Molecular mimicry in HLA-B27-related arthritis

A unique feature of patients with ankylosing spondylitis and reactive arthritis is that almost all share the HLA type B27. The primary structures of the HLA-B27 antigens have been determined. At least six variants exist. However, disease predisposition does not appear to be restricted to a particular variant. One hypothesis about the pathogenesis of arthritis is that the bacteria that cause the arthritis carry components that are cross-reactive with HLA-B27 antigens. Several reactive bacterial components have indeed been identified using monoclonal anti-HLA-B27 antibodies. Even more striking is the identification, through a computerized search, of a Klebsiella protein. This protein carries a stretch of six amino acids identical to residues 72 to 77 of two of the HLA-B27 variants. A synthetic peptide carrying these six amino acids of HLA-B27 protein is reactive with serum antibodies in some patients with arthritis. With this knowledge, investigators will be able to formulate new approaches for examining the pathogenesis of HLA-B27-associated arthritis.     

Anti-HLA-B27 antibodies in sera from patients with gram-negative bacterial infections

Several forms of seronegative polyarthritis are strongly associated with HLA-B27, and a number of microorganisms have been implicated in the etiology of these diseases. To explain the association between HLA-B27 and arthritis initiated by infection with these organisms, it has been proposed that there is immunologic cross-reactivity between the B27 molecule and 1 or more microbial antigens, and that this cross-reactivity leads to tolerance to such infection and/or to the production of anti-HLA-B27 cross-reactive antibodies. Such cross-reactive antibodies were detected in the sera of only 2 of 63 patients recently infected with Shigella flexneri, Campylobacter jejuni, or Yersinia enterocolitica who had highly significant antibody levels against the infecting bacterial species. Most striking was the absence of anti-HLA-B27 antibody in the serum of 16 of 17 patients who developed reactive arthritis following Yersinia infection.     

Anti-HLA–B27 antibodies in sera from patients with gram-negative bacterial infections

Several forms of seronegative polyarthritis are strongly associated with HLA-B27, and a number of microorganisms have been implicated in the etiology of these diseases. To explain the association between HLA-B27 and arthritis initiated by infection with these organisms, it has been proposed that there is immunologic cross-reactivity between the B27 molecule and 1 or more microbial antigens, and that this cross-reactivity leads to tolerance to such infection and/or to the production of anti-HLA-B27 cross-reactive antibodies. Such cross-reactive antibodies were detected in the sera of only 2 of 63 patients recently infected with Shigella flexneri, Campylobacter jejuni, or Yersinia enterocolitica who had highly significant antibody levels against the infecting bacterial species. Most striking was the absence of anti-HLA-B27 antibody in the serum of 16 of 17 patients who developed reactive arthritis following Yersinia infection.     

MOLECULAR MIMICRY IN THE PATHOGENESIS OF SPONDYLOARTHROPATHIES. A CRITICAL APPRAISAL OF CROSS-REACTIVITY BETWEEN MICROBIAL ANTIGENS AND HLA-B27

We describe an amino acid homology between a virulence plasmidencoded outer membrane protein of Yersinia, YadA (previouslycalled Yop1) and HLA-B27. This tetrapeptide is also includedin the hexapeptide, earlier found to be identical between Klebsiellanitrogenase and HLA-B27. The synthetic peptide based on theHLA-B27 homologous portion of the YadA does not stimulate lymphocytesobtained from HLA-B27+ patients with Yersinia-triggered reactivearthritis or from controls. One-third of the yersiniosis patientshave antibodies against the synthetic peptide. Instead of recognizingthe HLA-B27 homologous portion, the antibodies are directedagainst the left flanking sequence of the synthetic peptide.Similar results were obtained regarding antibody response toKlebsiella nitrogenase derived synthetic peptide included inthe panel of controls; the response was not restricted to patientswith reactive arthritis nor was it specifically directed againstthe sequence shared by HLA-B27 and Klebsiella pneumoniae nitrogenase.The present results do not support the role of molecular mimicryor cross-reactive antibodies in the pathogenesis of spondyloarthropathies. KEY WORDS: Reactive arthritis, Yersinia, Klebsiella, HLA-B27, Molecular mimicry     

