IL-12/23p40 overproduction by dendritic cells leads to an increased Th1 and Th17 polarization in a model of Yersinia enterocolitica-induced reactive arthritis in TNFRp55-/- mice.

Dendritic cells (DCs) play critical functions in the initiation of immune responses. Understanding their role in reactive arthritis (ReA) will help delineate the pathogenesis of this arthropathy. In early studies, we detected IL-12/23p40 deregulation in Yersinia entercolitica (Ye)-induced ReA in TNFRp55-deficient (TNFRp55-/-) mice. In this study, we assessed the contribution of DCs in this overproduction. First, greater levels of IL-12/23p40, IFN-γand IL-17A were confirmed in supernatants of lipopolysaccharide (LPS)-stimulated TNFRp55-/-splenocytes obtained on arthritis onset (day 14 after Ye infection). Later, DCs were identified as a precise source of IL-12/23p40 since increased frequency of splenic IL-12/23p40+DCs was detected in TNFRp55-/- mice. After robust in vivo amplification of DCs by injection of Fms-like tyrosine kinase 3-Ligand (Flt3L)-transfected BL16 melanoma, DCs were purified. These cells recapitulated the higher production of IL-12/23p40 under TNFRp55deficiency. In agreement with these results, TNFRp55-/- DCs promoted Th1 and Th17 programs by co-culture with WT CD4+lymphocytes. A mechanistic study demonstrated that JNK and p38 MAPK pathways are involved in IL-12/23p40 overproduction in purified TNFRp55-/- DCs as well as in the JAWS II cell line. This deregulation was once again attributed to TNFRp55 deficiency since CAY10500, a specific inhibitor of this pathway, compromised TNF-mediated IL-12/23p40 control in LPS-stimulated WT DCs. Simultaneously, this inhibition reduced IL-10 production, suggesting its role mediating IL-12/23p40 regulation by TNFRp55 pathway. These results provide experimental data on the existence of a TNFRp55-mediated anti-inflammatory circuit in DCs. Moreover, these cells may be considered as a novel target in the treatment of ReA.

Reactive arthritis: update 2018.

At this time, reactive arthritis (ReA) is considered to be part of the spectrum of the spondyloarthritis, previously known as Reiter's syndrome, and refers to an infection induced systemic illness, characterized by a sterile synovitis occurring in a genetically predisposed individual, secondary to an infection localized in a distant organ/system, but also accompanied with multiple extra articular manifestations.

Syphilis associated with paretic neurosyphilis mimicking Reiter's syndrome in HIV-infected patients.

HIV/syphilis co-infection is common because both conditions affect similar risk groups. HIV interferes with the natural history of syphilis, which often has atypical clinical features and nervous system involvement in the early stage of disease. We report the case of an HIV-positive patient with secondary syphilis, scaling palmoplantar keratoderma, scrotal eczema, balanitis and urethritis mimicking Reiter's syndrome. Immunohistochemistry using polyclonal antibodies against Treponema pallidum revealed the presence of spirochetes, associated with the paretic form of parenchymal neurosyphilis. The patient was given crystalline penicillin, with complete resolution of dermatological and neurological symptoms, and no sequelae.

Syphilis associated with paretic neurosyphilis mimicking Reiter’s syndrome in HIV-infected patients

HIV/syphilis co-infection is common because both conditions affect similar risk groups. HIV interferes with the natural history of syphilis, which often has atypical clinical features and nervous system involvement in the early stage of disease. We report the case of an HIV-positive patient with secondary syphilis, scaling palmoplantar keratoderma, scrotal eczema, balanitis and urethritis mimicking Reiter’s syndrome. Immunohistochemistry using polyclonal antibodies against Treponema pallidum revealed the presence of spirochetes, associated with the paretic form of parenchymal neurosyphilis. The patient was given crystalline penicillin, with complete resolution of dermatological and neurological symptoms, and no sequelae.

TNFRp55 controls regulatory T cell responses in Yersinia-induced reactive arthritis.

