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Non-viable structures of Yersinia enterocolitica O:3 were shown at the site of inflammation within mononuclear cells in the synovial membrane of eight out of 10 patients with yersinia triggered reactive arthritis. An avidin-biotin-peroxidase complex method, with a rabbit antiserum specific for Y enterocolitica O:3, was used to visualise yersinia structures. All 13 control samples were negative except for one with non-specific mast cell staining. The findings emphasise the significance of foreign material in the initiation of synovitis in reactive arthritis.

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The passive intestinal permeability of patients with yersinia triggered reactive arthritis was studied using different sized polyethylene glycols (PEGs) contained in a mixture of PEG 400 and PEG 1000. The investigation was carried out at least one year after the onset of yersinia infection, and patients had neither acute gastrointestinal nor joint symptoms. The control groups included patients with uncomplicated yersiniosis as well as healthy subjects who were either HLA-B27 positive or negative. An altered intestinal barrier function to PEG molecules was detected in patients with a history of yersinia infection compared with healthy controls. No significant differences in the permeability were found between patients with or without reactive arthritis, nor was there any association of increased permeability with HLA-B27. The passive permeability of the intestinal mucosa to the larger molecules was increased for an unexpectedly long time after the acute yersinia infection, probably contributing to the perpetuation of joint symptoms in subjects susceptible to a chronic joint disease.

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Synovial cells from nine patients with reactive arthritis following Salmonella enteritidis or Salmonella typhimurium infection were examined for salmonella antigens. Extensive bacterial cultures of the synovial fluid were negative. Eight synovial-fluid cell samples stained positively on immunofluorescence with rabbit antisera against heat-killed S enteritidis or S typhimurium or with monoclonal antibodies specific for the causative salmonella lipopolysaccharide (LPS). Synovial tissue from the ninth patient stained positively in the avidin-biotin-peroxidase complex method with the monoclonal antibody. Control samples (synovial-fluid cells from thirteen patients with other rheumatic diseases and synovial tissue from two) were negative. Synovial cells from eight patients and five controls were studied by western blotting with the same monoclonal antibodies. Four of the eight patients but no controls had blots indicating salmonella LPS in the synovial cells. The presence of bacterial LPS in the joint is a common and pathogenetically important feature of reactive arthritis.

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In order to investigate arthritis-triggering, serologically cross-reactive antigens, sera from patients infected with arthritis-associated microbes, Salmonellae, Chlamydia trachomatis, and Sindbis-like alphavirus, were reacted against SDS-PAGE separated and immunoblotted Yersinia enterocolitica 0:3 antigens. These sera reacted with Yersinia to the same extent as did the control sera taken from patients with streptococcal, staphylococcal and Bordetella pertussis infections or from healthy blood donors. Moreover, the various sera produced different reactivity patterns, directed against several different antigens. Although sera from test subjects, as well as from controls including healthy individuals, recognized some Yersinia antigens, these patterns differed markedly from those recognized by sera taken from patients with Yersinia infection. Significantly, analysis of the reactivities against the different molecular weight antigen components of Yersinia revealed no dominant band or pattern which could thus have been defined as arthritis-associated.

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The avidity of IgM, IgG, and IgA class antibodies against virulence plasmid encoded proteins of yersinia, so called released proteins (RPs), was studied in the serum samples of 22 patients with yersinia triggered reactive arthritis and 22 with uncomplicated yersiniosis. The avidity of anti-RP antibodies did not differ significantly between the patient groups, even though the total amount of IgA class anti-RP antibodies was significantly higher in patients with arthritis than in those with uncomplicated yersiniosis at the early stage of infection. Earlier results with whole bacterial extracts or lipopolysaccharide as the antigens have shown an increased avidity of IgA class anti-yersinia antibodies in patients with yersinia triggered reactive arthritis. This phenomenon was not observed in antibody response against RPs, and thus production of these proteins seems unimportant at later stages of infection for the yersinia organisms stimulating the persisting and maturing antibody response in the yersinia triggered reactive arthritis.

