Activation of iNKT Cells Prevents Salmonella-Enterocolitis and Salmonella-Induced Reactive Arthritis by Downregulating IL-17-Producing γδT Cells.

Reactive arthritis (ReA) is an inflammatory condition of the joints that arises following an infection. Salmonella enterocolitis is one of the most common infections leading to ReA. Although the pathogenesis remains unclear, it is known that IL-17 plays a pivotal role in the development of ReA. IL-17-producers cells are mainly Th17, iNKT, and γδT lymphocytes. It is known that iNKT cells regulate the development of Th17 lineage. Whether iNKT cells also regulate γδT lymphocytes differentiation is unknown. We found that iNKT cells play a protective role in ReA. BALB/c Jα18-/- mice suffered a severe Salmonella enterocolitis, a 3.5-fold increase in IL-17 expression and aggravated inflammation of the synovial membrane. On the other hand, activation of iNKT cells with α-GalCer abrogated IL-17 response to Salmonella enterocolitis and prevented intestinal and joint tissue damage. Moreover, the anti-inflammatory effect of α-GalCer was related to a drop in the proportion of IL-17-producing γδT lymphocytes (IL17-γδTcells) rather than to a decrease in Th17 cells. In summary, we here show that iNKT cells play a protective role against Salmonella-enterocolitis and Salmonella-induced ReA by downregulating IL17-γδTcells.

Functional CCR5 receptor protects patients with arthritis from high synovial burden of infecting Chlamydia trachomatis.

INTRODUCTION: The CCR5 chemokine receptor occurs in a wild-type (wt) and a nonfunctional deleted form (Δ32). Reports suggested that Chlamydia-induced reproductive tract pathology is attenuated in women bearing Δ32. The authors asked whether the mutation affects synovial prevalence and burden of Chlamydia trachomatis. METHODS: Polymerase chain reaction (PCR) defined CCR5 genotype in synovial tissue DNA from 218 individuals: 21 controls, 110 with reactive arthritis (ReA), 83 with undifferentiated oligoarthritis (UO), 4 with osteoarthritis (OA). Disease durations were 0.5 to 21 years. Additional PCR assays defined the presence of C trachomatis DNA. Bacterial load was assessed by real-time PCR in selected samples. RESULTS: Five controls were wt/Δ32, 16 were wt/wt; 2 of 21 controls (both wt/wt) were PCR positive for C trachomatis. Eighty-five (44%) patients with arthritis were PCR positive for C trachomatis (69 ReA and 16 UO). For patients with ReA, 14 (13%) had wt/Δ32, 10 (71%) of whom were PCR positive. Nineteen patients with UO (23%) were wt/Δ32, with 1 (1%) PCR positive. No differences existed for gender or other factors. One patient with OA had wt/Δ32. In ReA and UO samples, wt/Δ32 heterozygotes had a 5- to 10-fold higher bacterial burden than did wt/wt patients (P = 0.03), regardless of diagnosis. CONCLUSION: These results indicate that the wt/wt genotype is associated with attenuated synovial bacterial load compared with loads in wt/Δ32 patients. Although no alleles other than Δ32 were assessed, our data suggest that this allele provides little/no protection from ReA in patients infected with Chlamydia- but it may provide some protection in patients with UO. The basis of this possible differential effect of CCR5 genotype is under study.

Reactive arthritis and other musculoskeletal sequelae following an outbreak of Salmonella hadar in Castellon, Spain.

OBJECTIVE: In 2005 a large outbreak of Salmonella hadar occurred in Spain following the consumption of commercial precooked roast chicken. We estimated the incidence and risk factors for reactive arthritis (ReA) and other musculoskeletal sequelae in the patients of this outbreak in 2 health departments of Castellon province. METHODS: A prospective cohort study of the patients and their families was carried out. Clinical infection with Salmonella was considered as the exposure factor. The cohort was studied for ReA symptoms using a telephone questionnaire. Telephone interviews or medical examinations of subjects with musculoskeletal symptoms were conducted by a rheumatologist. Robust Poisson regression models were used in the analysis. RESULTS: From the cohort of 262 people, 248 (94.7%) participated in the telephone survey, 155 with clinical salmonellosis (infected), 78 noninfected, and 15 with some symptoms but not clinical salmonellosis. One hundred one infected patients (65%) reported musculoskeletal symptoms, compared to 19 noninfected (24%) (adjusted relative risk = 2.60, 95% CI 1.73-3.90). Of the infected group, 16 ReA (incidence 10%, 95% CI 6.0-16.2), 7 enthesopathies, and 2 arthralgias were detected, and zero in the noninfected group. The risk factors for ReA were age, weight loss, and duration of diarrhea. Antibiotic treatment for the infection protected against symptoms of peripheral or axial arthritis (adjusted relative risk = 0.73, 95% CI 0.55-0.98). CONCLUSION: The incidence of ReA and musculoskeletal symptoms after the infection was high. The use of antibiotics for S. hadar infection offered some protection against musculoskeletal symptoms.