In addition to its well-known pro-inflammatory effects, tumor necrosis factor (TNF) displays anti-inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (T(reg)) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4(+)CD25(+)FoxP3(+) T(reg) cells in the ReA animal model. The number of T(reg) cells as well as the FoxP3 mRNA expression and interleukin (IL)-10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55(-/-) mice vs wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of T(reg) cell in TNFRp55(-/-) was similar to WT mice. To explore the in vivo function of T(reg) cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4(+) T cells from TNFRp55-deficient mice of day 21, into naïve WT or TNFRp55(-/-) mice. When knockout mice were used as recipients we observed higher delayed-type hypersensitivity (DTH) responses and joint inflammation after heat-killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL-17, interferon (IFN)-γ, IL-6, transforming growth factor (TGF)-ß1 and IL-12/23p40 and lower IL-10 levels in RLN of paws challenged with HKY in TNFRp55(-/-) recipient mice. In addition, we found that CD4(+) T cells from TNFRp55(-/-) mice controlled antigen-specific IL-12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of T(reg) cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.

Ethnic influence in clinical and functional measures of Brazilian patients with spondyloarthritis.

OBJECTIVE: Spondyloarthritides (SpA) can present different disease spectra according to ethnic background. The Brazilian Registry of Spondyloarthritis (RBE) is a nationwide registry that comprises a large databank on clinical, functional, and treatment data on Brazilian patients with SpA. The aim of our study was to analyze the influence of ethnic background in SpA disease patterns in a large series of Brazilian patients. METHODS: A common protocol of investigation was prospectively applied to 1318 SpA patients in 29 centers distributed through the main geographical regions in Brazil. The group comprised whites (65%), African Brazilians (31.3%), and people of mixed origins (3.7%). Clinical and demographic variables and various disease index scores were compiled. Ankylosing spondylitis (AS) was the most frequent disease in the group (65.1%); others were psoriatic arthritis (18.3%), undifferentiated SpA (6.8%), enteropathic arthritis (3.7%), and reactive arthritis (3.4%). RESULTS: White patients were significantly associated with psoriasis (p = 0.002), positive HLA-B27 (p = 0.014), and use of corticosteroids (p < 0.0001). Hip involvement (p = 0.02), axial inflammatory pain (p = 0.04), and radiographic sacroiliitis (p = 0.025) were associated with African Brazilian descent. Sex distribution, family history, and presence of peripheral arthritis, uveitis, dactylitis, urethritis, and inflammatory bowel disease were similar in the 3 groups, as well as age at disease onset, time from first symptom until diagnosis, and use of anti-tumor necrosis factor-α agents (p > 0.05). Schober test and thoracic expansion were similar in the 3 groups, whereas African Brazilians had higher Maastricht Ankylosing Spondylitis Enthesitis Scores (p = 0.005) and decreased lateral lumbar flexion (p = 0.003), while whites had a higher occiput-to-wall distance (p = 0.02). African Brazilians reported a worse patient global assessment of disease (p = 0.011). Other index scores and prevalence of work incapacity were similar in the 3 groups, although African Brazilians had worse performance in the Ankylosing Spondylitis Quality of Life questionnaire (p < 0.001). CONCLUSION: Ethnic background is associated with distinct clinical aspects of SpA in Brazilian patients. African Brazilian patients with SpA have a poorer quality of life and report worse disease compared to whites.

Evidence that LPS-reactive arthritis in rats depends on the glial activity and the fractalkine-TNF-α signaling in the spinal cord.