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The opsonic capacity of 45 sera from patients with reactive arthritis after Yersinia enterocolitica O:3 infection and of 45 matched sera from yersiniosis patients without post-infection complications was studied at 1-3 months, 5-8 months and 12-20 months after the onset of the infection. Antibody-mediated opsonization of virulence-plasmid-containing Y. enterocolitica O:3 was studied by measuring complement-fixation on opsonized bacteria and opsonophagocytic function of the polymorphonuclear leucocytes (PMN). The PMN response against bacteria pre-opsonized by heat-inactivated sera was measured by using a chemiluminescence (CL) assay. The fixation of complement Clq and C3 on bacteria was determined by flow cytometry using fluorescein-conjugated Clq- and C3c-antisera. All the sera were strongly opsonic at the onset of the infection, and this capacity persisted in most of the patients still at the end of the follow-up. No difference was observed in complement-fixing capacity between the sera of the two groups, but the sera from arthritic patients showed stronger augmentation of PMN CL response at the early phase of the infection (P = 0.005 in the presence of complement, P = 0.04 in the absence of complement). These results suggest that enhanced opsonic capacity may play a role in the development of Yersinia-triggered reactive arthritis by leading to strong activation of the PMN and, consequently, to release of inflammatory mediators.

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Yersinia enterocolitica serovar O:3 bacteria with and without plasmid-encoded proteins were compared as antigens in an enzyme-linked immunosorbent assay. Good correlations between the two antigen preparations were obtained for immunoglobulin M (IgM), IgG, and IgA antibodies of patients with yersiniosis. For routine diagnostic purposes, these antigens are considered equal.

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We examined synovial-fluid cells from 15 patients with reactive arthritis after yersinia infection for the presence of yersinia antigens. Extensive bacterial cultures of the synovial fluid were negative. All the samples were studied by immunofluorescence with use of a rabbit antiserum to Yersinia enterocolitica O:3 and a monoclonal antibody to Y. enterocolitica O:3 lipopolysaccharide. Synovial-fluid cells from 41 patients with other rheumatic diseases served as controls. Synovial-fluid cells from 10 patients with reactive arthritis after yersinia infection stained positively on immunofluorescence; rabbit antiserum and the monoclonal antibody yielded similar results. In most patients the percentage of positive cells ranged from 1 to 10 percent, but in one patient nearly all the cells in the sample stained strongly. Most of the positively stained cells were polymorphonuclear leukocytes, but yersinia antigens were also found in mononuclear phagocytes. All the control samples were negative. Synovial-fluid cell deposits from nine patients were also studied by Western blotting with use of the same antibodies. The results were positive in six of the nine cell deposits from patients with reactive arthritis and in none of the 10 cell deposits from control patients with rheumatoid arthritis. We conclude that in patients with reactive arthritis after yersinia infection, microbial antigens can be found in synovial-fluid cells from the affected joints.

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It is apparent that in the development of reactive arthritis the patient fails in his first line of defence against the invading microorganism. This results in persistence of the microorganism probably in or close to the intestinal epithelium. Microbial antigens may appear also in the circulation, perhaps as part of the immune complexes, or within cellular elements. Through these transportation mechanisms they enter the synovium, triggering an inflammatory process that leads to reactive arthritis.

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IgM, IgG and IgA class serum antibodies against Yersinia enterocolitica O:3 and O:9 and Yersinia pseudotuberculosis 1a and 3 in 41 patients with thyroid disease and 50 healthy control persons were measured by enzyme-linked immunosorbent assay (ELISA). Concentrations of antibody levels against Yersinia enterocolitica O:9 and Yercinia pseudotuberculosis 1a and 3 did not differ significantly between the patients and controls. The median value of IgA class antibody Yersinia enterocolitica O:3 was 7.5 relative units (EIU, percentage of the reference serum) in the patients with thyroid disease and 0.7 EIU in the controls (P less than 0.01; Mann-Whitney's U-test), whereas IgM and IgG class antibodies did not show this difference. IgA class serum antibodies were especially high in patients with autoimmune thyroid diseases. These findings and two case reports support the concept that there may be a causal relationship between infections with Yersinia enterocolitica O:3 and autoimmune thyroid diseases.

