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)

An immunological basis has been postulated for the strong association between at least five subtypes of the HLA-B27 allele (B27.01, .02, .04, .05, and .06) and ankylosing spondylitis, namely that cytotoxic T lymphocyte (CTL) responses are induced against an "arthritogenic" peptide that these different subtypes can all present. This requires a degree of overlap between the peptide binding repertoires of different B27 molecules. The present work, using CTL responses to Epstein-Barr virus (EBV) as a model system in which to identify B27-restricted epitopes, provides the first direct evidence that different disease-related alleles can present the same immunodominant peptide. We first noted that EBV-specific CTL clones, whether from B27.05-, B27.02-, or B27.04-positive donors, were largely subtype-specific in their restriction, recognizing only EBV-transformed B cell lines of the relevant B27 subtype. However, when tested against targets expressing individual EBV proteins from recombinant vaccinia virus vectors, all B27.05-restricted, all B27.02-restricted, and a proportion of B27.04-restricted clones were reactive to the same viral nuclear antigen, Epstein-Barr nuclear antigen (EBNA)3C. In subsequent peptide sensitization assays, all the EBNA3C-specific clones tested and also the EBNA3C-specific component within polyclonal CTL preparations from B27.05-, B27.02-, or B27.04-positive donors recognized the same immunodominant viral peptide RRIYDLIEL (EBNA3C residues 258-266). This sequence accords well with the proposed B27.05 peptide motif and clearly must be accommodated within the different peptide binding grooves of B27.05, B27.02, and B27.04 molecules. Clonal analysis revealed a second component of the B27.04-restricted response that was not shared with other subtypes. This was directed against an EBV latent membrane protein LMP2 epitope whose sequence RRRWRRLTV satisfies some but not all requirements of the B27.05 peptide motif. We conclude that there is indeed a degree of functional overlap between different B27 subtypes in their selection and presentation of CTL epitopes.
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PMID:Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide. 768 91

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

Although a number of reports have now described an association between polymorphism of the LMP2 gene and disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis (AS), some describe associations with acute anterior uveitis, others with juvenile onset disease, and one report provides no association. A recent study describes yet a further association with disease severity in patients with juvenile rheumatoid arthritis. We therefore hypothesized that the discrepant findings in adult disease may be a reflection of an underlying association with disease severity. Our study population consisted of 100 HLA-B27 positive Caucasians with AS of ten or more years duration. Clinical assessment of disease severity was based on a metrology index scoring five measurements, the modified health assessment questionnaire for the spondyloarthropathies, and a disease activity index consisting of a visual analog scale to score the amount of pain, stiffness and fatigue. LMP2 genotypes were assigned following polymerase chain reaction amplification from genomic DNA and restriction enzyme digestion with CfoI. Despite confirmation of a significantly higher prevalence of the LMP2 BB genotype in AAU positive (66.0%) versus AAU negative (45.2%) patients (P < 0.05), we observed no association between LMP2 genotypes and any of the indices of disease severity. Furthermore, although a significant association was noted between the presence of peripheral synovitis and the functional index score (P < 0.05), a history of AAU was not associated with more severe disease. Our data is thus internally consistent in demonstrating no association between LMP2 genotypes and either disease severity or peripheral arthritis, and supports the notion that polymorphism of LMP2 primarily influences the development of AAU and not some other phenotype of AS.
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PMID:Polymorphism of the LMP2 gene and disease phenotype in ankylosing spondylitis: no association with disease severity. 934 40

HLA-B27 is highly associated with ankylosing spondylitis (AS), but the mechanism is unknown. Among the HLA-B27 alleles, B*2709, which differs by one amino acid from the susceptible B*2705, is not associated with the disease. Here, we analyze the reactivity, in patients with AS and in healthy controls carrying the B*2709 or B*2705 alleles, to an EBV epitope derived from LMP2 (236-244) and to a sequence-related self-peptide from vasoactive intestinal peptide receptor 1 (VIP1R 400-408). We found that both B*2705(+) and B*2709(+) subjects possess LMP2 236-244-specific, HLA-B27-restricted T cells, whereas only the B*2705(+) individuals respond significantly to VIP1R 400-408. These results prompted us to compare, by IFN-gamma ELISPOT analysis, the T-cell response to VIP1R 400-408 in patients with AS versus B*2705 healthy controls. The data show that VIP1R 400-408-specific reactivity is a major feature of the patients with AS. These findings show, for the first time to our knowledge, a widespread reactivity in patients with AS against a self-epitope that exhibits some features of a putative "arthritogenic" peptide.
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PMID:CD8(+) T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. 1088 47

