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Abstract
The various subtypes of HLA-B27 are described together with their worldwide distribution. None is uniquely related to AS but the evidence favours a direct role for B27 in the disease pathogenesis.
... The disease in severe cases can progress to form the classic`bamboo spine'. It is well established that HLA-B27 is associated with AS in all racial groups examined [7,8], but it must be noted that the majority of HLA-B27 carriers are free from disease. Class I major histocompatibility (MHC) molecules such as HLA-B27 are found on virtually all cells except mature erythrocytes and trophoblasts, whereas class II molecules like HLA-DR1=DR4 are present on B cells, monocytes and dendritic cells, where they are thought to play a role in antigen presentation to T cells. ...
It has been well established that many diseases are linked to HLA antigens. Two of the most interesting HLA associations may provide some insight into the pathogenesis of rheumatic inflammatory conditions. In ankylosing spondylitis (AS), 96% of patients possess HLA-B27, whilst the frequency of this marker in the general population is c. 8%. In rheumatoid arthritis (RA), >90% of patients possess either HLA-DR1 or some subtypes of HLA-DR4, whilst the frequency of this marker in the general population is c. 35%. The association between HLA-B27 and reactive arthritis (ReA) has also been well established. Furthermore, it has been shown that ReA is triggered by infection via the gastrointestinal tract due to Yersinia, Salmonella or Campylobacter spp. and in the genitourinary tract due to chlamydia. In a similar way, microbiological and immunological studies have revealed an association between Klebsiella pneumoniae in AS and Proteus mirabilis in RA. This article reviews the possible pathological implications of the associations between HLA-B27, K. pneumoniae and AS, as well as HLA-DR1/DR4, P. mirabilis and RA.
... Not everyone who is HLA-B27positive develops AS; it is likely that other genetic and/or environmental factors play a role in the etiology. 5 One recent theory is that AS is an autoimmune disorder that occurs subsequent to a Klebsiella pneumoniae infection in HLA-B27-positive individuals, with molecular mimicry between HLA-B27 and K pneumoniae bacterial antigens. 6 Elevated levels of antibodies to K pneumoniae have been noted in AS patients. ...
Ankylosing spondylitis is an inflammatory disease of unknown etiology that affects an estimated 350,000 persons in the United States and 600,000 in Europe, primarily Caucasian males in the second through fourth decades of life. Worldwide, the prevalence is 0.9%. Genetic linkage to HLA-B27 has been established. Ankylosing spondylitis primarily affects the axial skeleton and is characterized by inflammation and fusion of the sacroiliac joints, spine, and hips. The resultant deformity leads to severe functional impairment in approximately 30% of patients. Orthopaedic management primarily involves correction of hip deformity through total hip arthroplasty and, less frequently, correction of spinal deformity with spine osteotomy. Closing wedge osteotomies have the lowest incidence of complications. Whether patients with ankylosing spondylitis are at increased risk for heterotopic ossification remains controversial, but comparison with age- and sex-matched counterparts suggests no dramatically higher risk. Because of the high rate of missed fractures and complications after minor trauma in patients with ankylosing spondylitis, plain radiographs are usually not sufficient for evaluation. Thorough patient assessment should include a comprehensive history, physical examination, and laboratory studies.
Ankylosing spondylitis and Klebsiella is a comprehensive and informative text on the cause of Ankylosing spondylitis. Ankylosing spondylitis (AS) is a condition which affects 20 million people worldwide and is likely caused or initiated by a bowel infection from Klebsiella bacteria. When a patient is infected by Klebsiella bacteria, his or her immune system will make antibodies against all the antigens or molecules found in the microbe. Because some of the bacterial antigens resemble self tissues, the anti-bacterial antibodies will attack not only the bacteria but also the self tissues such as the joints and the cells having the same HLA molecules, which is how the disease AS starts. This is the concept of molecular similarity or "molecular mimicry" which previously has been found to work in two other autoimmune diseases; rheumatic fever and rheumatoid arthritis. The first paper on this subject was published in 1976 and since then over 100 papers on rheumatological topics have been published, from Prof Ebringer's group, at the Division of Life Sciences, King's College in London, UK. The relevant information from these papers is extracted and presented in this book format making it accessible to health professionals, research institutions, pharmaceutical companies and universities and the general public.
In the early 1970s, following Dr. Christian Barnard’s momentous first cardiac transplantation in the world, the field of organ transplantation acquired a new resonance, and tissue typing units were formed in many hospitals.
