Altered PKR Signalling and C / EBPß Expression is Associated with HLA-B27 Expression in Monocytic Cells.

Infection caused by certain gram-negative bacteria, e.g. Salmonella, can trigger inflammatory joint disease reactive arthritis (ReA). It is suggested that the disease-triggering bacteria or bacterial components persist in patients for an abnormally long time. Development of ReA is strongly associated with tissue antigen HLA-B27. Previously, we reported an enhanced replication of Salmonella enteritidis and altered p38 MAP kinase signalling in HLA-B27-expressing monocytic cells. Here we aimed to investigate the role of HLA-B27 in regulation of double-stranded RNA-activated kinase (PKR)-related signalling in Salmonella-infected or Salmonella lipopolysaccharide (LPS)-stimulated human U937 monocytic cells, as PKR has been reported to modify p38 signalling in Salmonella-infected cells. In cells expressing HLA-B27, PKR is overexpressed and hypophosphorylated, and the expression of transcription factor CCAAT enhancer binding protein beta (C/EBPß) is increased upon Salmonella infection and LPS stimulation. The expression of C/EBPß is PKR-dependent in LPS-stimulated mock cells, whereas in LPS-stimulated B27 cells the majority of C/EBPß is expressed in a PKR-independent manner. Our results show that the expression of HLA-B27 disturbs the PKR-mediated signalling pathway. Moreover, altered signalling is related to misfolding-linked Glu45 in the B pocket of the HLA-B27 heavy chain. We suggest that the expression of HLA-B27 HCs modulates the intracellular environment of monocyte/macrophages and the mechanisms that are important in eliminating intracellular S. enteritidis by altering the intracellular signalling. This phenomenon is at least partly dependent on the misfolding feature of the B27 molecule. These observations offer a novel mechanism by which HLA-B27 may modulate inflammatory response induced by ReA-triggering bacteria.

Reactive and undifferentiated arthritis in North Africa: use of PCR for detection of Chlamydia trachomatis.

Little is known about the possible role of Chlamydia in patients with reactive or unclassified arthritis in North Africa. This study used polymerase chain reaction (PCR) to survey this population. In addition, we compared the results in three different laboratories for PCR analyses for Chlamydia trachomatis (Ct) in synovial fluid (SF) and tissue (ST) from these North African patients with reactive arthritis (ReA), undifferentiated arthritis (UA), and in rheumatoid arthritis (RA) and osteoarthritis (OA). Eight ReA (six posturethritic, two postenteritic), 23 UA, 13 OA, and 12 RA patients were studied in Algeria, Morocco, and Tunisia. Serum, SF, and ST were obtained from each patient. Ct-PCR was performed in the three different laboratories and compared to Ct-serology [microimmunofluorescence (MIF) and anti-hsp60 enzyme-linked immunosorbent assay (ELISA)] performed in one laboratory. The rate of Ct-PCR positivity in SF/ST was low: none out of the eight ReA and three out of 23 UA patients. In the controls, Ct DNA was detected in two OA SF and in one RA SF. There was no concordance for Ct-PCR positivity between the three laboratories. MIF suggested previous Ct infection (IgG-positive) in two out of five posturethritic ReA, none out of one postenteritic ReA, one out of 17 UA, and nine out of 21 RA/OA patients tested. No MIF-positive patient was PCR-positive from SF or ST. However, anti-hsp60 IgG was detected in all four out of four patients positive by PCR and in 11 out of 44 PCR-negative patients (p = 0.002). In this multinational comparative study, the rate of Ct-PCR-positive synovial specimens in North African ReA/UA patients was low. Concordance among the three PCR testing laboratories was poor indicating the need for test standardization. All Ct-PCR-positive patients were found positive by anti-hsp60 IgG serology.

Work-related symptoms and Salmonella antibodies among wastewater treatment plant workers.

Wastewater treatment plant workers are exposed to microbes, including Salmonella, but the prevalence of antibodies against Salmonella species or serovars in their serum samples has not been studied. Antibodies against Salmonella Infantis and lipopolysaccharide antigen common to S. Enteritidis and S. Typhimurium in immunoglobulin classes IgA, IgM and IgG were measured from 79 serum samples of wastewater treatment plant workers and from 79 blood donor samples. Faecal samples for Salmonella and Campylobacter were studied. Gastrointestinal, dermal and other symptoms were compared between 81 wastewater treatment plant workers and 89 food-processing workers. The blood donors had more antibodies against all of the tested antigens expect for S. Infantis in IgM and IgA classes, even though the wastewater treatment plant workers had more gastrointestinal symptoms than the controls. No Salmonella or Campylobacter were found in any faecal samples. Salmonella is not a probable cause of symptoms among wastewater treatment plant workers.

