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)

The complete amino acid sequence of papain-solubilized HLA-B27, an antigen that presents a very strong association to the development of ankylosing spondylitis, has been determined. The overall sequence homology with the cross-reactive allelic products HLA-B7 and HLA-B40 (Bw60) is 93% and 92%, respectively. Half of the differences between HLA-B27 and -B7 are located in segments 63-83 and 113-116. Most of the known HLA class I antigens are different in these segments, and it is suggested that the corresponding residues may be involved in the alloantigenic determinants of HLA-B27. A free cysteine residue is present at position 67, and it is at least partially exposed to solvent. In addition, other differences are found in various areas of the two N-terminal domains. The comparison with available HLA class I sequences allows an evaluation of their contribution to the antigenic polymorphism of these molecules. The relevance of these data is discussed in connection with the mapping of functional sites of HLA class I antigens and with the association between HLA-B27 and ankylosing spondylitis.
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PMID:Primary structure of papain-solubilized human histocompatibility antigen HLA-B27. 240 63

The HLA class I molecules identified serologically as HLA-B27 are highly associated with ankylosing spondylitis and related human disorders. All known HLA-B27 amino acid sequences contain a cysteine residue at position 67; no other published HLA class I sequence contains a cysteine within the hypervariable region of the alpha 1 domain, which extends from amino acid residues 63-84. To investigate the role of this cysteine residue in the antigenic structure of HLA-B27, we isolated a genomic clone encoding a molecule of the HLA-B27.1 subtype and performed oligonucleotide-directed mutagenesis to convert the cysteine at position 67 to a tyrosine. When transfected into mouse L cells, both the wild-type and Cys67----Tyr67 mutant B27 genes directed the synthesis and surface expression of molecules reactive with the monomorphic anti-HLA class I antibody W6/32. However, only the L cells transfected with the wild-type B27 gene reacted with the anti-B27 antibody ME1; L cells transfected with the mutant B27 were completely unreactive with this antibody. Experiments with hybrid exons created from the HLA-B27 and HLA-A2 genes yielded results consistent with the mapping of the ME1 epitope to the B27 alpha 1 domain. A second anti-B27 antibody, GS145.2, also showed markedly reduced binding to the Cys67----Tyr67 mutant. These studies document the importance of the unique Cys67 residue in the antigenic structure of HLA-B27.
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PMID:In vitro mutagenesis of HLA-B27. Substitution of an unpaired cysteine residue in the alpha 1 domain causes loss of antibody-defined epitopes. 245 90

Antigen HLA-B27 is a high-risk genetic factor with respect to a group of rheumatoid disorders, especially ankylosing spondylitis. A cDNA library was constructed from an autozygous B-cell line expressing HLA-B27, HLA-Cw1, and the previously cloned HLA-A2 antigen. Clones detected with an HLA probe were isolated and sorted into homology groups by differential hybridization and restriction maps. Nucleotide sequencing allowed the unambiguous assignment of cDNAs to HLA-A, -B, and -C loci. The HLA-B27 mRNA has the structural features and the codon variability typical of an HLA class I transcript but it specifies two uncommon amino acid replacements: a cysteine in position 67 and a serine in position 131. The latter substitution may have functional consequences, because it occurs in a conserved region and at a position invariably occupied by a species-specific arginine in humans and lysine in mice. The availability of the complete sequence of HLA-B27 and of the partial sequence of HLA-Cw1 allows the recognition of locus-specific sequence markers, particularly, but not exclusively, in the transmembrane and cytoplasmic domains.
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PMID:Complete sequence of HLA-B27 cDNA identified through the characterization of structural markers unique to the HLA-A, -B, and -C allelic series. 348 86

