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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many human diseases are associated with HLA class I, class II and class III antigens. It appears that the class III antigen disease associations can be explained by a direct defect operating at the level of either the class III gene or its gene product. The mechanism underlying class I and class II antigen disease associations is at present unknown. In this review we have considered thirty diseases which have been ranked according to their relative risk as defined by the frequency of a given HLA antigen in patient and control populations. The chronic inflammatory disorder, ankylosing spondylitis and its association with HLA B27 has been used as a model to study the HLA linked diseases. We have suggested that the disease may be caused by the Gram-negative microorganism Klebsiella which has antigenic similarity to HLA B27. It is proposed that some antibodies made against Klebsiella bind to HLA B27, thereby acting as autoantibodies leading to the pathological sequelae of chronic inflammatory arthritis. This is the crosstolerance hypothesis or molecular mimicry model and it has been compared to the receptor model. It is further suggested that the crosstolerance hypothesis can be utilised as a general theory to explain the association of other diseases with the class I and class II antigens, and offer a possible explanation for the polymorphism of HLA.
Mol Aspects Med 1992
PMID:HLA and disease. 128 96

The authors have used the modified method of the direct gene cloning suggested by Nichols et al to isolate HLA-B27 gene from a patient suffering from ankylosing spondylitis. Five restriction enzymes (ClaI, HindIII, SnaBI, PvuI, SalGI) which had no recognition sites within the 6.0 kb EcoRI-BamHI-DNA fragment supposedly containing the HLA-B27 gene have been chosen by blotting-hybridization of the restriction fragments of the patients DNA with HLA-B27-specific probe. The 6.0 +/- 0.5 kb DNA fragments were isolated and cloned after the DNA treatment by 300 micrograms of all of these restriction enzymes. The obtained mini-library containing 280 recombinants has been screened with the use of HLA-B27 specific oligonucleotide probe. The clone PB27-2 has been isolated the restriction map of which is identical to HLA-B27k. The authors are planning to determine the sequence of the isolated gene in order to find a possible structural defect in it.
Mol Gen Mikrobiol Virusol 1990 Aug
PMID:[Directed cloning of the HLA-B27 gene isolated from a patient with ankylosing spondylitis (Bechterew's disease)]. 223 90

The possibility that plasmid genes, carried by enteric organisms previously indirectly implicated as disease agents, play a role in the pathogenesis of Ankylosing Spondylitis (AS) was explored. A particular Klebsiella isolate (K21) previously found to cross-react with cells from HLA-B27 positive (B27+) patients with AS, but not with cells from normal individuals, was found to contain a plasmid(s). This coded for the organism's ability to produce a factor which could modify B27+ normal cells (AS-) rendering them lysable by the anti-Klebsiella serum. Curing of this isolate resulted in the loss of the plasmid concerned and a loss of ability of its culture filtrate to modify B27+ lymphocytes of clinically healthy subjects. When plasmids from K21 were transferred to a plasmid free laboratory strain, E. coli JP995, the recipient strain acquired the ability to elaborate modifying factor. These data suggest that plasmids, harboured by some enteric bacteria, and their products, may be implicated in modifying cells bearing certain Major Histocompatibility Complex genes, and that such modification may be an important factor in the pathogenesis of a number of diseases including the seronegative arthropathies.
Mol Immunol 1983 May
PMID:Is a Klebsiella plasmid involved in the aetiology of Ankylosing Spondylitis in HLA-B27-positive individuals? 634 14

The purpose of the study was to estimate the relative frequency of the known HLA-B27 subtypes among HLA-B27 positive Chukot natives. Using oligotyping of the polymerase chain reaction amplified second and third exons of the HLA-B27 gene in 86 DNA samples from HLA-27 positive individuals were success-fully typed. All had HLA-B*2705, including nine patients with ankylosing spondylitis and Reiter's syndrome, except for one Eskimo who had HLA-B*2702. None had HLA-B*2704, a frequent subtype in Orientals. Considering the HLA-B27 subtypes, the Chukot population groups are genetically more closely related to Caucasians than to Orientals.
Mol Gen Mikrobiol Virusol
PMID:[DNA typing of allelic variants of HLA-B27: HLA-B*2705 is the predominant allele of the aboriginal population of the Chukot peninsula (Eskimos and Chukchi)]. 789 30