Infectious background of patients with a history of acute anterior uveitis.

OBJECTIVE: To study the infectious background of patients with a history of acute anterior uveitis (AAU) and healthy control subjects. METHODS: Sixty four patients with previous AAU and 64 sex and age matched controls were studied. Serum antibodies to Salmonellae, Yersiniae, Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, Campylobacter jejuni, and Borrelia burgdorferi were measured using enzyme linked immunosorbent assay (ELISA), and antibodies to Chlamydia trachomatis and Chlamydia pneumoniae by microimmunofluorescence test. Peripheral blood mononuclear cells (PBMCs), separated by density gradient centrifugation, were studied for Salmonella and Yersinia antigens by means of an immunofluorescence test, and for C pneumoniae DNA with a polymerase chain reaction (PCR). RESULTS: Neither prevalence nor levels of single microbial antibodies studied differed between the patients and control subjects, or between subgroups of patients created on the basis of clinical characteristics. In logistic regression analysis, the high number of recurrences (>10) of AAU was independently related to the presence of single or multiple bacterial antibodies (p=0.04). None of the PBMC samples of the patients were positive for Yersinia or Salmonella antigens. C pneumoniae PCR was positive in a patient who was negative for C pneumoniae antibodies. CONCLUSION: Although neither the prevalence nor the levels of single microbial antibodies studied differed between the patients and the controls, current data suggest that the presence of single or multiple antibodies in patients with many recurrences of AAU compared with patients with none or few recurrences may be a sign of repeated infections, antigen persistence, or raised innate immune responsiveness.

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.

Insights into the Role of Infection in the Spondyloarthropathies.

Certain infections play an important role in the pathogenesis of the human leukocyte antigen (HLA)-B27-associated reactive arthritis. Whether infections play a role in other forms of spondyloarthropathies is not as clear. The role of HLA-B27 as an antigen-presenting molecule is important in the pathogenesis of these diseases. Recent evidence has been obtained indicating that this molecule may have other functions unrelated to antigen-presentation in the interaction of reactive arthritis-triggering microbes and host. This paper reviews the recent studies on the role of infection in the spondyloarthropathies.

IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients.

OBJECTIVE: To investigate the association of microsatellites and single-nucleotide promoter polymorphisms (SNPs) in the gene for the cytokine interleukin-10 (IL-10) with susceptibility to and outcome of reactive arthritis (ReA). METHODS: From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions -1087 and -524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion in 85 Finnish patients with ReA and 62 HLA-B27-positive Finnish controls. ReA patients had been followed up for 20 years. Genotypes and haplotypes of IL-10 were correlated with distinct features of the disease course, such as triggering agent, chronic arthritis, development of ankylosing spondylitis, and other chronic features. RESULTS: There was a significant decrease in the promoter alleles G12 (allele frequency 0.206 versus 0.033; corrected P < 0.001, odds ratio 0.14) and G10 (0.183 versus 0.092; P < 0.05, odds ratio 0.44) in the ReA group compared with the HLA-B27-positive controls. Chronic arthritis developed significantly more frequently in the B27-positive subjects than in the B27-negative subjects (P < 0.05) as well as in patients with [corrected] the IL10.G8 allele. No associations were observed for either SNP or for the IL10.R microsatellite polymorphism. CONCLUSION: IL10.G12 and G10 microsatellite alleles show a strong protective effect against the development of ReA in Finnish subjects. Since these polymorphic markers themselves do not have direct functional implications, they most likely mark promoter haplotypes with distinct functional properties, suggesting that differential production of IL-10 is an important susceptibility factor for the development of ReA.

Expression of host defense scavenger receptors in spondylarthropathy.

OBJECTIVE: Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA-B27 could play a role in this process, but does not account for the many HLA-B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA). METHODS: Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues. CONCLUSION: Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.

Familial aggregation of ankylosing spondylitis in Southern China.

