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)

Although human leukocyte antigen (HLA) B27 has been directly implicated in the pathogenesis of ankylosing spondylitis (AS), additional evidence favours the involvement of an additional genetic factor(s). In a previous population analysis of AS patients selected for a history of acute anterior uveitis (AAU), we had demonstrated a phenotypic association between polymorphism in an HLA-linked proteasome subunit gene, LMP2, and the development of AAU and peripheral arthritis. In the present study, we have assessed the relative risk of homozygosity for the LMP2 arginine variant, the disease-associated genotype, for these complications in an unselected group of 86 patients with AS seen sequentially in 1 centre by 1 rheumatologist over a 2-y period. LMP2 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using the CfoI restriction enzyme. Homozygosity for the LMP2 arginine variants was observed in 68.4% of AS patients who had had AAU as compared to 41.7% without AAU (relative risk 3.0; chi 2 = 6.1, p < 0.02). The proportion of AS patients with peripheral arthritis homozygous for the arginine residue was 55.2% as compared to 52.6% without this complication (relative risk 1.1; p > 0.05). Our data suggest a primary association with the development of AAU and provide evidence for genetic heterogeneity in distinct clinical subgroups of patients with AS as a basis for phenotypic variation.
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PMID:Polymorphism in the LMP2 gene influences the relative risk for acute anterior uveitis in unselected patients with ankylosing spondylitis. 776 65

HLA-B27 is strongly associated with ankylosing spondylitis. Natural HLA-B27 ligands derived from polymorphic regions of its own or other class I HLA molecules might be involved in autoimmunity or provide diversity among HLA-B27-bound peptide repertoires from individuals. In particular, an 11-mer spanning HLA-B27 residues 169-179 is a natural HLA-B27 ligand with homology to proteins from Gram-negative bacteria. Proteasomal digestion of synthetic substrates demonstrated direct generation of the B27-(169-179) ligand. Cleavage after residue 181 generated a B27-(169-181) 13-mer that was subsequently found as a natural ligand of B*2705 and B*2704. Its binding to HLA-B27 subtypes in vivo correlated better than B27-(169-179) with association to spondyloarthropathy. Proteasomal cleavage generated also a peptide spanning B*2705 residues 150-158. This region is polymorphic among HLA-B27 subtypes and class I HLA antigens. The peptide was a natural B*2704 ligand. Since this subtype differs from B*2705 at residue 152, it was concluded that the ligand arose from HLA-B*3503, synthesized in the cells used as a source for B*2704-bound peptides. Thus, polymorphic HLA-B27 ligands derived from HLA-B27 or other class I molecules are directly produced by the 20 S proteasome in vitro, and this can be used for identification of such ligands in the constitutive HLA-B27-bound peptide pool.
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PMID:Identification of novel HLA-B27 ligands derived from polymorphic regions of its own or other class I molecules based on direct generation by 20 S proteasome. 1143 36

With the mapping of the human genome having been completed, our ability to investigate and ideally better understand the genetic basis of rheumatic diseases is advancing at a rapid pace. Substantial evidence strongly favors a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies, although the underlying molecular basis has yet to be identified. HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results. HLA-B27 itself is a serologic specificity, which encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles may have evolved from the most widespread subtype, B*2705, and two of them, B*2706 in Southeast Asia and B*2709 in Sardinia, seem not to be associated with ankylosing spondylitis. The distinction between the disease associated and nonassociated subtypes may provide clues to the actual role of B27 in disease pathogenesis.
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PMID:HLA-B27 and genetic predisposing factors in spondyloarthropathies. 1155 26

The association of HLA-B27 with ankylosing spondylitis and reactive arthritis is the strongest one known between an MHC class I Ag and a disease. We have searched the proteome of the bacterium Chlamydia trachomatis for HLA-B27 binding peptides that are stimulatory for CD8(+) cells both in a model of HLA-B27 transgenic mice and in patients. This was done by combining two biomathematical computer programs, the first of which predicts HLA-B27 peptide binding epitopes, and the second the probability of HLA-B27 peptide generation by the proteasome system. After preselection, immunodominant peptides were identified by Ag-specific flow cytometry. Using this approach we have identified for the first time nine peptides derived from different C. trachomatis proteins that are stimulatory for CD8(+) T cells. Eight of these nine murine-derived peptides were recognized by cytotoxic T cells. The same strategy was used to identify B27-restricted chlamydial peptides in three patients with reactive arthritis. Eleven peptides were found to be stimulatory for patient-derived CD8(+) T cells, of which eight overlapped those found in mice. Additionally, we applied the tetramer technology, showing that a B27/chlamydial peptide containing one of the chlamydial peptides stained CD8(+) T cells in patients with Chlamydia-induced arthritis. This comprehensive approach offers the possibility of clarifying the pathogenesis of B27-associated diseases.
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PMID:Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases. 1159 5