Low molecular weight polypeptide (LMP) genes are located within the major histocompatibility complex and have been associated with autoimmune diseases such as ankylosing spondylitis. In order to define the distribution of LMP genes in Mexican populations, the LMP2 and LMP7 polymorphism was analyzed in 312 Mexican individuals (95 Mexican Mestizos, 48 Nahuas, 56 Mazatecans, 50 Teenek, and 63 Mayos) belonging to different ethnic groups. In Mexican populations both Mestizos and Amerindians presented similar distribution of LMP2 and LMP7 polymorphisms, except Nahuas and Mayos who presented the higher frequencies of LMP2-H/H and the lowest frequencies of LMP2-H/R genotypes (P < 0.05 when compared with Mexican Mestizos). The LMP7-K/K genotype was absent in Nahuas, Teenek and Mayos and only one Mazatecan individual presented this genotype. Differences with other populations were found in Mexicans. An increased frequency of LMP2-H and a decreased frequency of LMP2-R alleles were observed in Mexican Amerindians (Nahuas and Mayos) when compared with Brazilian Amerindians (Kaingang and Guarani) and Caucasians (Spaniards) (P < 0.05). All Mexican populations (Mestizos and Amerindians) presented an increased frequency of LMP7-Q allele and a decreased frequency of LMP7-K allele when compared to Brazilian Amerindians (Kaingang), Caucasians (United States) and Asian (Japan) populations (P < 0.05). Genetic distances showed that Mexican Mestizos have an important relation with Spaniards and with all Mexican Amerindians. The present data corroborate the influence of Spaniard and Amerindian genes in the Mexican Mestizo population and could help to define the true significance of LMP polymorphism as genetic and evolutive marker in the Amerindian populations.
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PMID:LMP2 and LMP7 gene polymorphism in Mexican populations: Mestizos and Amerindians. 1220 65

To evaluate the role of LMP (low molecular weight protein) genes as susceptibility markers for spondyloarthritis (SpA), LMP gene polymorphisms were analyzed in 223 Mexican patients with SpA (81 undifferentiated SpA [U-SpA], 117 with ankylosing spondylitis [AS], 25 with reactive arthritis) and in 139 ethnically matched healthy individuals. LMP genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The LMP2 and LMP7 allele frequencies were similar in patients and healthy controls. Genotype analysis revealed an increased frequency of LMP2 R/R genotype in the whole group of SpA (pC = 0.003, OR = 2.06, 95%CI = 1.3-3.25) and in the clinical subgroups of AS (pC = 0.039, OR = 1.88, 95%CI = 1.1-3.22) and U-SpA (pC = 0.003, OR = 2.56, 95%CI = 1.37-4.8) compared with healthy controls. Analysis in the LMP7 did not reveal significant differences in patients and healthy controls. The HLA-B27-negative AS subgroup also showed an increased frequency of LMP2 R/R genotype (pC = 0.027, OR = 4.81, 95%CI = 1.21-22.13). The LMP2-R/R AS patients were younger than LMP2-H/R and H/H patients at onset of the disease (16.0 +/- 6.8 years for R/R, 22.0 +/- 11.2 years for H/R and 28.6 +/- 10.9 years for H/H) (p < 0.05). The data suggest that, besides HLA-B27, LMP2 genotypes are also involved in the genetic susceptibility to develop AS in Mexicans. Furthermore, the age at onset of this disease might also be influenced by genotypes of this gene.
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PMID:Association study of LMP gene polymorphisms in Mexican patients with spondyloarthritis. 1560 70

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