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)

In the thirty years since the initial discovery of a striking association between HLA-B27 and susceptibility to ankylosing spondylitis, numerous hypotheses have been proposed to explain the role of this molecule in the pathogenesis of spondyloarthropathies. In the past few years the focus has shifted from one centered largely on the physiological peptide-presenting function of HLA-B27, to include ideas based on aberrant aspects of its immunobiology. This has been driven in part by results from animal models of HLA-B27-associated disease where CD8+ T cells do not appear to be playing a major role in pathogenesis. In addition, the HLA-B27 heavy chain is unusual in that it has a tendency to misfold in the endoplasmic reticulum and to form disulfide linked heavy chain dimers that can be expressed on the cell surface. Although the data suggest misfolding and cell surface dimerization are fundamentally different processes, it appears that certain structural features of the heavy chain are common to both. Potential links between these aberrant characteristics of HLA-B27 and inflammatory disease are discussed in this and other reviews in this issue. Herein we consider how protein misfolding affects cell function through the activation of an 'unfolded protein response' and/or an 'ER overload response', and the potential impact on the immune system. Despite significant advances in the treatment of spondyloarthropathies over the past few years, a better understanding of pathogenesis is likely to improve outcome by identifying ways to provide greater and more sustained clinical responses.
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PMID:The immunobiology of HLA-B27: variations on a theme. 1501 56

Molecular mimicry is discussed as a possible mechanism that may contribute to the development of autoimmune diseases. It could also be involved in the differential association of the human major histocompatibility subtypes HLA-B(*)2705 and HLA-B(*)2709 with ankylosing spondylitis. These two subtypes differ only in residue 116 of the heavy chain (Asp in B(*)2705 and His in B(*)2709), but the reason for the differential disease association is not understood. Using x-ray crystallography, we show here that the viral peptide pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236-244) of Epstein-Barr virus) is presented by the B(*)2705 and B(*)2709 molecules in two drastically deviating conformations. Extensive structural similarity between pLMP2 and the self-peptide pVIPR (RRKWRRWHL, derived from vasoactive intestinal peptide type 1 receptor (residues 400-408)) is observed only when the peptides are presented by B(*)2705 because of a salt bridge between Arg(5) of both peptides and the subtype-specific heavy chain residue Asp(116). Combined with functional studies using pLMP2/pVIPR-cross-reactive cytotoxic T cell lines and clones, together with target cells presenting these peptides or a modified peptide analogue, our results reveal that a pathogen-derived peptide can exhibit major histocompatibility complex class I subtype-dependent, drastically distinct binding modes. Furthermore, the results demonstrate that molecular mimicry between pLMP2 and pVIPR in the HLA-B27 context is an allele-dependent property.
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PMID:Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes. 1553 60

HLA-B27 confers susceptibility to ankylosing spondylitis (AS) but the mechanism linking this association remains unknown. Other properties unrelated to its natural role of antigen presenting function may be important in disease pathogenesis. We determined here the impact of N97D substitution on the folding and expression of HLA-B*2704 transfected in the 721.221 cell line. The mutation at position 97 abolishes the surface expression of non-conformational (HC10) and conformational (ME1) forms. The expression of ME1 forms was found to be absent in B*2704 N97D by immunoprecipitation and flow cytometry of fixed and permeabilized cell experiments with the conformation-sensitive ME1 antibody. However, immunoblotting cell lysates with HC10 revealed the presence of unfolded heavy chain (HC) and HC-dimer forms. The impact of the N97D mutation in the exit from the endoplasmic reticulum (ER) was analysed by western blot after endoglycosidase-H treatment, and it was found that B*2704 N97D was retained and accumulated as unfolded molecules. We tested for mutant association with transporter associated with antigen processing (TAP), calnexin (CNX), calreticulin (CLR) and beta2 microglobulin (beta2m). The wild-type B*2704 and N97D mutants were associated with TAP, CNX and CLR, although HC10 forms of mutant N97D interact more weakly with TAP. Only folded molecules of HLA-B*2704 were associated with beta2m. Surprisingly, the peptide-binding assay demonstrated the ability of unfolded N97D molecules to bind high-affinity peptides. It has been suggested that AS may arise because of aberrant folding of HLA-B27 molecules within the ER. Future work must therefore aim to clarify the functional connection between the unfolded protein response pathway in response to the accumulation of HLA-B27 in the ER. This mutant could be useful as a model for the misfolding of HLA-B27.
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PMID:The amino acid at position 97 is involved in folding and surface expression of HLA-B27. 1636 12

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

More than three decades after the discovery of HLA-B27 as a major genetic clue to the origins of ankylosing spondylitis, much has been learned about pathogenesis. However, the role of this major histocompatibility complex class I allele remains undefined. Studies from animal models have demonstrated that HLA-B27 overexpression can cause inflammatory disease with spondyloarthritis features, and together with investigations of patient-derived material, both innate adaptive and immune responses have been implicated. The gastrointestinal immune response to pathogens and even normal flora, with subclinical or overt inflammation, may play a role as an environmental component of these diseases. Although there has been a large conceptual emphasis on mechanisms involving autoreactive T-cell recognition of HLA-B27 complexes displaying arthritogenic peptides, and more recently non-canonical recognition of abnormal forms of HLA-B27 free of beta(2)m (heavy-chain dimers or monomers), it remains unclear whether immunological recognition plays a role in pathogenesis. The recognition that the HLA-B27 heavy chain misfolds during assembly, and causes endoplasmic reticulum 'stress', has led to the observation that this activates the unfolded protein response. This has opened additional areas of investigation into the response of immune system cells to protein misfolding, and suggested novel alternative concepts that may explain the role of HLA-B27 in pathogenesis. This chapter will discuss available data and current concepts regarding the pathogenesis of ankylosing spondylitis.
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PMID:Pathogenesis of ankylosing spondylitis: current concepts. 1677 83