OBJECTIVE: To study the familial aggregation of ankylosing spondylitis (AS) in southern China and to compare the clinical and laboratory characteristics between the probands and their first-degree relatives with AS. METHODS: On the basis of questionnaires to 473 patients with AS, 402 responded and 36 self-reported having first-degree relatives with symptoms related to spondyloarthropathies. All together, 144 of 150 first-degree relatives of these 36 probands were examined for clinical and radiographic characteristics. HLA typing for HLA-B27 was performed by standard microlymphocytotoxicity method. RESULTS: The disease duration of the 36 probands was 5.03 +/- 3.76 years (0.5-14 yrs). Forty seven first-degree relatives of the 36 probands were diagnosed as having AS. The prevalence of AS among the first-degree relatives of these 36 aggregated families was 31.3%. The overall prevalence of AS among the first-degree relatives in these 402 families was estimated to be 2.8%. The recurrence risk of the first-degree relatives within these aggregated families was 31.3%, suggesting an excess risk to them of 120.4, while it was 10.8 to the general families. The probands more often had peripheral arthritis and enthesopathies (p < 0.001 and p = 0.01, respectively) than the AS patients among the first-degree relatives. HLA-B27 was associated with development of AS in the probands and the patients among the first-degree relatives. CONCLUSION: Although familial aggregation of AS in southern China is uncommon in general, the recurrence risk of the first-degree relatives of AS probands within the aggregated families is extremely high, according to our study among hospital based patients. As the disease of the first-degree relatives is often mild and atypical, familial background analysis should be encouraged to assist early diagnosis.

Frequency of triggering bacteria in patients with reactive arthritis and undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis.

OBJECTIVE: Reactive arthritis (ReA) triggered by Chlamydia trachomatis or enteric bacteria such as yersinia, salmonella, Campylobacter jejuni, or shigella is an important differential diagnosis in patients presenting with the clinical picture of an undifferentiated oligoarthritis (UOA). This study was undertaken to evaluate the best diagnostic approach. PATIENTS AND METHODS: 52 patients with ReA, defined by arthritis and a symptomatic preceding infection of the gut or the urogenital tract, and 74 patients with possible ReA, defined by oligoarthritis without a preceding symptomatic infection and after exclusion of other diagnoses (UOA), were studied. The following diagnostic tests were applied for the identification of the triggering bacterium: for yersinia induced ReA-stool culture, enzyme immunoassay (EIA), and Widal's agglutination test for detection of antibodies to yersinia; for salmonella or campylobacter induced ReA-stool culture, EIA for the detection of antibodies to salmonella and Campylobacter jejuni; for infections with shigella-stool culture; for infections with Chlamydia trachomatis-culture of the urogenital tract, microimmunofluorescence and immunoperoxidase assay for the detection of antibodies to Chlamydia trachomatis. RESULTS: A causative pathogen was identified in 29/52 (56%) of all patients with ReA. In 17 (52%) of the patients with enteric ReA one of the enteric bacteria was identified: salmonella in 11/33 (33%) and yersinia in 6/33 (18%). Chlamydia trachomatis was the causative pathogen in 12/19 (63%) of the patients with urogenic ReA. In patients with the clinical picture of UOA a specific triggering bacterium was also identified in 35/74 (47%) patients: yersinia in 14/74 (19%), salmonella in 9/74 (12%), and Chlamydia trachomatis in 12/74 (16%). CONCLUSIONS: Chlamydia trachomatis, yersinia, and salmonella can be identified as the causative pathogen in about 50% of patients with probable or possible ReA if the appropriate tests are used.

Expression of alpha4-integrins on human neutrophils.

alpha4 Integrins are important adhesion molecules mediating binding of lymphocytes, monocytes, and eosinophils to multiple cellular and extracellular ligands. Mature neutrophils have been recently suggested to express alpha4-integrins as well. We studied whether human neutrophils can synthesize alpha4-integrins upon activation in vitro or in vivo. Two anti-alpha4 mAbs, but not multiple subclass-matched non-binding controls, reacted with granulocytes in an inducer and time-dependent manner. Nevertheless, staining with Ig subclass-specific second-stage reagents surprisingly revealed that commercial anti-alpha4 mAbs contain two distinct Igs, the alpha4-specific IgG1 and an IgG2a of an unknown specificity. We showed that in vitro inductions used by us and others only induce the binding of nonspecific IgG2a from the commercial HP2/1 to activated neutrophils. By reverse-transcriptase polymerase chain reaction, alpha4 mRNA was not detectable in purified neutrophils. Our results show that alpha4 integrin protein and mRNA are absent from normal and stimulated human neutrophils.

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.

Detection of Salmonella infantis in synovial fluid cells of a patient with reactive arthritis.

