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)

Investigations have focused on the association between ankylosing spondylitis and HLA-B27; several theories have been offered, including linkage disequilibrium, molecular mimicry involving either autoimmunity or tolerance, and the functional role of the HLA molecule, specifically its role in immune recognition or as a membrane receptor for an infectious agent. The widespread distribution of B27 in the cells of the body versus the restricted anatomic distribution of the pathology of spondyloarthritis remains a major problem in explaining the association. Anterior uveitis, cardiac complications, and inflammation of the gastrointestinal and genitourinary tracts and other characteristic extraskeletal sites of involvement may reflect the basic disease process. Investigations need to focus on potential etiologic factors and their tropism for connective tissue at fibromuscular and fibroskeletal junctions, the cell mediated inflammatory response they precipitate, and their vascular routes to target sites.
 ...
PMID:Anatomic and genetic considerations in the pathogenesis of ankylosing spondylitis. 305 8

The pathogenic links between HLA antigens, certain bacterial infections and arthritis have not yet been characterized. The hypothesis of cross-reactivity between HLA B27, the marker of disease susceptibility for these disorders, and the provocative microorganism has been suggested by studies of Klebsiella and ankylosing spondylitis. The present study examines the possibility of molecular mimicry between HLA B27 and two organisms implicated more directly in reactive arthritis, Yersinia enterocolitica and Chlamydia trachomatis. Antibodies against these organisms were obtained both from patients and from antisera raised in rabbits. Neither source of antibacterial antibody was specifically cytotoxic for HLA B27-positive lymphocytes, even when the target cells were derived from patients with recent infections due to these organisms. In addition, monoclonal antibodies against HLA B27 (M1 and M2) showed no reactivity with antigens from these organisms in an ELISA system. These data do not support the notion of molecular mimicry as being the basis of immunogenetic susceptibility to reactive arthritis and Reiter's syndrome following infections with Y. enterocolitica and C. trachomatis.
 ...
PMID:Molecular mimicry in Reiter's syndrome: cytotoxicity and ELISA studies of HLA-microbial relationships. 348 63

Ankylosing spondylitis and reactive arthritis are seronegative spondyloarthropathies, which are strongly associated with HLA-B27. Despite intensive investigation, the basis for this association is not clear. However, in recent years one favored hypothesis to explain this linkage has been that of molecular mimicry, i.e., sharing of linear or conformational epitopes common to microbial antigens and host structures. During the past few years several examples of molecular mimicry between HLA-B27 and microbial antigens have been described. Heat shock proteins, among others, have been considered as target candidates for autoimmune phenomena, because of the high degree of homology between bacterial and mammalian species. Reactive arthritis triggered by Yersinia or Salmonella provides a unique model for studying the pathogenetic mechanisms underlying human inflammatory joint diseases in general, because the arthritogenic microbes are known and well-characterized. We have described two bacterial proteins that share amino acid homology with HLA-B27, namely YadA (Yersinia adhesin) and OmpH, outer surface proteins of Yersinia and Salmonella, respectively. Notably, the area of identity of these amino acid sequences is located in the same place on the HLA-B27 molecule as a hexapeptide identical between Klebsiella nitrogenase and HLA-B27, and a pentapeptide shared by a Shigella flexneri protein and HLA-B27. We have investigated immune responses to a panel of synthetic peptides based on the HLA-B27-homologous portions of pathogen-specific antigens in patients with reactive arthritis and ankylosing spondylitis. One third of the patients have antibodies to the synthetic peptides. However, instead of recognizing the HLA-B27-homologous portion, the antibodies are directed against the flanking sequences of the synthetic peptides. The concept of the role of molecular mimicry between HLA-B27 and microbial antigens in the pathogenesis of spondyloarthropathies is discussed, with a conclusion that no convincing evidence for its significance exists at the present.
 ...
PMID:Molecular mimicry: any role in the pathogenesis of spondyloarthropathies? 750 16

This study was performed in order to probe the possible pathogenesis of Klebsiella pneumoniae (KP) in ankylosing spondylitis (AS). 34 anti-KP antibody positive serum samples, including 26 patients with AS, 5 patients with rheumatoid arthritis (RA) and 2 healthy individuals, were selected to detect anti-subtypical KP antibodies by using an immunoblotting technique. The results showed that the number of antigenic bands to KP on nitrocellulose membrane was higher in AS patients than in RA patients and healthy individuals. Patients with AS had common antibodies response to KP components weight 64,600 (80.7%), 48,200 (61.5%) and 36,000 (65.4%), patients with RA and healthy individuals had anti-36,000 (75%) and anti-30,000 (50%) antibodies. Human anti-HLA-B27 serum and rabbit antisera against KP-derived synthetic peptide containing the hexapeptide sequence shared by HLA-B27 were able to cross react with 64,600 and 48,200 KP components. Our findings suggest that KP might play a role in the pathogenesis of AS by molecular mimicry between it and HLA-B27.
 ...
PMID:[Serum anti-subtypical Klebsiella pneumoniae antibodies in ankylosing spondylitis]. 764 43