Juvenile spondyloarthropathies associated with Mycoplasma pneumoniae infection

Background Reactive arthritis (ReA) has been sporadically reported as triggered by Mycoplasma pneumoniae. This study examined the potential relationship between the acute M. pneumoniae infection and juvenile spondyloarthropathy (jSpA) in children.Patients and methods Twelve patients with ReA secondary to acute M. pneumoniae were examined. M. pneumoniae-specific IgM, IgG and IgA antibodies were serologically confirmed by enzyme-linked immunosorbent assay (ELISA) tests (Savyon Diagnost., Israel). Due to the early appearance and relatively short life time of M. pneumoniae-specific IgM antibodies, their detection allowed the diagnosis of acute infection using single serum sample, confirmed by parallel serum in 7 of 12 patients. Specific IgM and IgG titers higher than 10 U/l were considered positive and those higher than 50 U/l as highly positive. Specific IgA antibodies were detected in only one patient.Results Four patients were female and eight were male. The mean age at onset was 9 years, and the mean duration of follow-up was 24.1 months (range 18–32). The mean number of involved joints was 2.8, and the knee joints were involved in 7 of 12 patients. The mean recovery time was 4.5 weeks (range 1–28) in eight reactive arthritis (ReA) cases; three patients developed enthesitis-related arthritis, and in one patient, genuine juvenile ankylosing spondylitis (jAS) was diagnosed. Two patients were HLA-B27-positive, and one patient was HLA-B7/B27-positive. Six patients had preceding respiratory symptoms, and five were treated with antibiotics.Conclusions Our findings provide clear evidence of ReA diagnosis following an acute M. pneumoniae infection that in four patients progressed to chronic jSpA. Our results suggest that detecting M. pneumoniae-specific antibodies in serological screening of jSpA patients might be useful. It is presently unclear whether antibiotic treatment would change the disease course in those patients.     

Modification of disease outcome in Salmonella-infected patients by HLA-B27

OBJECTIVE: To study whether HLA-B27 modifies the outcome of Salmonella infection in vivo. METHODS: The frequency of HLA-B27 was determined in 198 Salmonella-infected patients and 100 healthy controls by immunofluorescence and polymerase chain reaction. The excretion of Salmonella was monitored at monthly intervals. The symptoms of acute infection and possible joint involvement were evaluated using questionnaires. RESULTS: Thirty-eight of 198 Salmonella-infected patients (19.2%) and 13 of 100 healthy controls (13.0%) were HLA-B27 positive. The excretion of Salmonella did not differ significantly between HLA-B27-positive and -negative patients, or for patients with versus those without joint symptoms. As many as 35 patients (17.7%) reported Salmonella-triggered joint symptoms. Three of 14 patients (21.4%) with arthralgia, 5 of 13 patients (38.5%) with probable reactive arthritis (ReA), and 6 of 8 patients (75%) with confirmed ReA were HLA-B27 positive. The duration and severity of joint symptoms directly correlated with HLA-B27 positivity. Women reported Salmonella-induced pain and swelling of joints more frequently than men (P = 0.07 and P = 0.03, respectively). Patients with Salmonella-triggered joint symptoms reported abdominal pain and headache more frequently than patients without joint symptoms (P = 0.05 and P = 0.004, respectively). CONCLUSION: HLA-B27 did not (at least, not strongly) confer susceptibility to Salmonella infection. Salmonella excretion correlated neither with HLA-B27 positivity nor with the occurrence of joint symptoms. Joint symptoms were surprisingly common during or after Salmonella infection. HLA-B27-positive patients had a significantly increased risk of developing joint and tendon symptoms. Moreover, HLA-B27 positivity correlated with the development of more severe and prolonged joint symptoms.     

HLA-B27-Negative Arthritis Related to Campylobacter Jejuni Enteritis in Three Children and Two Adults

ABSTRACT. Five out of 37 patients with proven Campylobacter jejuni enteritis developed arthritis. Two adult patients presented with classical Reiter's syndrome. One of the three children had reactive arthritis, and clinical suspicion of septic arthritis could not be confirmed in two. The acute synovitis subsided usually without treatment in all patients within 3–7 days, while arthralgia persisted longer in 4 patients. HLA-B27 was not present in the 5 patients with arthritis, but was found in 4 others. In Northern Norway, Campylobacter fetus ssp. jejuni is more frequently isolated from stool specimens than Salmonella, Shigella and Yersinia enterocolitica. Synovial fluid should be cultured following Campylobacter jejuni enteritis in arthritis patients.     

Exacerbation of B27 positive spondyloarthropathy by enteric infections

Two patients developed reactive arthritis after enteritis secondary to Campylobacter jejuni and Salmonella Group B, respectively. Each patient had an established spondyloarthropathy and was HLA-B27 positive. While enteric pathogens are widely reported to cause reactive arthritis, these patients illustrate that exacerbations of arthritic syndromes may also be precipitated. Our findings support the concept that abnormalities of bowel flora may affect the course of B27 associated arthropathies     

Staphylococcus aureus triggered reactive arthritis.