The association of HLA-B27 with ankylosing spondylitis, a chronic inflammatory disease of the axial skeleton, and other spondyloarthropathies, is among the strongest of an MHC antigen and any disease. Yet, the basis for this association remains unknown. In this review the main current hypotheses concerning the pathogenetic role of HLA-B27 will be discussed. They focus on three molecular properties of the molecule: (1) its peptide-presenting specificity, (2) its slow folding and tendency to misfold, and (3) its capacity to form covalent heavy chain homodimers amenable to recognition by leukocyte receptors. On the basis of the peptide specificity spondyloarthropathies would be triggered through T-cell autoimmunity against a self-ligand of HLA-B27 elicited by a cross-reactive foreign antigen. HLA-B27 misfolding would trigger disease through activation of inflammatory pathways following induction of endoplasmic reticulum stress, thus independently of antigen presentation. Recognition of heavy chain homodimers by leukocyte receptors might be involved in disease through immunomodulation of both innate and adaptive responses to arthritogenic pathogens. None of these hypotheses can yet satisfactorily account for the pathogenesis of spondyloarthritides. It is proposed that the pathogenetic role of HLA-B27 will eventually be explained through a global understanding of its biology, in which the various features of this molecule are envisaged as inter-dependent in their contribution to disease.
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PMID:HLA-B27 and the pathogenesis of spondyloarthropathies. 1712 13

Analysis of antigen dissociation provides insight into peptide presentation modes of folded human leukocyte antigen (HLA) molecules, which consist of a heavy chain, beta2-microglobulin (beta2m), and an antigenic peptide. Here we have monitored peptide-HLA interactions and peptide dissociation kinetics of two HLA-B27 subtypes by fluorescence depolarization techniques. A single natural amino-acid substitution distinguishes the HLA-B*2705 subtype that is associated with the autoimmune disease ankylosing spondylitis from the non-disease-associated HLA-B*2709 subtype. Peptides with C-terminal Arg or Lys represent 27% of the natural B*2705 ligands. Our results show that dissociation of a model peptide with a C-terminal Lys (GRFAAAIAK) follows a two-step mechanism. Final peptide release occurs in the second step for both HLA-B27 subtypes. However, thermodynamics and kinetics of peptide-HLA interactions reveal different molecular mechanisms underlying the first step, as indicated by different activation energies of 95+/-8 kJ/mol (HLA-B*2705) and 150+/-10 kJ/mol (HLA-B*2709). In HLA-B*2709, partial peptide dissociation probably precedes fast final peptide release, while in HLA-B*2705 an allosteric mechanism based on long-range interactions between beta2m and the peptide binding groove controls the first step. The resulting peptide presentation mode lasts for days at physiological temperature, and determines the peptide-HLA-B*2705 conformation, which is recognized by cellular ligands such as T-cell receptors.
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PMID:Natural MHC class I polymorphism controls the pathway of peptide dissociation from HLA-B27 complexes. 1757 25

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

Refolding of the heavy chain of the Class I HLA molecule, HLA-B27, in the absence of beta(2)m, yields soluble high molecular weight (HMW) oligomers reminiscent of the oligomeric forms of beta(2)m-free heavy chains (FHCs) of class I HLA antigens observed on cell surfaces. Here we examine the structural characteristics of HMW B27 in respect of features potentially relevant to autoimmunity, such as: (a) retention of native-like structure, since this could facilitate non-canonical interactions with T-cell receptors even in the absence of bound beta(2)m and peptide, or (b) presence of non-native structure, since this could yield novel (non-self) antigenic conformational epitopes that could elicit immune attack. We report that HMW B27 is characterized by high secondary structural content, structural stability, stability to proteolysis by trypsin, and structural features that are both partly native-like, and partly non-native-like, as assessed through the binding of conformationally-distinguishing and cross-reacting scFv antibodies specifically selected against HMW B27. We also present cell ELISA data with conformation-specific scFv antibodies that distinguish between lymphocytes from individuals who are healthy and B27 positive, and those who are B27 positive but suffering from ankylosing spondylitis.
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PMID:Refolding of HLA-B27 heavy chains in the absence of beta2m yields stable high molecular weight (HMW) protein forms displaying native-like as well as non-native-like conformational features: implications for autoimmune disease. 1803 53

Human leukocyte antigen (HLA) class I molecules consist of a heavy chain, beta(2)-microglobulin, and a peptide that are noncovalently bound. Certain HLA-B27 subtypes are associated with ankylosing spondylitis (such as HLA-B*2705), whereas others (such as HLA-B*2709) are not. Both differ in only one residue (Asp116 and His116, respectively) in the F pocket that accommodates the peptide C-terminus. An isotope-edited IR spectroscopy study of these HLA-B27 subtypes complexed with the self-peptide RRKWRRWHL was carried out, revealing that the heavy chain is more flexible in the HLA-B*2705 than in the HLA-B*2709 subtype. In agreement with these experimental data, molecular dynamics simulations showed an increased flexibility of the HLA-B*2705 binding groove in comparison with that of the HLA-B*2709 subtype. This difference correlates with an opening of the HLA-B*2705 binding groove, accompanied by a partial detachment of the C-terminal peptide anchor. These combined results demonstrate how the deeply embedded polymorphic heavy-chain residue 116 influences the flexibility of the peptide binding groove in a subtype-dependent manner, a feature that could also influence the recognition of the HLA-B27 complexes by effector cells.
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PMID:HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution. 1817 23


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