It is known that primary afferent central terminal sensitization can influence peripheral inflammation, however, it remains to be understood whether spinal cord glia can also contribute to this process. Our aim was to investigate the effect of spinal cord glia inhibition on the pathogenesis of LPS-induced knee-joint monoarthritis in rats and also to investigate the role of fractalkine and TNF-α. LPS was injected into the knee-joint previously primed with carrageenan to cause articular incapacitation, edema, synovial leukocyte infiltration, and GFAP and CD11b/c spinal immunoreactivity (glia-IR) increase. Articular edema was more sensitive to the inhibition by intrathecal fluorocitrate and minocycline than nociception and synovial leukocyte content. The higher doses of both drugs were ineffective when given by intraperitoneal route. Corticosteroid synthesis inhibition by aminoglutethimide did not change the glia inhibitors effect. The inhibitory effect of the dorsal root potential inhibitor, furosemide, was not additive to that caused by fluorocitrate and minocycline. Intrathecal anti-fractalkine and anti-TNF-α inhibited edema, nociception, and synovial leukocytes, while fractalkine caused the opposite effects. The fractalkine effect was inhibited by fluorocitrate and anti-TNF-α. Finally, fluorocitrate, minocycline and anti-fractalkine attenuated, but fractalkine increased, GFAP and CD11b/c IR. The evidence reported herein supports the hypothesis that spinal fractalkine release is involved in glia activation, which via the spinal release of TNF-α, seems to be involved in the development and maintenance of this arthritis model. A possible modulation of the dorsal root reflexes is discussed. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Yersinia-triggered arthritis in IL-12p40-deficient mice: relevant antigens and local expression of Toll-like receptor mRNA.

OBJECTIVES: To study the role of IL-12p40 at the onset of reactive arthritis (ReA) after Yersinia enterocolitica O:3 infection, and analyse relevant microbial antigens and articular expression of Toll-like receptor (TLR) mRNA. METHODS: Wild-type C57BL/6 and IL-12p40-deficient (IL-12p40-/-) mice were orogastrically infected with Y. enterocolitica O:3. Early (day 3) and late (day 21) after infection, the number of bacteria were determined in Peyer's patches (PP), mesenteric lymph nodes (MLN), the spleen, and joints. Histological studies of joints were performed. Collagen-specific and anti-Yersinia antibodies were measured by enzyme-linked immunosorbent assay (ELISA). The presence of Yersinia antigens was studied by dot blot. Induction of articular mRNA of TLR2, TLR4, and tumour necrosis factor (TNF)-alpha was analysed by reverse transcription-polymerase chain reaction (RT-PCR). TNFalpha protein levels were measured by ELISA. RESULTS: At day 3, bacterial recovery in PP, MLN, and spleen was significantly increased in IL-12p40-/- mice. Histopathological changes were observed in IL-12p40-/- mice at day 21 after infection, and correlated with higher antibody response against type II collagen. Although live bacteria could not be isolated at day 21 after infection, articular microbial components, especially from the outer membrane (OM), were detected. Moreover, intra-articular immunoglobulins to Yersinia antigens were significantly higher in IL-12p40-/- mice. Furthermore, mRNA levels for TLR2, TLR4 and TNFalpha, and TNFalpha protein were increased in joints from IL-12p40-/- mice. CONCLUSIONS: We concluded that IL-12p40 influences the resistance against Yersinia-triggered ReA. Bacterial products such as Yersinia OM could contribute to the ReA by induction of articular TLR expression, which results in an inflammatory response in the joint.

Role of TNFRp55 in Yersinia enterocolitica O:3-induced arthritis: triggering bacterial antigens and articular immune response.