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No homology was observed between Yersinia enterocolitica O:3 and HLA-B27 at DNA level when Yersinia enterocolitica chromosomal probes were hybridized with human HLA-B27 positive leukocyte DNA or in the hybridization of Yersinia DNA with HLA-B27 specific probe. Our results do not exclude the existence of molecular mimicry between Yersinia proteins and HLA-B27 antigen, since the crossreactive epitope might be a conformational determinant not detected with hybridization.

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We have determined the opsonic capacity of specific antibodies in patient sera obtained after Yersinia infection. The results indicate that Yersinia antibodies lead to complement activation through the classical pathway, thus overcoming the inhibition of complement-mediated opsonization in the absence of specific antibodies provided by the virulence plasmid in Yersinia enterocolitica and Yersinia pseudotuberculosis. Further, antibodies against plasmid-encoded structures, the Yersinia outer membrane proteins (YOPs), are not necessary in this effect. This is indicated by two facts. (i) Monoclonal antibodies directed against the O polysaccharide of Y. enterocolitica O:3 are capable of opsonizing the plasmid-containing bacteria through C1q binding. (ii) Rabbit antisera show opsonic activity when obtained by immunization both with plasmid-containing Y. enterocolitica expressing the YOPs and a plasmid-cured variant not expressing these proteins.

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Total rheumatoid factor (RF) activity and RF isotypes were measured in the sera of 33 patients with Yersinia infection using enzyme-linked immunosorbent assay. Twenty out of 33 patients developed reactive arthritis as a postinfectious complication. Yersinia infection does not seem to stimulate formation of RFs. The serum samples were practically negative, except two consecutive samples of one patient with Yersinia enterocolitica 0:3 triggered reactive arthritis which were strongly positive for all RFs tested. Although in Yersinia triggered reactive arthritis continuous response against Yersinia is seen, especially in the form of persisting IgA response, RF do not seem to be involved.

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The role of the causative microorganism in the generation of reactive arthritis is decisive, but host factors are also of major importance. Patients who develop reactive arthritis after Yersinia enteritis show several interesting features in the immunological defence against Yersinia when compared to those who recover uneventfully. When all these peculiarities are taken together, they strongly indicate that in the patients developing reactive arthritis the causative microorganism enters host tissues to persist within the body for prolonged periods of time.

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Twelve to 16 months after Yersinia enterocolitica O:3 enteritis 33 (85%) of the 39 patients who developed reactive arthritis as a postinfection complication had IgA class and 28 (72%) had IgG class anti-yersinia antibodies. In contrast, 7 (32%) of the 22 patients who did not develop arthritis were positive in the IgA test and 11 (50%) positive in the IgG test. The results were about the same when the material was divided into cases with diagnosis of yersiniosis verified by stool culture or by serology. These results confirm the value of enzyme linked immunosorbent assay (ELISA) in the diagnosis of yersiniosis, particularly in cases with postinfection complications when the stool isolations remain negative.

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Avidity of IgM, IgG, and IgA class anti-Yersinia antibodies was compared in sera of 22 patients with yersiniosis and subsequent reactive arthritis versus sera of 22 patients without postinfection complications. An enzyme-linked immunosorbent assay was used for antibody determination. Less than 2 months after onset of the infection, the patients with arthritis had fewer high-avidity IgM antibodies against the bacterial lipopolysaccharide (P = 0.035) and more high-avidity IgA antibodies against bacterial cell extract (P = 0.039) than did the patients without arthritis. This difference increased with time.

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