Bovine spongiform encephalopathy (BSE) is a neurological disorder which has affected cattle in the UK. It has been suggested that it is caused by prions and these may also be responsible for scrapie in sheep and Creutzfeldt-Jakob disease (CJD) in humans. The molecular mimicry theory is an alternative model which suggests that BSE could be an autoimmune disease caused by exposure of cattle to bacteria showing cross-reactivity with nervous tissue. Acinetobacter calcoaceticus , Ruminococcus albus , Agrobacterium tumefaciens and Escherichia coli have been shown to contain molecular sequences which resemble brain tissue. Neurological damage is caused either by prions or by autoimmune mechanisms and the contrasting features of these two theories are reviewed. Furthermore, the autoimmune theory implies that there is no need for a cull of cattle, and that humans will not develop CJD provided they are not exposed to these bacteria.
Abstract HLA-A, B, C and DR antigen frequencies were determined in a group of patients with juvenile periodontitis and rapidly progressive periodontitis. In juvenile periodontitis patients. HLA-A24 and DR4 were found at a significantly higher level than in the control group, and in rapidly progressive periodontitis patients, A9 and DR4 were found at a significantly higher level than the control group. The presence of these antigens gives evidence as to the susceptibility of various forms of early onset periodontitis.
Periodontal diseases are essentially infectious in origin, their outcome depending on interaction between the pathogenic challenge and host response. Host genotype has been implicated in certain of the more unusual forms, but together these account for only a small proportion of periodontal patients. Nevertheless, the genes for these rarer conditions, some of which have already been located and/or cloned, are of considerable importance, since they may ultimately provide clues leading to a better understanding of the whole spectrum of periodontal disease. For the majority of periodontal patients, although inherited susceptibility is suspected, evidence of a significant genetic component is scanty. The priority here is therefore to establish the existence of contributing genes. This may be possible by using approaches designed to minimise the confounding effect of environmental variation that has probably been a source of confusion in the past.
Seronegative spondyloarthropathies (SSA) are a group of inflammatory disorders, which clinically involve the axial skeleton and the sacroiliiac and shoulder joints. The aim of the present study was to study the association of HLA B27, B7, Bw4 and Bw6 with some inflammatory diseases, in SSA patients in our area. A total of 220 SSA patients were studied and HLA typing for these antigens were done by the complement-mediated microcytotoxicity method. The total positivity of B27 was found to be 68.64% in SSA patients. Tubercular infection (chi(2) = 8.06) and acute anterior uveitis (chi(2) = 6.19) were found to be statistically significant (P < 0.05) in B27-positive SSA patients. Tuberculosis was also found to be significantly (chi(2) = 6.40) associated with Bw4. In SSA urinary tract infection, gastrointestinal infection and streptococcal infection were not significantly associated with B27, B7, Bw4 or Bw6 antigens. Our study concludes that microbial infections do have some pathogenic role in causing SSA.
A critical examination of the five different models proposed to explain the "AS-B27" problem, has demonstrated, that two of these, the two-gene theory and the plasmid theory are no longer considered to provide satisfactory explanations of the phenomena. The remaining three theories are molecular mimicry, chemotaxis hypothesis and the receptor theory. It is difficult at this stage to decide which of these three models provides the best solution to the "AS-B27" problem, but a majority of research workers favour the receptor theory.
Sequence analysis and site-directed mutagenesis of HLA-B27 indicate an unpaired cysteine at position 67 of the hypervariable region corresponding to its serologically defined, disease-associated epitope. We investigated whether chemical modification of this thiol group affected the serological reactions of B27. B27-positive cells were treated with thiol-blocking agents and then tested for recognizable B27 expression. Anti-HLA-B27 alloantisera and monoclonal antibodies were used in cytotoxicity, absorption, and cellular ELISA (cELISA). The semi-quantitative cytotoxicity-based assays showed some decrease in both B27 and controls. However, cELISA indicated that the inhibition of B27 was significantly greater than control antigens, and dependent on thiol-blocker concentration. This suggests that a proportion of HLA-B27 molecules have a free, reactive thiol at the antibody-defined epitope. Incomplete inhibition by thiol-blocking agents indicates that the remainder are inaccessible.
Synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been shown in cells from knee joint synovial fluid of 20 patients with inflammatory rheumatoid disease, reactive or psoriatic arthritis, or gout, all of which had high synovial fluid cell counts, and by cells from a patient with aseptic necrosis of a femoral condyle after short term (less than 24 hours) or long term (seven days) primary culture. Cells from 18 patients with inflammatory arthritis, five of which had low synovial fluid cell counts and cells from six patients with osteoarthritis were unable to synthesise this metabolite from 25-hydroxyvitamin D3 (25(OH)D3). Macrophages are believed to be the cells responsible for synthesising 1,25(OH)2D3 because these were significantly more numerous in samples that formed 1,25(OH)2D3; they were also the predominant cell type present in the aseptic necrosis sample and the only cell type present in preparations maintained for one week in monolayer culture.