A monoclonal antibody to high-molecular weight kininogen is therapeutic in a rodent model of reactive arthritis.

We reported that high-molecular weight kininogen is proangiogenic by releasing bradykinin and that a monoclonal antibody to high-molecular weight kininogen, C11C1, blocked its binding to endothelial cells. We now test if this antibody can prevent arthritis and systemic inflammation in a Lewis rat model. We studied 32 animals for 16 days. Group I (negative control) received saline intraperitoneally. Group II (disease-treated) received peptidoglycan-polysaccharide simultaneously with C11C1. Group III (disease-untreated) received peptidoglycan-polysaccharide simultaneously with isotype-matched mouse IgG. Group IV (disease-free-treated) and group V (disease-free isotype-treated) received saline and C11C1 or mouse IgG. Analysis of joint diameter changes showed a decrease in the C11C1 disease-treated group compared to the disease-untreated group. The hind paw inflammatory score showed a decrease in the intensity and extent of inflammation between the disease-untreated and the C11C1 disease-treated group. Prekallikrein, high-molecular weight kininogen, factor XI, and factor XII were decreased in the disease-untreated group compared to the C11C1 disease-treated group. T-kininogen was increased in the disease-untreated group when compared with the C11C1 disease-treated group. Disease-free groups IV and V did not show any sign of inflammation at any time. This study shows that monoclonal antibody C11C1 attenuates plasma kallikrein-kinin system activation, local and systemic inflammation, indicating therapeutic potential in reactive arthritis.

Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis.

OBJECTIVE: To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1beta-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. METHODS: PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)-induced arthritis, an animal model of RA. RESULTS: As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34. CONCLUSION: These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.

Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: role for glycine-gated chloride channel.

Peptidoglycan polysaccharide (PG-PS) is a primary structural component of bacterial cell walls and causes rheumatoid-like arthritis in rats. Recently, glycine has been shown to be a potential immunomodulator; therefore, the purpose of this study was to determine if glycine would be protective in a PG-PS model of arthritis in vivo. In rats injected with PG-PS intra-articularly, ankle swelling increased 21% in 24 to 48 h and recovered in about 2 weeks. Three days prior to reactivation with PG-PS given intravenously (i.v.), rats were divided into two groups and fed a glycine-containing or nitrogen-balanced control diet. After i.v. PG-PS treatment joint swelling increased 2.1 +/- 0.3 mm in controls but only 1.0 +/- 0.2 mm in rats fed glycine. Infiltration of inflammatory cells, edema, and synovial hyperplasia in the joint were significantly attenuated by dietary glycine. Tumor necrosis factor alpha (TNF-alpha) mRNA was detected in ankle homogenates from rats fed the control diet but not in ankles from rats fed glycine. Moreover, intracellular calcium was increased significantly in splenic macrophages treated with PG-PS; however, glycine blunted the increase about 50%. The inhibitory effect of glycine was reversed by low concentrations of strychnine or chloride-free buffer, and it increased radiolabeled chloride influx nearly fourfold, an effect also inhibited by strychnine. In isolated splenic macrophages, glycine blunted translocation of the p65 subunit of NF-kappaB into the nucleus, superoxide generation, and TNF-alpha production caused by PG-PS. Further, mRNA for the beta subunit of the glycine receptor was detected in splenic macrophages. This work supports the hypothesis that glycine prevents reactive arthritis by blunting cytokine release from macrophages by increasing chloride influx via a glycine-gated chloride channel.

Acute rheumatic fever and poststreptococcal reactive arthritis: diagnostic and treatment practices of pediatric subspecialists in Canada.

OBJECTIVE: We conducted a survey of pediatric specialists in rheumatology, cardiology, and infectious diseases to ascertain present Canadian clinical practice with respect to diagnosis and treatment of acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSReA), and to determine what variables influence the decision for or against prophylaxis in these cases. METHODS: A questionnaire comprising 6 clinical case scenarios of acute arthritis occurring after recent streptococcal pharyngitis was sent to members of the Canadian Pediatric Rheumatology Association, and to heads of divisions of pediatric cardiology and pediatric infectious diseases at the 16 university affiliated centers across Canada. RESULTS: There is considerable variability with respect to diagnosis in cases of ReA following group A streptococcal (GAS) infection both within and across specialties. There is extensive variability regarding the decision to provide prophylaxis in cases designated as ARF or PSReA. Findings indicated that physicians are most comfortable prescribing antibiotic prophylaxis in the presence of clear cardiac risk and are less inclined to such intervention for patients diagnosed with PSReA. When prophylaxis was recommended for cases of PSReA, the majority of respondents prescribed longer term courses of antibiotics. CONCLUSION: The lack of observed consistency in diagnosis and treatment in cases of reactive arthritis post-GAS infection likely reflects the lack of universally accepted criteria for diagnosis of PSReA and insufficient longterm data regarding carditis risk within this population. There is a need for clear definitions and treatment guidelines to allow greater consistency in clinical practice across pediatric specialties.

A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice.

