID:Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with spondyloarthritis. 1705 60

The product of the human major histocompatibility (HLA) class I allele HLA-B*1402 only differs from that of allele HLA-B*1403 at amino-acid position 156 of the heavy chain (Leu in HLA-B*1402 and Arg in HLA-B*1403). However, both subtypes are known to be differentially associated with the inflammatory rheumatic disease ankylosing spondylitis (AS) in black populations in Cameroon and Togo. HLA-B*1402 is not associated with AS, in contrast to HLA-B*1403, which is associated with this disease in the Togolese population. The products of these alleles can present peptides with Arg at position 2, a feature shared by a small group of other HLA-B antigens, including HLA-B*2705, the prototypical AS-associated subtype. Complexes of HLA-B*1402 with a viral peptide (RRRWRRLTV, termed pLMP2) and a self-peptide (IRAAPPPLF, termed pCatA) were prepared and were crystallized using polyethylene glycol as precipitant. The complexes crystallized in space groups P2(1) (pLMP2) and P2(1)2(1)2(1) (pCatA) and diffracted synchrotron radiation to 2.55 and 1.86 A resolution, respectively. Unambiguous solutions for both data sets were obtained by molecular replacement using a peptide-complexed HLA-B*2705 molecule (PDB code 1jge) as a search model.
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PMID:Expression, purification and preliminary X-ray crystallographic analysis of the human major histocompatibility antigen HLA-B*1402 in complex with a viral peptide and with a self-peptide. 1762 Jul 30

This retrospective study analyzed the HLA-B 27 alleles in a group of 20 consecutive patients with the diagnosis of Reiter syndrome (RS) followed in a tertiary referral university hospital in Brazil, during the period 1990-2006, and compared the data with that observed in other patients with spondyloarthropathies followed at the same institution. Eight cases were associated to gastrointestinal infection, eight cases to previous urethritis, and four cases presented no established preceding infection. HLA-B 27 alleles were typed by polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes (HLA-B 2,701 to HLA-B 2,721). They were compared to a group of 108 patients with ankylosing spondylitis (AS), 40 with undifferentiated spondyloarthropathy (uSpA) and 111 healthy controls. Among the 20 patients, 17 were HLA-B 27 positive (85%). Two HLA-B 27 alleles were observed: HLA-B 2,705 (65%) and HLA-B 2,702 (35%). In the other spondyloarthropathies, the observed alleles were HLA-B 2,705 (90% in AS and 92.5% in uSpA), HLA-B 2,702 (8% in AS and 5% in uSpA), HLA-B 2,704 (1% in AS and 2.5% in uSpA) and HLA-B 2,713 (1% in AS). Among the 111 healthy controls, 80% presented HLA-B 2,705, followed by HLA-B 2,702 in 10%, HLA-B 2,703 in 6%, HLA-B 2,707 in 3% and HLA-B 2,713 in 1%. Concluding, in the HLA-B 27 positive patients with RS in this study there was predominance of HLA-B 2,705 allele, in a lower frequency than that observed in patients with other spondyloarthropathies and healthy controls.
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PMID:Frequency of HLA-B27 and its alleles in patients with Reiter syndrome: comparison with the frequency in other spondyloarthropathies and a healthy control population. 1771 70

Analysis of HLA-B27 is usually performed by flow cytometry using commercial single or two colour fluorescence reagents. The CELL-DYN Sapphire (CD-Sapphire) is a high-volume routine haematology analyser that allows cell population analysis by monoclonal antibody fluorochromes analogous to flow cytometry. In this study, in-house flow cytometry analysis (n = 96, HLA-B27, One Lambda) performed on routine patient samples was used as the comparison method for analysis of HLA-B27, One Lambda (n = 40) and HLA-B27/HLA-B7, Immunotech (n = 96) reagents on the CD-Sapphire. The One Lambda results agreed 100% with the comparison method and offered clear population discrimination. The Immunotech combination also had a high level of agreement, but interpretation was more complex because of the wider cross-reactivity of the ABC-m3 antibody with B7 and other HLA-B alleles. When analysing HLA-B27 with antibodies showing nonspecific reactivity, a cut-off staining level yielding high specificity should be chosen, as the primary diagnostic value of HLA-B27 is as a 'rule-out' test for ankylosing spondylitis. The CD-Sapphire incorporates automated sampling and lysis, and medical scientists familiar with the instrument would require little additional technical training to perform the analysis. The reduced preanalytical work and total turnaround time constitute an important step towards automation of HLA-B27 and similar simple high-volume flow cytometry analysis.
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PMID:Evaluation of a method for monoclonal antibody HLA-B27 analysis with the CELL-DYN Sapphire haematology analyser. 1798 1

