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

The objective was to determine the role of the TAP 1 gene in influencing the phenotype of disease in adult patients with ankylosing spondylitis (AS). The distribution of TAP 1 gene alleles was determined using the PCR RFLP method and restriction enzymes Bcl I and Acc I. The study population included 115 HLA-B27 positive patients with well-documented AS and 41 HLA-B27 positive normal controls. No significant difference in distribution of TAP 1 alleles was noted in comparisons of all AS patients with normal controls. However, AS patients with extraspinal disease were noted to have a significantly increased prevalence of the TAP 1B allele (17.0%) as compared to AS patients without extraspinal disease (2.9%) (P = 0.005) or normal controls (1.9%) (P = 0.005). Polymorphism at the TAP 1 locus may influence disease outcome in patients with AS.
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PMID:Allelic variation at the TAP 1 locus influences disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis. 765 40

The polymorphic TAP1 and TAP2 genes encode subunits of the transporter that delivers peptides to the HLA class I molecules. Because the polymorphism of the TAP genes has been shown to affect peptide transport, it has been suggested that TAP genes are potential regulators of the immune response. We studied TAP1 and TAP2 polymorphism in two multifactorial HLA-B27-associated diseases, ankylosing spondylitis (N = 30) and reactive arthritis (N = 30), in order to establish whether TAP genes are involved in the different pathogenesis of these diseases. Healthy HLA-B27-positive individuals (N = 55) were chosen as the primary controls and 93 individuals represented the random Finnish population as secondary controls. We found differences between the random and HLA-B27-positive populations, thus suggesting that certain TAP alleles are prevalent in HLA-B27 haplotypes. No differences were found between the AS and ReA groups nor between either of them and the healthy HLA-B27-positive controls. Thus it seems unlikely that TAP polymorphism, ar the level studied, has a dominant role in the pathogenesis of these diseases. However, a family study is needed in order to determine whether the same TAP complexes are carried by the same haplotypes in these diseases.
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PMID:TAP1 and TAP2 polymorphism in HLA-B27-positive subpopulations: no allelic differences in ankylosing spondylitis and reactive arthritis. 877 Jun 37

HLA-B*2705 is strongly associated with ankylosing spondylitis (AS) and reactive arthritis. In contrast, B*2709 has been reported to be more weakly or not associated to AS. These two molecules differ by a single amino acid change: aspartic acid in B*2705 or histidine in B*2709 at position 116. In this study, we analyzed the degree of T cell epitope sharing between the two subtypes. Ten allospecific T cell clones raised against B*2705, 10 clones raised against B*2703 but cross-reactive with B*2705, and 10 clones raised against B*2709 were examined for their capacity to lyse B*2705 and B*2709 target cells. The anti-B*2705 and anti-B*2703 CTL were peptide dependent as demonstrated by their failure to lyse TAP-deficient B*2705-T2 transfectant cells. Eight of the anti-B*2705 and five of the anti-B*2703 CTL clones lysed B*2709 targets. The degree of cross-reaction between B*2705 and B*2709 was donor dependent. In addition, the effect of the B*2709 mutation (D116H) on allorecognition was smaller than the effect of the other naturally occurring subtype change at this position, D116Y. These results demonstrate that B*2705 and B*2709 are the antigenically closest HLA-B27 subtypes. Because allospecific T cell recognition is peptide dependent, our results imply that the B*2705- and B*2709-bound peptide repertoires are largely overlapping. Thus, to the extent to which linkage of HLA-B27 with AS is related to the peptide-presenting properties of this molecule, our results would imply that peptides within a relatively small fraction of the HLA-B27-bound peptide repertoire influence susceptibility to this disease.
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PMID:High T cell epitope sharing between two HLA-B27 subtypes (B*2705 and B*2709) differentially associated to ankylosing spondylitis. 1043 75

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

Recent therapeutic advances, in particular the use of anti-tumour necrosis factor (anti-TNF) agents, have revived interest in the seronegative spondyloarthropathies (SpA), a group of arthritides characterised by axial skeletal involvement and the absence of rheumatoid factor. The purpose of this article is to review the studies that have been done in the Asia Pacific region, as a broad understanding of the scope and severity of this group of diseases would enable rheumatologists and physicians in this part of the world to better manage their patients. The majority of genetic studies have focused on the associations of HLA-B27 with ankylosing spondylitis (AS) and SpA, while a few studies examined the associations of the CARD, IL-1, LMP2, TAP and TGF with AS. There are a handful of studies on the immunological responses to bacteria and cytokine levels in AS. The onset and clinical features of SpA have been reported from most countries in the region, but no data on patient outcomes, using current measurement tools such as the Bath Ankylosing Spondylitis Disease Activity index (BASDAI), is available. Validation of these instruments of measurement as well as classification criteria in different ethnic populations is necessary where no prior data exist. Future studies will likely be focused on better clinical characterisation of patient cohorts, particularly with regard to the use of currently used measurement tools for disease activity and spinal function and mobility, and the identification of the need for biologic therapy in each country.
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PMID:Seronegative spondyloarthropathy--studies from the Asia Pacific region. 1736 81

HLA-B27 is strongly associated with ankylosing spondylitis (AS). We analyzed the relationship between structure, peptide specificity, folding, and stability of the seven major HLA-B27 subtypes to determine the role of their constitutive peptidomes in the pathogenicity of this molecule. Identification of large numbers of ligands allowed us to define the differences among subtype-bound peptidomes and to elucidate the peptide features associated with AS and molecular stability. The peptides identified only in AS-associated or high thermostability subtypes with identical A and B pockets were longer and had bulkier and more diverse C-terminal residues than those found only among non-AS-associated/lower-thermostability subtypes. Peptides sequenced from all AS-associated subtypes and not from non-AS-associated ones, thus strictly correlating with disease, were very rare. Residue 116 was critical in determining peptide binding, thermodynamic properties, and folding, thus emerging as a key feature that unified HLA-B27 biology. HLA-B27 ligands were better suited to TAP transport than their N-terminal precursors, and AS-associated subtype ligands were better than those from non-AS-associated subtypes, suggesting a particular capacity of AS-associated subtypes to bind epitopes directly produced in the cytosol. Peptides identified only from AS-associated/high-thermostability subtypes showed a higher frequency of ERAP1-resistant N-terminal residues than ligands found only in non-AS-associated/low-thermostability subtypes, reflecting a more pronounced effect of ERAP1 on the former group. Our results reveal the basis for the relationship between peptide specificity and other features of HLA-B27, provide a unified view of HLA-B27 biology and pathogenicity, and suggest a larger influence of ERAP1 polymorphism on AS-associated than non-AS-associated subtypes.
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PMID:Peptide handling by HLA-B27 subtypes influences their biological behavior, association with ankylosing spondylitis and susceptibility to endoplasmic reticulum aminopeptidase 1 (ERAP1). 2518 74