OBJECTIVES--To report two patients who developed reactive arthritis in association with Staphylococcus aureus infection. METHODS--A review of the case notes of two patients. RESULTS--Two adult female patients have developed sterile arthritis in association with Staph aureus infection. The first patient has had two episodes of arthritis; the first followed olecranon bursitis, the second followed infection of a central venous catheter used for dialysis. The second patient developed sterile arthritis while being treated for pyomyositis. Both patients had a self limited arthritis and were HLA-B27 negative. CONCLUSION--Reactive arthritis may rarely follow Staph aureus infection. HLA-B27 negativity may be associated with a self limited arthritis in these cases.     

SERONEGATIVE ARTHRITIS ASSOCIATED WITH SEROLOGICAL EVIDENCE OF YERSINIA INFECTION IN AUSTRALIA

Infection due to yersinia enterocolitica is a common antecedent illness in patients with reactive arthritis in Scandinavia, but appears to be less frequent in other countries. In order to examine the frequency of yersinia infection in patients with seronegative arthritis in Australia we examined 22 patients, 15 with ankylosing spondylitis (AS) and seven with Reiter's syndrome (RS). A sensitive ELISA assay was used to detect serum antibodies to the most common serotypes. Six patients (29%) had positive yersinia serology, all were HLA B27 and four had a history of diarrhea preceding the onset of their disease. Four patients with positive yersinia serology had AS and two had RS. Antibodies were directed against Y. enterocolitica biotype 0:3 in three cases, Y. enterocolitica 0:9 in two cases and Y. enterocolitica 0:8 in one subject. Twenty-nine control subjects (13 HLA B27) had no serum antibodies to yersinia. The results of this study indicate that preceding yersinia infection occurs in a significant (p < 0.05; compared to controls) proportion of patients with HLA B27 related seronegative arthropathies.     

HLA-B27 antigen and rheumatoid factor negative (seronegative) peripheral arthritis : Studies in younger patients with early-diagnosed arthritis

HLA-B27, a valuable genetic marker for spondyloarthritis, offers a means for improved definition of rheumatoid factor negative (seronegative) peripheral arthritis. A group of 109 early-diagnosed patients with seronegative peripheral arthritis, who were under 45 years of age at the onset of disease, were studied prospectively. HLA-B27 prevalence was 23 per cent in the total group (25 of 109) and in those initially diagnosed as having rheumatoid arthritis (seven of 30) as compared to 7 per cent in normal subjects (six of 91). The age at onset of B27-associated arthritis was significantly concentrated in those 12 to 24 years of age (p < 0.005), especially in black males. The 25 patients who had the B27 antigen were matched on selected entry variables with 25 patients who did not. Clinical features and laboratory results were highly similar at entry to study and after three years average follow-up, with one exception found at the last examination. A striking prevalence of 83 per cent roentgenologic sacroiliitis was found in patients who had HLA-B27 compared to 21 per cent in those who did not, despite a paucity of spinal manifestations in both groups. These data emphasize the predominance of roentgenologic sacroiliitis in a varied spectrum of B27-associated arthritis, i.e., peripheral as well as spinal. The spectrum of seronegative peripheral arthritis includes an important subgroup who have B27, especially those with onset in adolescence or the early twenties. Clinical manifestations are often indistinguishable from matched patients without B27 and they may be frequently diagnosed as having seronegative rheumatoid arthritis during the early course of disease.     

False-negative serological HLA-B27 typing results may be due to altered antigenic epitopes and can be detected by polymerase chain reaction

Serological typing with the microlymphocytotoxicity test (MLCT) and flow cytometry (FC) using HLA-B27 antisera is commonly used for the determination of HLA-B27. However, in some patients tested more than once, negative results have turned out to be positive at following investigations. We retested by polymerase chain reaction (PCR) samples from 20 randomly selected patients with reactive arthritis or Reiter's syndrome who had now been followed for 20 yr. Ten of the patients were originally tested to be HLA-B27 positive and 10 HLA-B27 negative by the MLCT. All 10 serologically HLA-B27 positive individuals were also positive in the PCR. However, 2/10 patients interpreted as being HLA- B27 negative were positive by PCR. At this time, the same two patients were also positive in the routine MLCT and FC using four different monoclonal antibodies against HLA-B27. PCR is superior to serological techniques to determine HLA-B27 positivity unequivocally, since it is based on the detection of HLA-B27 gene sequences.      

Chlamydia pneumoniae as a triggering infection in reactive arthritis.

