Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55−/− mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-γ and IL-17 in arthritic joints of TNFRp55−/− mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-γ production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55−/− mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4+IL-17+, CD4+IFN-γ+, and IL-17+IFN-γ+ cells in TNFRp55−/− mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-γ resulted in reduced joint histological scores in TNFRp55−/− mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-γ and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

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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)-β1 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.

Reactive arthritis (ReA) is a sterile synovitis which occurs after a gastrointestinal or urogenital infection. ReA belongs to Spondyloarthritis (SpA), a group of diseases that share several clinical and radiological features including familiar clustering, absence of rheumatoid factor and association with HLA-B27. Clinically, ReA is characterized by an asymmetric arthritis predominantly affecting the lower limbs, often associated with urethritis, conjunctivitis and other extraarticular symptoms. The ReA prevalence depends on the incidence of causative pathogens. The ReA diagnosis is based on clinical features and serological tests to evidence previous infection. Different treatment including antibiotics, disease modifying antirheumatic drugs (DMARs) and biologic agents has been recommended. Even though knowing that infections trigger the joint inflammation, the ReA pathogenesis remains to be poorly understood. Several animal models and in vitro studies have been used to elucidate the mechanisms involved in ReA development. In this sense, HLA-B27 transgenic rat or mice have been used to explain the role of this molecule in SpA aetiopathogenesis. Moreover, the infectious model of Yersinia-induced ReA in rodents has shed some lights on the relationship between host genetic susceptibility to infection and abnormal immune response in ReA development. Understanding the immune mediators triggering ReA will contribute to find a specific treatment for this arthritis. In this review, we focus on clinical features, epidemiology, treatment, and the different attempts to understand the pathogenesis of ReA.