Homocysteine-treated cells can be specifically lysed by cytotoxic T lymphocytes (CTL) identifiable in patients with ankylosing spondylitis and reactive arthritis. Sensitization of target cells involves disulfide bonding and the interaction between homocysteine and HLA antigens occurs in a pre-Golgi compartment in the cells. Salmonella-infected B cells are also lysed by homocysteine-specific CTL, suggesting that intracellular invading microorganisms may provide homocysteine which would gain access to the newly synthesized intracellular HLA molecules and modify them inside the cells. Two different mechanisms for homocysteine modification of HLA antigens are proposed: homocysteine could bind directly to the unpaired cysteine residues in HLA antigens, or it could bind indirectly to HLA antigens through cysteine-containing peptides bound to them. Thus, HLA antigens containing unpaired cysteine residues (e.g. HLA B27) could be modified by homocysteine directly or indirectly, while HLA antigens without unpaired cysteine residues (e.g. HLA A68) could only be modified indirectly. The results are discussed in relation to the potential involvement of homocysteine-specific CTL in ankylosing spondylitis and reactive arthritis, both of which are related to bacterial infections, associated with HLA B27, and considered to be autoimmune diseases.
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PMID:Homocysteine modification of HLA antigens and its immunological consequences. 876 45

Immunoglobulin A-alpha-1-antitrypsin complex (IgA-AT) is a nonimmune complex formed by disulphide bonding between an active thiol group available on the cysteine residue of alpha heavy chains of IgA and a cysteine in position 232 of alpha l-antitrypsin in single polypeptide chain. The level of the complex can easy be determined using the ELISA method and findings are expressed in arbitrary units. In the healthy adults' sera the IgA-AT complex level is lower than 0.4 arbitrary unit. The elevated levels of the complex were found in a number of rheumatic diseases. In 50% of SLE patients, its levels are increased, particularly in those with current central nervous system involvement. Similarly, in approximately 50% sera derived from RA patients they are also found to be higher. Their presence correlates with anatomical progression of the disease. IGA-AT complex is found in RA (in 90% of cases) but not in the osteoarthritis synovial fluid. Our findings can be applied in clinical praxis in differential diagnosis of early rheumatoid arthritis and osteoarthritis. The IGA-AT complex can be also found in ankylosing spondylitis. The complex has been determined in a relatively large number of IgA myeloma sera. In 30% of the cases its levels were 10-fold higher than the upper limit for healthy adults.
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PMID:Immunoglobulin A--alpha-1-antitrypsin complex in rheumatic diseases. 930 36

The strong association of the HLA class 1 allele HLA B27 with ankylosing spondylitis (AS) has been recognized for over 25 yr, however the pathogenic mechanism linking HLA B27 with AS and other spondyloarthropathies remains a mystery. We now know that the principal natural function of HLA B27 is an immunologic one, namely to bind antigenic peptides and then present them to T lymphocytes. I have shown that HLA B27 functions as an excellent antigen-presenting molecule in both spondyloarthropathy patients and healthy individuals. A working molecular model of how T cells recognize HLA B27 has been generated and tested. Evidence that T cells have a role in spondyloarthritis has also been found. First, expanded populations of T lymphocytes were found in both the blood and synovial fluid of patients with reactive arthritis (ReA). Secondly, a strong cytotoxic T-cell response to an HLA B27-restricted peptide epitope from Chlamydia trachomatis was found in a patient with ReA. This peptide, derived from a bacterium known to trigger ReA, is thus a candidate 'arthritogenic' peptide. We have also found evidence that HLA B27 has an unusual cell biology compared with other HLA molecules. HLA B27 demonstrates an unusual ability to form heavy chain homodimers in vitro. Dimerization is dependent upon disulphide bonding through an unpaired cysteine at position 67. Remarkably these dimers lack beta2 microglobulin, previously thought to be an essential component of all mature MHC class 1 molecules. HLA B27 homodimer formation has also been demonstrated in certain cell lines in vivo, and preliminary data suggest that significant numbers of T cells from patients with spondyloarthropathy express a ligand for HLA B27 homodimers. These findings have extended our understanding of the beneficial immunologic function of HLA B27, and have also led us to propose the testable new hypothesis that HLA B27 heavy chain dimerization may be involved in the pathogenesis of spondyloarthritis.
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PMID:HLA B27 in health and disease: a double-edged sword? 1215 2

