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)

Crohn's disease (CD) is an immune-mediated gastrointestinal inflammatory disease, which could arise from an interplay between genetic and environmental factors. Klebsiella microbes were suggested to have a vital role in the initiation and perpetuation of the disease through the mechanism of molecular mimicry. This proposition is based on the results of various studies where significantly elevated levels of antibodies against the whole bacteria or preparations from Klebsiella microbes and antibodies to collagen types I, III, IV, and V were detected in patients with CD and patients with ankylosing spondylitis (AS). Molecular similarities were found between Klebsiella nitrogenase and HLA-B27 genetic markers and between Klebsiella pullulanase and collagen fibers types I, III, and IV. Furthermore, significantly positive correlations and cross-reactivity binding activities were observed between anti-Klebsiella and anticollagen antibodies among patients with CD and AS. Early treatment of CD patients with anti-Klebsiella measures is proposed, which may involve the use of antibiotics and low starch diet together with other traditionally used immunomodulatory, immunosuppressive, or biologic agents.
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PMID:A possible link between Crohn's disease and ankylosing spondylitis via Klebsiella infections. 1694 Dec 2

"B27 disease" is a new autoimmune disease that afflicts millions of people throughout the world. "B27 disease" occurs in individuals who have ankylosing spondylitis (AS) or preankylosing spondylitis and/or uveitis and are also positive for HLA-B27. Molecular mimicry between the bowel microbe Klebsiella and the HLA-B27 molecule, as well as the spinal collagens types I, III, and IV, indicates a pathological mechanism involving autoimmunity. Antibodies to Klebsiella microbes have been reported in AS patients from 18 different countries. Sera from patients with AS show complement-dependent cytopathic activity against sheep red cells coated with HLA-B27 peptide antigens. Diagnosis of B27 disease can lead to early treatment, involving low-starch diet, sulfasalazine, and immunosuppressive and biological agents so as to prevent the irreversible bony changes of established classical AS. The concept of B27 disease provides a new approach to the study and treatment of these disorders and needs to be evaluated in prospective studies by the world rheumatological community.
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PMID:B27 disease is a new autoimmune disease that affects millions of people. 1791 26

Peptide binding is a central biological property of HLA-B27. The availability of HLA-B27 subtypes differentially associated to ankylosing spondylitis provides a unique tool to explore the relationship between peptide specificity and pathogenetic potential. Many studies have focused on defining the nature of subtype-bound repertoires, aiming to identify peptide features that may correlate with association to disease and to find constitutive self-ligands with sequence homology to microbial epitopes. These studies were pursued on the assumption that molecular mimicry between self and foreign ligands of HLA-B27 might trigger autoimmunity. A second level of involvement ofpeptide repertoires in the biology and immunopathology of HLA-B27 is through their critical influence on folding, maturation and cell surface expression and stability. Recent studies have emphasized the mechanisms ofpeptide loading and optimization, the interactions ofHLA-B27 with other components of the peptide-loading complex and the contribution of these interactions to shaping HLA-B27-bound peptide repertoires. A novel, more comprehensive and integrative, view is emerging in which the peptide binding specificity is a critical determinant of the whole HLA-B27 biology. A proper understanding of the relationships between peptide specificity and other molecular and functional features of HLA-B27 should provide the key to unveiling its pathogenetic role in spondyloarthritis.
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PMID:HLA-B27-bound peptide repertoires: their nature, origin and pathogenetic relevance. 1973 30

This article reviews the literature concerning rheumatic manifestations of inflammatory bowel disease (IBD), including common immune-mediated pathways, frequency, clinical course and therapy. Musculoskeletal complications are frequent and well-recognized manifestations in IBD, and affect up to 33% of patients with IBD. The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations, notably in HLA-B27 transgenic rats. The autoimmune pathogenic mechanisms shared by IBD and spondyloarthropathies include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms. Rheumatic manifestations of IBD have been divided into peripheral arthritis, and axial involvement, including sacroiliitis, with or without spondylitis, similar to idiopathic ankylosing spondylitis. Other periarticular features can occur, including enthesopathy, tendonitis, clubbing, periostitis, and granulomatous lesions of joints and bones. Osteoporosis and osteomalacia secondary to IBD and iatrogenic complications can also occur. The management of the rheumatic manifestations of IBD consists of physical therapy in combination with local injection of corticosteroids and nonsteroidal anti-inflammatory drugs; caution is in order however, because of their possible harmful effects on intestinal integrity, permeability, and even on gut inflammation. Sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide should be used for selected indications. In some cases, tumor necrosis factor-alpha blocking agents should be considered as first-line therapy.
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PMID:Rheumatic manifestations of inflammatory bowel disease. 1993 89

Seronegative spondyloarthritides are inflammatory rheumatic diseases which are classified together because of numerous common and similar clinical, epidemiologic and genetic characteristics. Pathogenesis of seronegative spondyloarthritides is usually described as development of clinical characteristics of the disease in genetically susceptible person in the presence of favorable environmental factors. Development of seronegative spondyloarthritides, notably ankylosing spondylitis, is strongly connected with presence of the HLA-B27 gene. There are clear evidence that HLA-B27 positive individuals have significantly higher risk for disease development. The role of infection in occurence of seronegative spondyloarthritides is not completely understood--its role is better clarified in the case of reactive arthritis than in ankylosing spondylitis. The relation between HLA-B27 gene and infection is not clarified. Molecular mimicry theory is based on similarities between HLA-B27 molecule and microbial particle.
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PMID:[Etiology and pathogenesis of spondyloarthritides]. 2223 44