We investigated a patient with Salmonella infantis triggered reactive arthritis (ReA) for a possible occurrence of S. infantis-specific antigens and DNA in the synovial fluid (SF) cells. S. infantis-specific antigens were abundantly observed by immunofluorescence in SF cells of the patient during acute joint inflammation. Salmonella-specific DNA was detected by Southern blotting of the amplified polymerase chain reaction product once, but the result could not be repeated. It seems that if bacterial DNA exists in inflamed joints in Salmonella triggered ReA, its amount is extremely low. This is the first report of intraarticular S. infantis antigens and potentially of Salmonella DNA in Salmonella triggered ReA.

Modulation of peripheral blood mononuclear cell activation status during Salmonella-triggered reactive arthritis.

OBJECTIVE: To determine the activation status of mononuclear cells in the peripheral circulation during the acute phase and the recovery phase of Salmonella-triggered reactive arthritis (ReA). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 8 patients with Salmonella infection (4 with ReA and 4 without) and were studied by reverse transcription-polymerase chain reaction for messenger RNA (mRNA) of proinflammatory and antiinflammatory cytokines, by flow cytometry (FC) for cell surface activation and adhesion molecules, by immunofluorescence (IF) microscopy for bacterial antigens, and by FC, IF, and DNA fragmentation on gel for signs of apoptosis. RESULTS: During the acute phase of the infection, PBMC were activated in all patients, as characterized by high levels of expression of CD14, CD11b, and CD11c on monocytes. In the patients with ReA, PBMC also had the capacity to produce interleukin-1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor alpha. During the amelioration of disease, monocyte activation was decreased in all patients. A complete down-regulation of CD14 was detected only in the patients with ReA, whereas the expression of CD14 in the patients without ReA was positive and was similar to that in healthy controls. In addition, cytokine mRNA levels decreased regardless of the presence of Salmonella antigens in blood cells in all 4 patients with ReA. CONCLUSION: High levels of expression of some activation and adhesion molecules and elevated levels of mRNA for certain cytokines that are predominantly produced by monocytes were found in PBMC from patients with acute Salmonella-triggered ReA, which suggests that these cells are activated. On the other hand, complete down-regulation of CD14 and a marked decrease in the cytokine production capacity during amelioration of the disease suggest that suppression of PBMC activity might be involved in recovery from ReA.

Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis.

The findings of bacterial antigens in the joint and persistent triggering infection elsewhere in the body are thought to be important in the pathogenesis of reactive arthritis (ReA). We describe a patient with clinical and laboratory features consistent with this. The initial presentation with erythema nodosum and periarthritis due to infection with Yersinia pseudotuberculosis IV was followed 13 months later by recurrent erythema nodosum with joint effusion. At that time, synovial fluid was shown to contain Yersinia antigens, and, surprisingly, Yersinia-specific 16S ribosomal RNA (rRNA) sequences were also identified by reverse transcriptase-polymerase chain reaction and sequencing. Since there was no serologic evidence of reinfection, we postulate that a silent persistent Yersinia infection was reactivated, leading to dissemination of organisms to the joint, with consequent induction of ReA. Although the finding of synovial Yersinia antigens years after the original infection in ReA has previously been reported, the presence of Yersinia 16S rRNA indicates that viable organisms were also able to reach the joint.

Enterobacterial infection modulates major histocompatibility complex class I expression on mononuclear cells.

Major histocompatibility complex (MHC) class I expression is reduced in several viral infections, but it is not known whether the same happens during infections caused by intracellular enterobacteria. In this study, the expression of MHC class I antigens on peripheral blood mononuclear cells (PBMC) from 16 patients with Salmonella, Yersinia, or Klebsiella infection was investigated. During or after the acute infection, the expression of MHC class I antigens was markedly decreased in eight patients, all with genotype HLA-B27, and six out of eight with reactive arthritis (ReA). A significant decrease of monomorphic MHC class I was found in three patients, of HLA-B27 in eight (P<0.05) and of HLA-A2 in two. However, patients negative for the HLA-B27 genotype, or healthy HLA-B27-positive individuals, did not have a significant decrease of MHC class I antigens. During the decreased expression on the cell surface, intracellular retention of MHC class I antigens was observed, whereas HLA-B27 mRNA levels did not vary significantly. This is the first evidence that enterobacterial infection may down-regulate expression of MHC class I molecules in vivo and that down-regulation is predominant in patients with the HLA-B27 genotype.

No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study.