Ankylosing spondylitis (AS), reactive arthritis (ReA) and other related spondyloarthropathies (SpAs) are characterized by a strong association with the major histocompatibility complex allele HLA-B27. Experimental evidence from humans and transgenic rodents suggests that HLA-B27 is itself involved in the pathogenesis of SpA. Population and peptide-specificity analysis of HLA-B27 suggest it has a pathogenic function related to antigen presentation. Putative roles for infectious agents have been proposed in ReA and suggested in AS. However, the mechanism by which HLA-B27 and bacteria interact to induce arthritis is not clear. Molecular mimicry between bacterial epitopes that cross-react with self-B27 peptides is the most persuasive explanation for the pathogenesis of SpA. The experimental studies reviewed here have greatly increased our knowledge of the structure, function and disease association of HLA-B27.
Mol Med Today 1998 Dec
PMID:The role of HLA-B27 polymorphism and molecular mimicry in spondylarthropathy. 986 24

HLA-B27 appears to play a direct role in the pathogenesis of ankylosing spondylitis and almost all patients with this disease have HLA-B27. Therefore, a diagnosis of ankylosing spondylitis can virtually be excluded in the absence of HLA-B27. Many techniques have been used for HLA-B*27 typing. Of these, molecular methods are the most sensitive and specific but require extracted DNA as the testing material. A technique where HLA-B*27 is amplified directly from whole blood using sequence specific primers has been developed. This technique uses small sample volumes, is not restricted by choice of anticoagulant or sample age up to at least six weeks, and can be applied to other clinical polymerase chain reaction based procedures.
Mol Pathol 1999 Oct
PMID:HLA-B*27 typing by sequence specific amplification without DNA extraction. 1074 81

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins >90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.
Hum Mol Genet 2000 Jul 01
PMID:Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. 1086 Dec 82

The human leukocyte antigen class I allele HLA-B27 is a major histocompatibility complex (MHC) antigen that is strongly associated with the spondyloarthritic group of human rheumatic diseases, the most common of which is ankylosing spondylitis. Although the mechanism underlying this disease association remains unknown, numerous theories have been proposed. Much more is known of the natural role of HLA-B27 in binding and presenting antigenic peptides to T cells. The 'arthritogenic peptide hypothesis' suggests that the role of HLA-B27 in disease relates to its specificity for binding certain peptides. Recently, it has also been shown that HLA-B27 has an unusual cell biology and can adopt a novel homodimeric structure. In this review, a molecular model of the HLA-B27 homodimer is presented and the possible pathogenic significance of such a structure is discussed.
Expert Rev Mol Med 1999 Oct 26
PMID:HLA-B27 and disease pathogenesis: new structural and functional insights. 1458 19

Ankylosing spondylitis is a highly heritable, common rheumatic condition, primarily affecting the axial skeleton. The association with HLA-B27 has been demonstrated worldwide, and evidence for a role of HLA-B27 in disease comes from linkage and association studies in humans, and transgenic animal models. However, twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk for disease. Furthermore, there is compelling evidence that non-B27 genes, both within and outwith the major histocompatability complex, are involved in disease aetiology. In this post-genomic era we have the tools to help elicit the genetic basis of disease. This review describes methods for genetic investigation of ankylosing spondylitis, and summarises the status of current research in this exciting area.
Curr Mol Med 2004 Feb
PMID:Genetic susceptibility to ankylosing spondylitis. 1501 55

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.
Curr Mol Med 2004 Feb
PMID:The immunobiology of HLA-B27: variations on a theme. 1501 56


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