The discovery that HLA-B27 is linked to ankylosing spondylitis (AS) and HLA-DR1/DR4 to rheumatoid arthritis (RA) has provided new approaches to the study of the possible causation of these diseases. Several theories have been proposed to explain these associations but only one, namely "molecular mimicry", has provided a specific aetiological agent for each of these diseases. Molecular mimicry between HLA-B27 and two molecules in Klebsiella microbes: nitrogenase and pullulanase D has been reported whilst in Proteus microbes, the haemolysin molecule shows sterochemical similarity to HLA-DR1/DR4. Elevated immune responses to Klebsiella microbes have been demonstrated in AS patients from 10 different countries and this wide geographical distribution suggests that the same aetiological agent is probably acting in producing this condition. Furthermore RA patients show similar immune responses to Proteus microbes. Whether AS or RA are caused by these bacteria can only be resolved by tissue typing all rheumatological patients early, in the course of their disease and then assessing their response to antibiotic chemotherapy in longitudinal studies involving double-blind crossover trials. It is possible that in the future, the course of AS or even RA could be modified by adequate antibiotic chemotherapy or even diets which affect the substrates on which these bacteria grow.
 ...
PMID:Molecular mimicry: the geographical distribution of immune responses to Klebsiella in ankylosing spondylitis and its relevance to therapy. 883 5

In the search for the pathogenic consequences of the molecular mimicry between the Klebsiella pneumoniae nitrogenase and the HLA-B27 antigen, sera from individuals belonging to 16 kindreds with juvenile-onset ankylosing spondylitis cases, were analyzed for antibodies against nitrogenase-positive and -negative K. pneumoniae whole bacterial extracts. An initial screening for nitrogenase producing K. pneumoniae strains was performed in 31 clinical isolates. The best nitrogenase producing strain was selected as well as a non producing one for immunoblot analysis using sera from 82 subjects, 55 HLA-B27 positive, of which 26 had some clinical manifestations. Even though electrophoretic patterns were different in both strains, there was no distinctive differential recognition of the 30-40 kDa proteins where the nitrogenase subcomponent which shares the sequence QTDRED with the HLA-B27 molecule is located. On the other hand, strong recognition of a protein of 60 kDa (p60Kp) was detected in 75% of HLA-B27 positive tested subjects independently of their clinical status. Studies on the nature of this protein and its participation in the pathogenesis of ankylosing spondylitis are now in progress.
 ...
PMID:Antibody response to nitrogenase-positive and -negative Klebsiella pneumoniae strains in juvenile-onset ankylosing spondylitis patients and their first degree relatives: lack of differential recognition of the bacterial nitrogenase. 898 12

Specific immunoreactive anti-Klebsiella antibodies are found in patients with ankylosing spondylitis (AS), a significant proportion of whom have occult inflammatory bowel disease. Molecular mimicry between Klebsiella or other bacterial antigens and HLA-B27 has been suggested in the pathogenesis of AS. The specificity of increased immunoreactivity against Klebsiella remains to be assessed against the abundant anaerobic bacterial flora, present either in healthy controls or in patients with ulcerative colitis (UC) and Crohn's disease (CD). Total immunoglobulin (Ig; IgG, IgA, IgM) immunoreactivity was measured by ELISA against Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli and ten anaerobic isolates of the predominant normal bowel flora in 35 patients with active AS, 60 patients with inflammatory bowel disease (30 CD, 30 UC), 60 patients with active rheumatoid arthritis (RA) and 60 healthy controls. Ig immunoreactivity to K. pneumoniae was significantly elevated in AS (P < 0.001), CD (P < 0.001) and UC (P < 0.001) patients compared with RA patients and healthy controls. Furthermore, Ig immunoreactivity to P. mirabilis was significantly elevated only in RA patients, compared with the other inflammatory groups (P < 0.001) and controls (P < 0.001). There was no significant antibody response against E. coli or the ten obligate anaerobes in any of the test groups. The data suggested an increased immune response to Klebsiella in patients with AS, UC, CD and to Proteus in patients with RA. The specificity of these responses in some patients supported a possible role for enteric Klebsiella in the pathogenesis of AS and Proteus in RA. The role of Klebsiella in inflammatory bowel disease requires further study.
 ...
PMID:Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn's disease and ulcerative colitis. 919 9

Structural and functional homology between bacterial proteins and host antigens, called molecular mimicry, is considered as significant pathogenic factor involved in several autoimmune diseases. The most important examples of this phenomenon reviewed in this work, involve rheumatic fever, Graves' disease, ankylosing spondylitis, Reiter's syndrome and rheumatic arthritis caused by infections with Streptococcus, Yersinia, Klebsiella, Escherichia coli, respectively.
 ...
PMID:[Molecular mimicry of bacteria as a factor in bacterial pathogenicity]. 1054 58

A growing body of evidence suggests that T lymphocytes play an important role in initiating and maintaining the inflammatory process characteristic of the human leukocyte antigen (HLA)-B27-associated spondyloarthropathies. T cells seem to be involved in the primary defense reaction against arthritis-triggering gram-negative bacteria at the site of extra-articular infection, in determining the systemic cytokine pattern, in the recirculation process between gut mucosa and the joint, and in mediating secondary autoimmune joint inflammation. The factors involved in disease chronicity (namely in ankylosing spondylitis and psoriatic arthritis) are still unknown. Autoreactive T cells may contribute to this process by recognition of cross-reactive self-epitopes (ie, molecular mimicry between bacterial and self-antigens). Autoreactive T cells may as well be inappropriately upregulated by bacterial superantigens, or by local inflammatory reactions leading to the uncovering of former cryptic self-epitopes. In this paper, we review recent studies on peripheral blood and synovial T cells in patients with reactive arthritis, enteropathic spondyloarthropathy, psoriatic arthritis, and ankylosing spondylitis.
 ...
PMID:T-cell studies in the spondyloarthropathies. 1112 74

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.
 ...
PMID:Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes. 1553 60


<< Previous 1 2 3 Next >>