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

Major histocompatibility complex (MHC) class I molecules provide the molecular basis for the comprehensive surveillance of an organism by the cytotoxic arm of the adaptive immune system. To exert this function correctly, class I molecules must be loaded with peptide ligands of appropriate length, sequence and affinity that provide a rapidly updated and sufficiently comprehensive picture of the state of the cell. This is accomplished by a sophisticated cellular machinery using a blend of cellular house-keeping proteins and dedicated transporters, chaperones and peptidases. The last 10 years have seen substantial progress in our comprehension of this machinery. It seems now clear that a large proportion of MHC class I ligands are derived from short-lived products of the ribosomal apparatus, many of which correspond to defective proteins. Despite much effort to identify alternative proteolytic pathways, cytosolic production of epitopes still appears to depend almost entirely on the proteasome, while cytosolic aminopeptidases act mainly to limit antigen presentation. In contrast, clear evidence for a critical role of trimming peptidases residing in the endoplasmic reticulum has emerged. These enzymes play a role in responses against pathogens and are associated with autoimmune diseases, most notably ankylosing spondylitis. Much has also been learned about the intricate chaperone interactions in peptide-loading complexes, especially with respect to the structural role of tapasin-ERp57 conjugates and to the editing function of tapasin. In contrast, cross-presentation of exogenous antigens by MHC class I molecules still remains somewhat poorly understood and is likely to attract much research effort for years to come.
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PMID:Running the gauntlet: from peptide generation to antigen presentation by MHC class I. 2173 66

Autoimmune diseases are a heterogeneous group of disorders affecting different organs and tissues. New tools, such as genome-wide association studies, have provided evidence for new susceptibility loci and candidate genes in the disease process including common susceptibility genes involved in the immunological synapse and T cell activation. Close linkages have been found in a number of diseases, including ankylosing spondylitis, multiple sclerosis, Crohn's disease and insulin-dependent diabetes mellitus (Type 1 diabetes mellitus). Evidence for some association with Type 1 diabetes was previously found in the region containing 5q15/ERAP1 (endoplasmic reticulum aminopeptidase 1) (rs30187, ARTS1). Recent data suggest that in eukaryotic cells in addition to the ubiquitin/proteasome system another proteolytic pathway may have a significant role in the autoimmunity process, i.e. the autophagic pathway which constitutes the principal regulated catabolic process mediated by lysosomes. Autophagy could play a role in MHC class I and class II self-antigen presentation at the basis of the autoimmunity process. Furthermore cross-talk among different proteolytic pathways was recently highlighted i.e. components processed in the ubiquitin/proteasome system possibly engaged in autophagic pathways. T1D is an autoimmune disease characterised by the destruction of pancreatic beta cells by autoreactive T cells. Immunological abnormalities can precede months to years the initial symptoms and clinical diagnosis. Our hypothesis suggests that in the autoimmune process autophagy can intervene at different levels, during the thymic selection process of T lymphocytes causing escape of autoreactive T cells, at the initiation stage of the disease, in the preclinical period or subsequently to the disease onset having a role at the level of perpetuation of the autoimmunity process. Supporting evidence derives from the already reported discovery of polymorphisms in autophagy-related genes in patients affected by several autoimmune conditions such as Systemic Lupus Erithematosus. In addition deregulated autophagy was detected in T cells from lupus-prone mice and also found in T cells from patients. Autophagy was found activated in osteoclasts from RA patients as demonstrated by the increased expression of Atg7 and Beclin-1. Our hypothesis to be unraveled could have, if correct, relevant implications for the management of autoimmune conditions such as Type 1 diabetes. In principle, novel therapeutic approaches could be established by targeting deregulated autophagy offering novel opportunities to personalized medicine in patients affected by the disease.
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PMID:The putative role of proteolytic pathways in the pathogenesis of Type 1 diabetes mellitus: the 'autophagy' hypothesis. 2458 32

Given that ankylosing spondylitis (AS) occurs in approximately 5 out of 1,000 adults of European descent and the unclear pathogenesis, the aim of the research was to further predict the molecular mechanism of this disease. The Affymetrix chip data GSE25101 were available from Gene Expression Omnibus database. First of all, differentially expressed genes (DEGs) were identified by Limma package in R. Moreover, DAVID was used to perform gene set enrichment analysis of DEGs. In addition, miRanda, miRDB, miRWalk, RNA22 and TargetScan were applied to predict microRNA-target associations. Meanwhile, STRING 9.0 was utilized to collect protein-protein interactions (PPIs) with confidence score >0.4. Then, the PPI networks for up- and down-regulated genes were constructed, and the clustering analysis was undergone using ClusterONE. Finally, protein-domain enrichment analysis of modules was conducted using DAVID. Total 145 DEGs were identified, including 103 up-regulated and 42 down-regulated genes. These DEGs were significantly enriched in phosphorylation (p = 1.21E-05) and positive regulation of gene expression (p = 1.25E-03). Furthermore, one module was screened out from the up-regulated network, which contained 39 nodes and 205 edges. Moreover, the nodes in the module were significantly enriched in ribosomal protein (RPL17, ribosomal protein L17 and MRPL22, mitochondrial ribosomal protein L22) and proteasome (PSMA6, proteasome subunit, alpha type 6, PSMA4)-related domains. Our findings that might explore the potential pathogenesis of AS and RPL17, MRPL22, PSMA6 and PSMA4 have the potential to be the biomarkers for the disease.
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PMID:Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches. 2543 79