OBJECTIVE: To investigate the effect of long-term antibiotic treatment in patients with reactive arthritis (ReA) and undifferentiated oligoarthritis. METHODS: One hundred twenty-six patients were treated with ciprofloxacin (500 mg twice a day) or placebo for 3 months, in a double-blind, randomized study. Of these patients, 104 (48 treated with ciprofloxacin and 56 treated with placebo) were valid for clinical evaluation: 55 were diagnosed as having ReA with a preceding symptomatic urogenic or enteric infection and 49 as having undifferentiated oligoarthritis. These 2 groups were randomized separately. The triggering bacterium was sought by serology and/or culture. The percentage of patients in remission after 3 months of treatment was chosen as the primary efficacy parameter. RESULTS: A triggering bacterium could be identified in 52 patients (50%): Chlamydia trachomatis in 13, Yersinia in 14, and Salmonella in 25. No patient was positive for Campylobacter jejuni or for Shigella. No difference in outcome was found between treatment with ciprofloxacin or placebo in the whole group or in subgroups of patients with ReA or undifferentiated oligoarthritis. No difference was seen in patients with a disease duration <3 months. Ciprofloxacin was not effective in Yersinia- or Salmonella-induced arthritis but seemed to be better than placebo in Chlamydia-induced arthritis. This difference was not significant, however, which might be due to the small sample size. CONCLUSION: Long-term treatment of ReA with ciprofloxacin is not effective; however, it might be useful in the subgroup of patients who have Chlamydia-induced arthritis. This has to be proven in a bigger study focusing on patients with Chlamydia-induced arthritis.

Human monocytic U937 cells kill Salmonella in vitro by NO-independent mechanisms.

Nitric oxide (NO) has a central role in host defense against intracellular microbes. HLA-B27 has been shown to directly modulate host-microbe interaction in vitro, leading to the impaired elimination of Salmonella in human monocytic U937 cells. Here, we studied whether impaired elimination of Salmonella would result from differences in NO production between HLA-B27- and HLA-A2-transfected U937 cells. Both human monocytic transfectants produced NO equally well and killed Salmonella via NO-independent mechanisms.

Ankylosing spondylitis in monozygotic twins: studies on immunological parameters.

OBJECTIVE: To examine immunological parameters that might explain disease discordance in monozygotic twin pairs with ankylosing spondylitis (AS). METHODS: 11 monozygotic twin pairs (nine with AS, two with undifferentiated spondyloarthropathy) were investigated. The peripheral T cell receptor Vbeta repertoire was investigated using FACS analysis and 14 different Vbeta antibodies. In addition serum samples were tested for antibodies to Klebsiella pneumoniae, Streptococcus pyogenes, Candida albicans, Proteus mirabilis, and Escherichia coli. Peripheral blood lymphocyte reactivity against a number of bacteria was investigated by interferon gamma ELISPOT assays. RESULTS: Twins suffering from AS showed cellular hyporeactivity against K pneumoniae, S pyogenes, C albicans in the ELISPOT assays compared with healthy twins. In contrast with the antibody data, where no significant differences were observed between the two groups, AS concordant twins showed the most pronounced differences in their Vbeta repertoire on CD4+ and CD8+ lymphocytes. CONCLUSIONS: Cellular hyporeactivity of peripheral blood cells to bacterial antigens might reflect defective T cell responses allowing bacterial antigens to persist in diseased patients. There are probably other environmental factors that influence disease concordance.

Monocytes that have ingested Yersinia enterocolitica serotype O:3 acquire enhanced capacity to bind to nonstimulated vascular endothelial cells via P-selectin.

Reactive arthritis is usually a self-limiting polyarthritis which develops after certain gastrointestinal or urogenital infections. Microbial antigens found in the inflamed joints are thought to play a key role in the development of this disease. It is not known how antigens of the pathogenic organisms migrate from the mucosal tissues into the joints. The data presented here show that mononuclear phagocytes which mediate the dissemination of several intracellular pathogens acquire an enhanced capacity to bind to nonstimulated vascular endothelial cells after phagocytosis of Yersinia enterocolitica O:3, one of the causative organisms of reactive arthritis. The increased binding to previously nonstimulated endothelial cells was mediated by P-selectin, whose translocation to the endothelial cell surface was induced by monocytes with intracellular Yersinia bacteria. These results suggest that mononuclear phagocytes may be responsible for the dissemination of bacterial antigens and the initiation of the joint inflammation in reactive arthritis.