OBJECTIVE: Platelet factor 4 (PF-4) is a critical alpha chemokine in inflammation and injury responses, with multiple effects upon cellular activities. Discrete peptide sequences of the PF-4 molecule have been shown to retain biological activity. Our aim was to examine the influence of the PF-4 derived octapeptide (CT-112; TTSQVRPR) on type II collagen induced arthritis in mice, to determine if this peptide exhibited antiinflammatory properties. METHODS: DBA/1 mice were treated with CT-112 from either the time of immunization with type II collagen or from the initial onset of arthritis. RESULTS: CT-112 both prevented the development of arthritis in mice treated prophylactically and reduced progression of disease in animals treated therapeutically, and was active when delivered by either subcutaneous injection or oral gavage. No marked immunosuppressive effects were observed during CT-112 treatment, with only moderate decrease in antibody levels and mitogen responses. A significant reduction of the circulating levels of IL-1 was a consistent finding in mice treated therapeutically with CT-112. CONCLUSION: These data suggest PF-4 derived octapeptide exerts antiinflammatory effects of experimental arthritis in mice.

Experimental Yersinia-triggered reactive arthritis: effect of a 3-week course of ciprofloxacin.

Lewis rats were injected i.v. with live Yersinia enterocolitica, resulting in 1-2 weeks in an arthritis greatly resembling human reactive arthritis. Starting on day 3, 5, 10 or 13 after the bacterial inoculation, the rats were treated for 3 weeks with 20 mg/kg/day of ciprofloxacin. The development of arthritis was completely prevented if the antibiotic treatment was started on day 3. In a group of rats treated with ciprofloxacin from day 5 onwards, 2/14 rats already showed mild arthritis at the time when the treatment was started. Antibiotic treatment cured the arthritis of these rats as well as that of one additional individual in this group which developed arthritis. No later exacerbations occurred. If the antibiotic treatment was started on day 10 or 13, i.e. at the time of well-developed arthritis, no effect on arthritis was observed; rather, increased faecal excretion of Yersinia occurred following the antibiotic treatment. We conclude that experimental Yersinia reactive arthritis can be cured by antibiotics introduced at an early phase of arthritic development. Regarding acute human enterogenic arthritis, the decision on antibiotic treatment is not a straightforward matter. Our experimental results indicate that the earlier the treatment is started, the better the result, whereas late treatments seem to favour bacterial persistence.

Antibiotic prophylaxis and treatment of reactive arthritis. Lessons from an animal model.

OBJECTIVE: To study the effect of antibiotic prophylaxis and treatment of reactive arthritis (ReA), using an experimental model. METHODS: Yersinia enterocolitica O:8, when injected intravenously into Lewis rats, causes a sterile arthritis closely resembling human ReA in 70% of the animals. Arthritis develops in 1-2 weeks; in some of the animals it remains chronic, and exacerbations occur. This model was applied to study the effect of a 7-day treatment with ciprofloxacin, using 2 different dosages (20 or 100 mg/kg/day) and 4 different schedules for initiation of treatment. The effects were evaluated by determining the daily arthritis score, the number of rats developing arthritis, and fecal excretion of Yersinia. In addition, weight gain was monitored. At autopsy (35 or 60 days after inoculation with bacteria), samples were obtained for determination of Yersinia-specific antibodies in the serum. At the same time, samples were collected from mesenteric lymph nodes, lung, spleen, and liver for bacterial cultures, and from the ankle joints for histologic evaluation. In a separate experiment, ciprofloxacin concentrations in samples from serum and mesenteric lymph nodes were analyzed by high performance liquid chromatography. RESULTS: A 7-day course with 100 mg/kg/day of ciprofloxacin, started on day 3 after bacterial inoculation, completely prevented the development of ReA and eliminated Yersinia during the 60-day experiment. If a dosage of 20 mg/kg/day was used, development of acute arthritis was prevented, but some of the animals had positive fecal cultures at the end of experiment. If antibiotic treatment was started on day 5, the preventive effect was still observed, but was less pronounced. If the treatment was started at the peak of the development of arthritis, no effect on arthritis was observed. CONCLUSION: These results indicate that if any effect of antibiotic treatment in Yersinia-triggered ReA is to be expected, the treatment must be started early and given in sufficient dosage. However, antibiotic treatment has no effect on fully developed arthritis.

AB0 and Lewis blood groups in reactive arthritis.

In this study we evaluated secretor status in patients with reactive arthritis. Previous evidence indicates that non-secretion of AB0 and Lewis blood group antigens to saliva and other secretions is associated with susceptibility to certain bacterial infections and certain diseases with suspected autoimmune etiology. Secretor status can be determined based on the Lewis phenotype. We studied AB0, Lewis and Rhesus blood groups of 54 patients with previous reactive arthritis, 26 of whom had uroarthritis and 28 of whom had arthritis after enteric infection. Furthermore, 25 patients with uncomplicated yersiniosis and 57 healthy controls were studied. We did not find any correlation between secretor status and reactive arthritis or gastroenteritis due to Yersinia. AB0 blood group antigen B appeared to be protective against uroarthritis.