OBJECTIVES: The pathogenesis of reactive arthritis (ReA), an aseptic synovitis that follows an extra-articular infection, is incompletely known. We studied the impact of tumour necrosis factor receptor (TNFR) p55 deficiency on the progression to ReA after oral Yersinia enterocolitica O:3 infection, the Yersinia antigens triggering articular inflammation and a possible articular TNFRp55-mediated mechanism that protects against ReA. METHODS: Wild-type C57BL/6 and TNFRp55-/- mice were orogastrically infected with Y. enterocolitica O:3 and monitored for survival and arthritis development. The bacterial load was determined in mesenteric lymph nodes (MLNs), the spleen and joints. Interferon (IFN)-gamma, TNF-alpha and IL-10 mRNA expression in MLN and joints were analysed by reverse transcription-polymerase chain reaction (RT-PCR). Articular antibodies to Yersinia antigens, TNF-alpha protein and nitric oxide (NO) levels were assessed. Acute arthritis was evaluated after joint injection of Yersinia antigens. RESULTS: The survival rate was 60% in TNFRp55-/- mice. They showed impaired bacterial clearance in MLN, the spleen and joints, and excessive mRNA expression of pro-inflammatory cytokines in MLN. Clinical and histological examinations revealed that TNFRp55-/- mice developed severe arthritis. Moreover, augmented articular outer membrane protein (OMP)-specific antibodies and TNF-alpha but impaired NO levels were detected in TNFRp55-/- mice. Synovial inflammatory response was detected by joint OMP injection. CONCLUSIONS: TNFRp55-mediated immune mechanisms prevent ReA development after oral infection with Y. enterocolitica O:3. Yersinia OMPs are the relevant antigens triggering ReA. NO induction through TNFRp55 signalling could have a local antibacterial function to prevent ReA. This study could contribute to ReA-specific therapeutic studies.

Contribution of TNFalpha, IL-1beta and CINC-1 for articular incapacitation, edema and cell migration in a model of LPS-induced reactive arthritis.

The protective effect of anti-CINC-1, -TNFalpha and -IL-1beta antisera on articular inflammatory incapacitation, articular diameter and synovial fluid cell content, which are correlated to nociception, edema and cell migration, respectively, were evaluated in a rat model of LPS-induced reactive arthritis. In this model, Escherichia coli lipopolysaccharide (LPS; 30 ng) was injected in a knee-joint previously primed with carrageenan (300 microg). Articular incapacitation was evaluated hourly by the automated registering of the knee-joint function during animal walking, and the knee-joint edema was evaluated by measuring the articular diameter increase. After 6 h, the animals were euthanized for collecting synovial fluid for the evaluation of cell migration. LPS produced dose-dependent incapacitation and edema. Anti-TNFalpha, -IL-1beta, and -CINC-1 antisera (20 and 40 microl) were used as pretreatment into knee-joint before LPS injection. At higher dose, Anti-TNFalpha and anti-CINC-1 were able to inhibit incapacitation, articular edema and mononuclear (MON) migration. Anti-IL1beta did not affect incapacitation at any dose, although inhibited edema and cell migration. Surprisingly, the higher dose of anti-IL1beta antisera did not inhibit cell migration, although inhibited articular edema. These findings corroborate the role TNFalpha has in different forms of arthritis, but points out the idea that CINC-1 (the homologue for human IL-8) may constitute a promising target for reactive arthritis management. Indeed, the potent antiedematogenic effect, and principally the anti-migration effect of anti-CINC-1, raises the possibility of a better control of disease progression than with anti-IL-1beta therapies.

Reiter's syndrome associated with the Acquired Immunodeficiency Syndrome: a case report.

The association of Reiter's Syndrome (RS) with the Acquired Immunodeficiency Syndrome (AIDS) is seldom mentioned in the medical literature. This report illustrates this relationship in a 46 years old male patient suffering from AIDS (CD(4)(+) = 240 cells/mm(3), CD(8)(+) = 1,301 cells/mm(3) and viral load = 330,000 copies/ml), pulmonary tuberculosis (positive catarrhal bacilluscopy), and RS. The diagnosis of RS was based on the combination of dermatological and articular alterations. The patient s cutaneous lesions were characterized by exfoliation and the formation of crusts located on the face, scalp, genitals, hands, and feet; onychodystrophy with opacity; yellowish coloring; and hyperkeratosis of the nails. Articular lesions led to progressive deformity of phalangeal joints of the hands, and intensive arthralgia, mainly of the larger joints (shoulders, elbows, hips and knees). AIDS treatment was administered with anti-retroviral drugs (zidovudine and didanosine); for tuberculosis (isoniazid, rifampicine, and pyrazinamide); and (prednisone and inometacine) for the RS. The patient recovered with the improvement of articular symptoms; however, on the eighth day of treatment, the patient showed significant hemoptysis and hypovolemic shock, and died. The association of RS and HIV infection is reviewed.