OBJECTIVE: To determine the role of Chlamydia pneumoniae as a triggering infection in reactive arthritis (ReA). METHODS: Sixty patients with acute arthritis were screened for the evidence of triggering infections. In all patients, bacterial stool cultures, culture of Chlamydia trachomatis in urethra/cervix, and/or bacterial serology were studied. Chlamydia pneumoniae antibodies were measured by specific microimmunofluorescence test. RESULTS: Thirty-five of 60 patients fulfilled the diagnostic criteria for ReA. Thirty-one patients had microbial/serological evidence of preceding infection due to Salmonella, Yersinia, Campylobacter or Chlamydia trachomatis, or they had enteritis or urethritis prior to arthritis. Four additional patients had high antibody titre for C. pneumoniae. Three of these four patients had preceding lower respiratory symptoms, and were positive for HLA-B27. The clinical picture of C. pneumoniae-positive ReA patients was similar to that of ReA patients with other definite aetiology. CONCLUSION: Chlamydia pneumoniae is a triggering factor in approximately 10% of patients with acute ReA.     

Reactive arthritis after an outbreak of Yersinia pseudotuberculosis serotype O:3 infection

OBJECTIVE: To determine the occurrence and clinical characteristics of reactive arthritis (ReA) after an outbreak of Yersinia pseudotuberculosis serotype O:3 infection. METHODS: From 15 October to 6 November 1998, a widespread outbreak of Y pseudotuberculosis serotype O:3 occurred in Finland. A questionnaire on musculoskeletal symptoms was mailed to 38 patients with infection confirmed by culture. All patients who reported joint symptoms were interviewed by phone and their medical records of outpatient visits or hospital admission because of recent joint symptoms were reviewed. RESULTS: Thirty three of 38 (87%) patients returned the questionnaire. Reactive musculoskeletal symptoms were reported by 5/33 (15%): four patients (12%) fulfilled the criteria for ReA and one additional patient had reactive enthesopathy. The patients with ReA were adults (age range 40-47 years), whereas the patient with reactive enthesopathy was a 14 year old boy. In all patients with ReA, the arthritis was polyarticular. In addition to peripheral arthritis, other musculoskeletal symptoms included sacroiliitis (one patient), pain in Achilles tendon (one patient), and heel pain (two patients). HLA-B27 was positive in all the three patients tested. In three of four patients with ReA, the duration of acute arthritis was over six months. CONCLUSION: Y pseudotuberculosis serotype O:3 infection is frequently associated with ReA and the clinical picture is severe.     

Invasion of Salmonella into human intestinal epithelial cells is modulated by HLA-B27

OBJECTIVE: To investigate the influence of the major histocompatibility complex (MHC) class I molecule HLA-B27 on (i) the invasion of Salmonella and Yersinia into human intestinal epithelial cells, (ii) the survival of intracellular Salmonella in these cells, and (iii) the production of certain inflammatory cytokines by the cells after Salmonella infection. METHODS: The human intestinal epithelial cell line Henle-407 was transfected with HLA-B27 DNA. These cells and HLA-B27-negative control cells were infected with Salmonella or Yersinia, and viable intracellular bacteria were determined as colony-forming units. Cytokine production was assayed with ELISA. RESULTS: Salmonella invaded HLA-B27-positive Henle cells in higher numbers than HLA-B27-negative control cells. However, HLA-B27 did not affect the invasion of Yersinia or the survival of the intracellular bacteria in these intestinal epithelial cells. Salmonella infection induced production of interleukin-8 (IL-8), IL-6 and monocyte chemotactic protein 1 (MCP-1) by Henle cells that was not affected by HLA-B27 in a specific way. CONCLUSIONS: These findings suggest that HLA-B27 enhances the invasion of Salmonella into intestinal epithelial cells. The interaction between bacteria and intestinal epithelial cells plays an important role during the early phases of ReA. HLA-B27-linked modulation of Salmonella invasion may lead to an increased load of Salmonella in intestinal tissue and thus increased susceptibility to reactive arthritis.     