HLA-A, B, C and DR antigen frequencies were determined in a group of patients with juvenile periodontitis and rapidly progressive periodontitis. In juvenile periodontitis patients, HLA-A24 and DR4 were found at a significantly higher level than in the control group, and in rapidly progressive periodontitis patients, A9 and DR4 were found at a significantly higher level than the control group. The presence of these antigens gives evidence as to the susceptibility of various forms of early onset periodontitis.
This study has been designed to investigate the immunogenetic susceptibility of Cyclosporine-A (CsA) immunosuppressed renal transplant patients to development of gingival overgrowth, and the amplifying effect of calcium channel blockers on the severity of this clinical entity. 52 renal transplant recipients were selected and initially grouped as follows: group (Gp)1: CsA (n = 7); Gp 2: CsA + verapamil (n = 26); Gp 3: CsA + diltiazem (n = 6); Gp 4: CsA + nifedipine (n = 13). These groups were not found to be significantly different in age, sex, plaque index (PlI), gingival index (GI), calculus index, periodontal probing depth, serum CsA level, or duration of CsA therapy (p > 0.05). No significant (p > 0.05) additive effect of the calcium channel blockers on the gingival overgrowth (GO) was assessed. The main group (n = 52) was evaluated for the correlations between the clinical and the pharmacological variables and the GO. GI (rs = 0.60) and the periodontal probing depth (rs = 0.71) were found to be moderately correlated with the GO. The patients were regrouped based on the severity of overgrowth and recognized as responders (n = 26) and nonresponders (n = 26). Age, sex, calculus index, serum CsA level, duration of the CsA therapy, were not statistically different among these groups (p > 0.05). PlI, GI, periodontal probing depth, and GO were significantly higher in the responder group (p > 0.05). Analysis of HLA distribution of the responders and the nonresponders and comparison with the controls (n = 3731) revealed that a statistically significant (p < 0.001)% of the nonresponders were positive for HLA-DR1. These data would indicate that an immunogenetic predisposition should be suspected in the pathogenesis of the entity, and that HLA-DR1 would have a protective rôle against gingival overgrowth induced by CsA.
Molecular mimicry is one of the pathological mechanisms proposed to explain the association between microorganisms and autoimmune diseases. This review deals with the association between bacteria and rheumatic diseases with a special emphasis on rheumatoid arthritis where upper urinary tract infection by Proteus mirabilis is the possible cause of this severe, arthritic condition. Prospective trials involving anti-Proteus therapy should be carried out.
Gram negative bacteria precipitate reactive arthritis and may be concerned in the pathogenesis of ankylosing spondylitis and other spondyloarthropathies. Susceptibility to many infectious agents is associated with ABO blood group or secretor state, or both. The distribution of the ABO blood group or secretor state, or both, was therefore determined in 87 patients with ankylosing spondylitis and 32 with other forms of spondyloarthropathy. The prevalence of non-secretors was significantly increased in the total patient group (54/114; 47%) and in the subgroup with ankylosing spondylitis (41/84; 49%) compared with local controls (89/334; 27%) (p less than 0.001). Other subgroups of patients showed a similarly increased prevalence of non-secretion (33-47%). The distribution of ABO blood groups did not differ between patients and controls. The association between non-secretor state and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis is a form of reactive arthritis. It also suggests several pathogenic mechanisms which may be relevant to the initial hostparasite interaction in ankylosing spondylitis.
Despite major advances in genetic and structural studies of the HLA-B27 antigen, the underlying mechanism responsible for the remarkable association between this antigen and spondylarthropathies remains unknown. At a molecular level, the use of B27M1 and B27M2 monoclonal antibodies has permitted the identification of distinct allospecific epitopes on the B27 molecule. One of these epitopes, B27M2, is polymorphic and has allowed us to define B27 variants: B27M2[+], B27M2[-], and B27M2[int]. The heterogeneity of the B27 antigen correlates well with biochemical and cytotoxic evidence of genetic heterogeneity. These variants exhibit ethnic variation and also appear to correlate, in preliminary studies, with disease susceptibility, especially among Orientals. HLA gene probing is potentially an even more precise tool than monoclonal antibodies for the study of MHC-related disease susceptibilities. Initial work in our laboratory has resulted in the production of probes with specificity for HLA-B locus genes and current efforts are directed toward the derivation of B27 allele-specific probes. It seems likely that, when such probes are applied to B27-positive individuals, complexity in addition to the B27M2 variants will be revealed. Yet to be defined is the mechanism behind the association between B27 and AS. Is the association causal for disease, or is B27 indeed just a marker for other pathogenic factors somehow linked to it? Available evidence points to both causal and linked roles for B27 in ankylosing spondylitis. Products of both HLA and non-HLA gene families may interact with infectious disease pathogens in susceptible individuals to produce a disorder which may not be specific in its association with any one pathogenic factor.