Background:In the acute phase of adult-onset Still’s disease (AOSD), elevated levels of proinflammatory cytokines including interferon-γ (IFN-γ) are shown. Moreover, IFN-γ impacts on activating macrophages which play a crucial role in the pathogenesis of AOSD. Natural killer (NK) cells and T helper cells are in charge of secreting IFN-γ in the innate and adaptive immune systems of disease, respectively. However, the features of their IFN-γ-producing variation depending on disease activity are still uncertain in AOSD.Objectives:We investigated characteristics of IFN-γ-producing CD4+T cells and NK cells in patients with AOSD.Methods:Twenty-four patients in the acute phase of AOSD (active AOSD), 8 of them after treatment (remission), and 12 healthy controls (HC) were recruited in this study. Peripheral blood mononuclear cells and serum samples were provided from them for the experimental analysis. Flow cytometry was used for analyzing CD4+T cells, CD4+regulatory T cells (Tregs), NK cells, and their intracellular IFN-γ expression levels as well as suppression assay of Tregs. The serum concentration of interleukin-18 (IL-18) was measured using commercially available ELISA kit. Relationship between the analyzed data and clinical findings related to disease activity were statistically evaluated.Results:IFN-γ expression in CD4+T cells was significantly higher in active AOSD than in HC (p < 0.05). Tregs also significantly indicated higher expression of IFN-γ in active AOSD than in HC (p < 0.0001); and moreover, Tregs were significantly impaired in their suppression ability (p < 0.05). In both CD4+T cells and Tregs, expression of IFN-γ was significantly correlated with serum ferritin levels in active AOSD (p < 0.05). IFN-γ expression in CD4+T cells was significantly higher in patients with splenomegaly than those without that (p < 0.05). The proportion of NK cells was significantly lower in active AOSD than in HC (p < 0.005), whereas IFN-γ expression in NK cells was significantly higher in active AOSD than in HC (p < 0.0005). The number of NK cells and IFN-γ-expressing NK cells had inverse relationship with serum ferritin levels in active AOSD (p < 0.05 and p < 0.005, respectively). Increased number of NK cells and their decreased expression of IFN-γ were significantly demonstrated in remission (p < 0.05). In the analyses of NK cell subsets, lower expression of IFN-γ in CD56brightNK cells and higher that in CD56dimNK cells were significantly indicated in active AOSD than HC (p < 0.05). In remission, IFN-γ expression was significantly decreased in CD56dimNK cells (p < 0.05) despite no significant recovery of that in CD56brightNK cells (p = 0.311). Meanwhile, increased expression of IFN-γ in CD56brightNK cells was demonstrated in only patients who were treated with biologics. Although serum levels of IL-18 were significantly higher in active AOSD than in remission and HC; however, they had no significant correlations with any analyzed data.Conclusion:CD4+T cells and NK cells promote IFN-γ expression in the acute phase of AOSD. Meanwhile, increased expression of IFN-γ in CD4+T cells and decreased number of NK cells were correlated with serum ferritin levels, suggesting that they are indicators of disease activity. Furthermore, high disease activity may impact on the alteration of IFN-γ-producing balance in two distinct population of NK cells, and the plasticity of Tregs leading to defect in suppression ability.Disclosure of Interests:None declared
Salmonella typhimurium Infection in Mice Induces Nitric Oxide-Mediated Immunosuppression through a Natural Killer Cell-Dependent Pathway