The human HLA-B27 class I molecule exhibits a strong association with the inflammatory arthritic disorder ankylosing spondylitis and other related arthropathies. Major histocompatibility complex class I heavy chains normally associate with beta(2)-microglobulin and peptide in the endoplasmic reticulum before transit to the cell surface. However, an unusual characteristic of HLA-B27 is its ability to form heavy chain homodimers through an unpaired cysteine at position 67 in the peptide groove. Homodimers have previously been detected within the ER and at the cell surface, but their mechanism of formation and role in disease remain undefined. Here we demonstrate, in the rat C58 thymoma cell line and in human HeLa cells transfected with HLA-B27, that homodimer formation involves not only cysteine at position 67 but also the conserved structural cysteine at position 164. We also show that homodimer formation can be induced in the non-disease-associated HLA class I allele HLA-A2 by slowing its assembly rate by incubation of cells at 26 degrees C, suggesting that homodimer formation in the endoplasmic reticulum may occur as a result of the slower folding kinetics of HLA-B27. Finally, we report an association between unfolded HLA-B27 molecules and immunoglobulin-binding protein at the cell surface.
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PMID:Formation of HLA-B27 homodimers and their relationship to assembly kinetics. 1468 42

MHC class I molecules are predominantly involved in the presentation of antigens from viral proteins to CD8+ T cells of the immune system. However, MHC proteins can also be linked to autoimmune diseases, and the HLA-B27 allele is expressed by 95% of people with the rheumatic condition ankylosing spondylitis (AS). A precise molecular explanation for the association between HLA-B27 and AS is still lacking, although it is known that inappropriately disulfide bonded HLA-B27 heavy chains can be found at both the cell surface and in the endoplasmic reticulum (ER) of HLA-B27 expressing cells. This papers shows that HLA-B27 heavy chain misfolding does not depend on any unpaired cysteine residue per se when HLA-B27 is highly expressed. Also shown is that major differences exist in the disulfide-dependent conformations of two HLA-B27 subtypes, HLA-B2704 and HLA-B2705. The results imply that residues 77, 152, and/or 211 influence the redox potential of the MHC class I heavy chain and suggest that manipulating the redox environment can alter the conformational state of HLA-B27 subtypes.
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PMID:Differential oxidation of HLA-B2704 and HLA-B2705 in lymphoblastoid and transfected adherent cells. 1667 75

Hydrophobins are a family of small, moderately hydrophobic proteins with eight cysteine residues arranged in a conserved pattern. A full-length cDNA, designated Po.hyd, corresponding to a hydrophobin gene of Pleurotus ostreatus was obtained in our previous work. The Po.hyd gene contains a 333 bp open reading frame (ORF), which is interrupted by two typical classI introns. There was no consensus signal for a polyA tail detected in the 3'untranslated region. However, an analogous T- or TG-rich motif was observed that probably influence the formation of the mRNA 3' end. We assign the putative Po.HYD protein to the classI hydrophobins since its sequence arrangement and hydropathy pattern has a high consensus to other known class I hydrophobins. Northern analysis showed that the Po.hyd gene was abundantly expressed throughout the fruiting process (from primordium to mature fruiting body) but silenced during vegetative growth of the mycelium. Southern blot analysis showed Po.hyd to be a single copy gene in the genome of dikaryotic strain likely to locate at the same locus within the two parental genomes.
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PMID:Characterization of a Pleurotus ostreatus fruiting body-specific hydrophobin gene, Po.hyd. 1764 10

Resistin is a recently described adipokine which is a member of cysteine-rich secretory protein family. Although it has been primarily defined in human adipocytes, it has been identified that its level was higher in mononuclear leukocytes, macrophages, spleen, and bone marrow cells. Because ankylosing spondylitis is an inflammatory disease, it is suspected that upregulation of proinflammatory cytokines is effective in its immunopathogenesis. The aim of our study is to determine the serum resistin levels in patients with AS and to research the relationship with disease activity markers. A total of 30 patients with AS and 30 healthy controls were included in this study. Serum resistin concentrations, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath AS Disease Activity Index (BASDAI) were evaluated. In results resistin levels in ankylosing spondylitis group were significantly higher than in control group. But, there was no correlation between resistin and ESR, CRP, BASDAI. In conclusion, higher serum resistin levels in patients with AS compared to healthy subjects give clues that resistin could have a role in the pathogenesis of AS.
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PMID:The serum levels of resistin in ankylosing spondylitis patients: a pilot study. 2114 Feb 66


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