A single amino acid exchange between the major histocompatibility complex molecules HLA-B(*)2705 and HLA-B(*)2709 (Asp-116/His) is responsible for the emergence of distinct HLA-B27-restricted T cell repertoires in individuals harboring either of these two subtypes and could correlate with their differential association with the autoimmune disease ankylosing spondylitis. By using fluorescence depolarization and pK(a) calculations, we investigated to what extent electrostatic interactions contribute to shape antigenic differences between these HLA molecules complexed with viral, self, and non-natural peptide ligands. In addition to the established main anchor of peptides binding to HLA-B27, arginine at position 2 (pArg-2), and the secondary anchors at the peptide termini, at least two further determinants contribute to stable peptide accommodation. 1) The interaction of Asp-116 with arginine at peptide position 5, as found in pLMP2 (RRRWRRLTV; viral) and pVIPR (RRKWRRWHL; self), and with lysine in pOmega, as found in gag (KRWIILGLNK; viral), additionally stabilizes the B(*)2705 complexes by approximately 5 and approximately 27 kJ/mol, respectively, in comparison with B(*)2709. 2) The protonation state of the key residues Glu-45 and Glu-63 in the B-pocket, which accommodates pArg-2, affects peptide binding strength in a peptide- and subtype-dependent manner. In B(*)2705/pLMP2, protonation of Glu-45/Glu-63 reduces the interaction energy of pArg-2 by approximately 24 kJ/mol as compared with B(*)2705/pVIPR. B(*)2705/pVIPR is stabilized by a deprotonated Glu-45/Glu-63 pair, evoked by allosteric interactions with pHis-8. The mutual electrostatic interactions of peptide and HLA molecule, including peptide- and subtype-dependent protonation of key residues, modulate complex stability and antigenic features of the respective HLA-B27 subtype.
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PMID:Molecular determinants of major histocompatibility complex class I complex stability: shaping antigenic features through short and long range electrostatic interactions. 1850 34

Inflammatory processes are accompanied by the posttranslational modification of certain arginine residues within proteins to yield citrulline, although it is largely unknown how this modification influences antigen presentation. We employed crystallographic and functional studies to investigate whether the exchange of arginine to citrulline affects the display of a peptide by two human major histocompatibility antigen class I subtypes, HLA-B(*)2705 and HLA-B(*)2709. Both differ only in residue 116 within the peptide binding groove despite their differential association with ankylosing spondylitis, an inflammatory rheumatic disorder. The crystal structures described here show that a modified self-peptide, pVIPR-U5 (RRKWURWHL; U = citrulline), is presented by the two HLA-B27 molecules in distinct conformations. These binding modes differ not only drastically from each other but also from the conformations exhibited by the non-citrullinated peptide in a given subtype. The differential reactivity of HLA-B27-restricted cytotoxic T cells with modified or unmodified pVIPR supports the structural findings and shows that the presentation of citrullinated peptides has the potential to influence immune responses.
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PMID:Citrullination-dependent differential presentation of a self-peptide by HLA-B27 subtypes. 1865 Apr 41

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B (*)2705 strongly associated with AS and B (*)2709 which is not, and show the co-occurrence of the B (*)2705 allele with a single nucleotide polymorphism (SNP) mapping at 3'-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B (*)2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a 'danger' signal might influence susceptibility to AS.
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PMID:A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B*2705 in Sardinia. 1866 20

The objective of this study is to investigate the relationship between clinical features of ankylosing spondylitis (AS) and HLA-B27 status or its subtypes. Clinical data and blood samples were collected with patients' informed consent. Luminex liquid array combining polymerase chain reaction-sequence specific oligonucleotide probe was used to do the low-resolution HLA-B genotype typing. Polymerase chain reaction-sequence specific primer was applied to do the high resolution HLA-B27 typing. In 98 subjects, 93 were HLA-B27 positive, of which three subtypes were detected: B*2704 (n = 76), B*2705 (n = 12), and B*2715 (n = 5). The onset age for B27 negative and positive group was 28 +/- 7.9 and 21.1 +/- 6.2 years, respectively (chi(2) = -2.047, P = 0.041). The onset age for B*2704, B*2705 and B*2715 group was 20.45 +/- 4.50, 26.67 +/- 9.95 and 17.8 +/- 11.12 years, respectively (chi(2) = 7.888, P = 0.019). No significant difference was found between B27 positive and negative group, or among three B27 subtypes groups for other clinical features. In conclusion, the clinical features of AS may be correlated with HLA-B27 status and its polymorphism.
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PMID:Clinical features of ankylosing spondylitis may correlate with HLA-B27 polymorphism. 1895 40

The HLA region encodes several molecules that play key roles in the immune system. Strong association between the HLA region and autoimmune disease (AID) has been established for over fifty years. Association of components of the HLA class II encoded HLA-DRB1-DQA1-DQB1 haplotype has been detected with several AIDs, including rheumatoid arthritis, type 1 diabetes and Graves' disease. Molecules encoded by this region play a key role in exogenous antigen presentation to CD4+ Th cells, indicating the importance of this pathway in AID initiation and progression. Although other components of the HLA class I and III regions have also been investigated for association with AID, apart from the association of HLA-B*27 with ankylosing spondylitis, it has been difficult to determine additional susceptibility loci independent of the strong linkage disequilibrium (LD) with the HLA class II genes. Recent advances in the statistical analysis of LD and the recruitment of large AID datasets have allowed investigation of the HLA class I and III regions to be re-visited. Association of the HLA class I region, independent of known HLA class II effects, has now been detected for several AIDs, including strong association of HLA-B with type 1 diabetes and HLA-C with multiple sclerosis and Graves' disease. These results provide further evidence of a possible role for bacterial or viral infection and CD8+ T cells in AID onset. The advances being made in determining the primary associations within the HLA region and AIDs will not only increase our understanding of the mechanisms behind disease pathogenesis but may also aid in the development of novel therapeutic targets in the future.
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PMID:The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. 1941 18

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