Long term prognosis of reactive salmonella arthritis

OBJECTIVES—Reactive joint complications triggered by salmonella gastroenteritis are increasingly reported, but the outcome and long term prognosis of the patients is incompletely known. This study looked at the prognosis of salmonella arthritis in patients hospitalised in 1970-1986.
METHODS—Hospital records from two hospitals in southern Finland were screened for patients with the discharge diagnosis of salmonellosis or reactive, postinfectious arthritis or Reiter's disease. For the patients with confirmed diagnosis of reactive salmonella arthritis, data about the acute disease were collected from the hospital records. A follow up study was performed.
RESULTS—There were 63 patients (28 women, 35 men, mean age 36.5 years) with salmonella arthritis. Urethritis occurred in 27%, eye inflammation in 13%, and low back pain in 44% of the patients. HLA-B27 was present in 88%. More men than women were HLA-B27 positive. HLA-B27 positive patients had higher erythrocyte sedimentation rate (mean 80.9 v 46.5 mm 1st h, p = 0.0180). Also, extra-articular features and radiological sacroiliitis were seen only in HLA-B27 positive patients. A follow up study was performed on 50 patients mean 11.0 (range 5-22 years) later. Twenty patients had recovered completely. Ten patients had mild joint symptoms, 11 patients had had a new acute transient arthritis, and five acute iritis. Eight patients had developed chronic spondyloarthropathy. Radiological sacroiliitis was seen in six of 44 patients, more frequently in male than in female patients (32% v 0%; p = 0.0289). Recurrent or chronic arthritis, iritis or radiological sacroiliitis developed only in HLA-B27 positive patients.
CONCLUSION—Joint symptoms are common after reactive salmonella arthritis. HLA-B27 contributes to the severity of acute disease and to the late prognosis.

     

Triggering infections in reactive arthritis.

Certain microbes like yersinia, salmonella, shigella, campylobacter, chlamydia, and possibly gonococcus can trigger reactive arthritis especially in patients of the HLA-B27 type. In the present study we have used serological and culture methods to identify the probable triggering infection in 50 consecutive HLA-B27 positive patients diagnosed as having reactive arthritis. The two most common triggering agents thus identified were Yersinia enterocolitica (12 patients) and Chlamydia trachomatis (11 patients). In addition six patients had high antistreptolysin O titres and two high teichoic acid antibody titres suggesting group A streptococci and Staphylococcus aureus as triggering agents. In 13 patients no preceding infection could be identified. The identity of the infective agent seems to have very little effect on the clinical picture of the reactive arthritis - the only difference between the various aetiological groups in the present material was absence of fever in the patients with a preceding C. trachomatis infection, of whom only one out of 11 had a temperature greater than or equal to 38 degrees C, whereas 13 of 16 patients with a preceding enterobacterial, and five of the eight patients with a streptococcal or staphylococcal infection had raised temperatures.     

Lower level of synovial fluid interferon-gamma in HLA-B27-positive than in HLA-B27-negative patients with Chlamydia trachomatis reactive arthritis

OBJECTIVES: To compare the synovial fluid (SF) concentrations of various cytokines in rheumatoid arthritis (RA) and in reactive arthritis, and to look for a correlation between cytokine levels and the presence of HLA-B27 antigen in reactive arthritis patients. METHODS: Concentrations of interleukin (IL) 10, IL-12, IL-18, interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) were determined by commercially available enzyme-linked immunosorbent assays (ELISA) in the SF from 48 patients with reactive arthritis, 33 with RA and 13 with osteoarthritis (non-inflammatory controls). RESULTS: The SF concentrations of IL-10 were significantly lower in patients with reactive arthritis (median 2.3 pg/ml) than in RA patients (median 14.6 pg/ml). The SF levels of IFN-gamma were not significantly different but the ratios of IFN-gamma to IL-10 were significantly higher in patients with reactive arthritis (median 9.2) than in RA patients (median 0.83). When the subset of patients with Chlamydia trachomatis reactive arthritis was considered, the SF concentration of IFN-gamma was significantly lower in HLA-B27-positive (median 2.9 pg/ml) than in HLA-B27-negative patients (median 42.4 pg/ml). After 2 yr of follow-up, two HLA-B27-positive patients, who had low SF levels of IFN-gamma, had a chronic course of arthritis, whereas after 1 yr all HLA-B27-negative patients had complete resolution of arthritis. CONCLUSIONS: The lower IFN-gamma concentrations in HLA-B27-positive patients with C. trachomatis reactive arthritis could be related to the tendency of these patients to have more severe or chronic arthritis.     

Two forms of reactive arthritis?

Inflammatory arthritides developing after a distant infection have so far been called reactive or postinfectious, quite often depending on the microbial trigger and/or HLA-B27 status of the patient. For clarity, it is proposed that they all should be called reactive arthritis, which, according to the trigger, occurs as an HLA-B27 associated or non-associated form. In addition to the causative agents and HLA-B27, these two categories are also distinguished by other characteristics. Most important, HLA-B27 associated arthritis may occur identical to the Reiter's syndrome with accompanying ureteritis and/or conjunctivitis, whereas in the B27 non-associated form this has not been clearly described. Likewise, only the B27 associated form belongs to the group of spondyloarthropathies.