A general consensus supports fundamental roles for both genetic and environmental, mainly microbial, factors in the development of autoimmune diseases. One form of autoimmune rheumatic diseases is confined to a group of nonpyogenic conditions which are usually preceded by or associated with either explicit or occult infections. A previous history of clinical pharyngitis, gastroenteritis/urethritis, or tick-borne skin manifestation can be obtained from patients with rheumatic fever, reactive arthritis, or Lyme disease, respectively, whilst, other rheumatic diseases like rheumatoid arthritis (RA), ankylosing spondylitis (AS), and Crohn's disease (CD) are usually lacking such an association with a noticeable microbial infection. A great amount of data supports the notion that RA is most likely caused by Proteus asymptomatic urinary tract infections, whilst AS and CD are caused by subclinical bowel infections with Klebsiella microbes. Molecular mimicry is the main pathogenetic mechanism that can explain these forms of microbe-disease associations, where the causative microbes can initiate the disease with consequent productions of antibacterial and crossreactive autoantibodies which have a great impact in the propagation and the development of these diseases.
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PMID:Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry. 2245 61

Molecular mimicry and arthritogenic peptides form the basis of hypotheses that attempt to explain the pathogenesis of HLA-B27-positive ankylosing spondylitis (AS). We propose, therefore, that certain human viruses may possess peptide sequences that mimic HLA-B27-binding human 'self' peptides which might induce or play a significant role in AS. In the present study, we performed bioinformatic analysis, using BLASTP, of the human virus proteome and HLA-B27-binding human 'self' peptides including peptides derived from arthritogenic sequences. We identified that some HLA-B27-binding peptides, particularly those present in proteins of the cartilage and bone, are highly similar to those present in viruses known to cause chronic infection. We suggest that the identical short amino acid sequences shared between human viruses and HLA-B27 peptides may play a role in the pathogenesis of AS.
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PMID:Short peptide sequence identity between human viruses and HLA-B27-binding human 'self' peptides. 2436 32

Inflammatory arthritis is a condition which is characterised by recurrent episodes of joint pain and swelling. It encompasses a spectrum of disorders ranging from rheumatoid arthritis to ankylosing spondylitis. In these conditions, for reasons that are poorly understood, the immune system raises an inflammatory response within the joint space. In some cases, autoantigens have been identified (e.g., anticitrullinated peptides in rheumatoid arthritis), but the absence of these, in the seronegative arthritides, for example, raises question as to the underlying pathogenesis. Interest has, therefore, turned to host-pathogen interactions and whether aberrant immune responses to these could explain the development of arthritis. This has been most widely studied in reactive arthritis (ReA), where an infectious episode precedes the development of the joint symptoms. In this review, we present the evidence for the role of host-bacterial interactions in the pathogenesis of joint inflammation with particular emphasis on ReA. We discuss a range of possible mechanisms including molecular mimicry, persistent low grade infections, and abnormal host responses to common bacterial causes of reactive arthritis as well as discussing some of the clinical challenges that we face in making the diagnosis and in treatment of persistent symptoms.
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PMID:The role of intracellular organisms in the pathogenesis of inflammatory arthritis. 2499 43

Diarrheic episodes caused by the foodborne pathogens Campylobacter , Salmonella , Shigella or Yersinia may lead to a sterile arthritis such as reactive arthritis, Reiter's syndrome or ankylosing spondylitis. Reiter's syndrome and reactive arthritis have been shown to be sequelae in a few well-studied bacterial food poisoning outbreaks. Reactive arthritis, Reiter's syndrome and ankylosing spondylitis show strong familial association related to the gene for HLA-B27 (HLA = human leucocyte antigen) antigen. Why HLA-B27-positive individuals are more susceptible to arthritis is not known, but molecular mimicry between the HLA-B27 antigen and antigens of triggering bacteria has been demonstrated and this mimicry has been proposed as a mechanism involved in etiology of the arthritides. Antigens from bacteria that triggered the arthritis are present in arthritic joints but bacterial cells are not found. Antibodies and T-cells specific for the triggering bacteria have been demonstrated in arthritic patients. T-cells present in synovial joints respond specifically to the particular arthritic triggering pathogen. The cells that respond to bacterial antigens belong to the T-cell subset TH1 that secrete a limited number of cytokines but it is not known if cytokines are involved in arthritis. A few studies have demonstrated that T-cells from the joints of arthritic patients respond to both bacterial and human heat shock proteins indicating that autoimmunity may be involved in causation of arthritis. While only about 2% of a population exposed to a triggering infection will acquire arthritis, these individuals undergo pain and suffering as well as economic hardships as a result of their disease.
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PMID:Arthritis and Foodborne Bacteria. 3112

The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.
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PMID:Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection. 3211 5


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