Yersinia enterocolitica O:8 and O:5 lipopolysaccharide arthritogenicity in hamsters.

OBJECTIVE: To assess the arthritogenicity of Yersinia enterocolitica O:8 and O:5 lipopolysaccharide (LPS) administered separately as single antigens in hamsters. METHODS: Male hamsters of the Syria strain were intramuscularly injected into each of the hind paws with two doses of Y. enterocolitica LPS O:8 or O:5. The measurement of swelling using a plethysmometer, the analysis of histological changes by routine techniques and the kinetics of LPS-specific antibodies and autoantibodies evaluated by enzyme-linked immunosorbent assay (ELISA) were performed. RESULTS: LPS O:8 was demonstrated to be more arthritogenic than LPS O:5, inducing acute arthritis on day 3 post-injection as well as more significant and longer lasting joint swelling after a second dose. LPS O:8 caused severe histopathological changes in the joints. Important LPS O:8-specific IgG responses and antibodies against type I and II collagen were observed. CONCLUSION: LPS O:8 administered alone has arthritogenic power and induces activation of autoreactive clones. This study supports the key role of LPS in the development of reactive arthritis.

Juvenile onset Reiter's syndrome. A retrospective study of 26 patients.

Clinical, laboratory and radiological findings were evaluated in 26 children with Reiter's syndrome, all of whom met the 1982 diagnostic criteria of A. Calin. Twenty-two of the patients (85%) were male and 4 were female (15%); the mean age at onset was 10.5 years (range 4-15.5 yrs). Mean follow-up time was 28.6 months. Diarrhea prior to onset was observed in 18 cases (69%), but there was no report of venereal disease. The full classic triad was initially observed in only 9 patients (35%), urethritis alone in 6 (23%) and conjunctivitis alone in 4 (15%). Arthritis was present in all patients, with the lower limb joints involved in 25 cases (96%); the pattern was pauciarticular in 18 (69%), polyarticular in 7 (27%) and monoarticular in one (4%). There was complete remission in 15 out of the 26 patients (58%), while a sustained and fluctuating course was seen in 7 (27%) and 3 (11.5%) patients, respectively; a single patient showed a remitting course. Balanitis was present in 11 out of the 22 male (50%) cases. Twelve out of 18 patients tested (67%) proved to be HLA B27 positive and there was radiological evidence of sacroiliitis in 5 out of 24 patients (21%). Reiter's syndrome should be included in the differential diagnosis of the arthritic child. As a rule, the course of joint involvement is remittent and sequelae affecting functional capacity are indeed exceptional.

HLA-B27-associated spondyloarthritis and enthesopathy in childhood: clinical, pathologic, and radiographic observations in 58 patients.

HLA-B27 typing of all arthritic children helped to identify and focus attention on a subset whose disease was pathogenetically related to and demonstrated clinical features of ankylosing spondylitis and Reiter syndrome, but only rarely fulfilled current diagnostic criteria for those disorders (spondyloarthritis). In contrast to other forms of childhood arthritis, enthesopathy (inflammation at the sites of attachment of ligaments and tendons to bone) was a prominent feature in 75%; a family history of similar arthritis was obtained from 60%; boys were more frequently affected (2:1); urethritis, acute iritis, conjunctivitis, or keratoderma blennorrhagicum occurred at some time in 42%; and the initial attack followed an unexplained febrile illness, known dysentery or urethritis, or severe musculoskeletal trauma in 41%. The arthritis was generally pauciarticular, asymmetric, and primarily in the feet and large joints of the lower extremities. Distinctive radiographic features included periostitis, severe osteopenia, calcaneal erosions, and heel spurs; three of 58 had rapid destruction of a single joint. Only ten patients (all boys) were found to have radiographic sacroiliitis after an average of five years of disease, and only three had the Reiter triad. The lifetime risk of sacroiliitis and spinal ankylosis can only be determined by long-term follow-up of such prospectively identified groups of spondyloarthritic children.