Myeloid-derived suppressor cells (MDSCs) are heterogenous populations of immature myeloid progenitor cells with immunoregulatory function. MDSCs play critical roles in controlling the processes of autoimmunity but their roles in rheumatoid arthritis (RA) are controversial. The present study was undertaken to investigate whether MDSCs have therapeutic impact in mice with collagen-induced arthritis (CIA), an animal model of RA. We also examined the mechanisms underlying the anti-arthritic effect of MDSCs. In vitro treatment with MDSCs repressed IL-17 but increased FOXP3 in CD4+ T cells in mice. In vivo infusion of MDSCs markedly ameliorated inflammatory arthritis. Th17 cells and Th1 cells were decreased while Tregs were increased in the spleens of MDSCs-treated mice. MDSCs profoundly inhibited T cell proliferation. Addition of anti-IL-10 almost completely blocked the anti-proliferative effects of MDSCs on T cells. Anti-IL-10 blocked the expansion of Tregs by MDSCs. However, infusion of MDSCs from IL-10 KO mice failed to suppress inflammatory arthritis. MDSCs could reciprocally regulate Th17/Treg cells and suppress CIA via IL-10, suggesting that MDSCs might be a promising therapeutic strategy for T cell mediated autoimmune diseases including RA.

Objective: This study was undertaken to assess the effect of myeloid‐derived suppressor cells (MDSCs) on various B cell subsets, including regulatory B cells, as well as to assess the potential therapeutic effects of MDSC infusion in an animal model of systemic lupus erythematosus (SLE).Methods: Splenocytes were cultured with MDSCs, and the populations of various B cells and effector T cell subsets were analyzed by flow cytometry. Lupus mice (roquin^san/san mice) were treated intravenously with MDSCs obtained from C57BL/6 mice, and the levels of serum autoantibodies, degree of proteinuria, histologic changes in the kidney, and populations of various B cell and T cell subsets in the spleen were analyzed.Results: Coculture of MDSCs with splenocytes from C57BL/6 mice resulted in an expansion of the population of interleukin‐10–producing B cells. The expansion of regulatory B cells was completely blocked by the addition of N^G‐monomethyl‐l‐arginine, an inhibitor of inducible nitric oxide synthase (iNOS). Infusion of MDSCs resulted in a reduction of serum anti–double‐stranded DNA antibody levels and degree of proteinuria and an improvement in renal pathology in the roquin^san/san mice. MDSC coculture also resulted in a decrease in the population of effector B cells, such as germinal center B cells and plasma cells. Moreover, infusion of MDSCs resulted in an expansion of the regulatory B cell population as well as a decrease in follicular helper T cells, Th1 cells, and Th17 cells in the spleens of roquin^san/san mice.Conclusion: Our results indicate the MDSCs induce expansion of regulatory B cells via iNOS and ameliorate autoimmunity in a murine model of SLE. These findings indicate that MDSCs may be a promising therapeutic strategy for targeting B cell–mediated autoimmune diseases.

Rheumatoid arthritis (RA) is a systemic autoimmune disease caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental factor that affects the development of RA. Metabolites secreted by the gut microbiota maintain homeostasis in the gut through various mechanisms [e.g., butyrate, which is one of the major metabolites of gut microbiota, exerts an anti-inflammatory effect by activating G-protein-coupled receptors and inhibiting histone deacetylases (HDACs)]. Here, we focused on the inhibition of the HDACs by butyrate in RA. To this end, we evaluated the therapeutic effects of butyrate in an animal model of autoimmune arthritis. The arthritis score and incidence were lower in the butyrate-treated group compared to the control group. Also, butyrate inhibited HDAC2 in osteoclasts and HDAC8 in T cells, leading to the acetylation of glucocorticoid receptors and estrogen-related receptors α, respectively. Additionally, control of the T_H17/T_reg cell balance and inhibition of osteoclastogenesis were confirmed by the changes in target gene expression. Interleukin-10 (IL-10) produced by butyrate-induced expanded T_reg cells was critical, as treatment with butyrate did not affect inflammatory arthritis in IL-10-knockout mice. This immune-cell regulation of butyrate was also detected in humans. These findings suggest that butyrate is a candidate agent for the treatment of RA.

Introduction: Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades adjacent cartilage and bone in rheumatoid arthritis (RA). The study was undertaken to determine the effect of interleukin-17 (IL-17) on the survival and/or proliferation of FLSs from RA patients and to investigate whether signal tranducer and activator of transcription 3 (STAT3) is implicated in this process. Methods: Bcl-2 and Bax expression in FLSs was determined using the real-time PCR and western blot analysis. The expression of Bcl-2 and phosphoSTAT3 in synovial tissues was investigated by confocal microscope. Apoptosis of FLSs was detected by Annexin V/propidium iodide staining and/or phase contrast microscopy. The proliferation of FLSs was determined by CCK-8 ELISA assay. Results: The pro-apoptotic Bax is decreased and anti-apoptotic Bcl-2 is increased in FLSs from RA patients compared with those from patients with osteoarthritis (OA). IL-17 upregulated the expression of Bcl-2 in FLSs from RA patients, but not in FLSs from OA patients. STAT3 was found to mediate IL-17-induced Bcl-2 upregulation in FLSs from RA patients. Additionally, IL-17 promoted the survival and proliferation of FLSs from RA patients. Most importantly, treatment with STAT3 inhibitor reversed the protective effect of IL-17 on FLSs apoptosis induced by sodium nitroprusside (SNP). Conclusions: Our data demonstrate that STAT3 is critical in IL-17-induced survival of FLS from RA patients. Therefore, therapeutic strategies that target the IL-17/STAT3 pathway might be strong candidates for RA treatment modalities.

Introduction: Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined. Methods: Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells. Results: Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5. Conclusions: Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.

Systemic lupus erythematosus (SLE) is an autoimmune disease featuring enhanced expression of type I interferon (IFN) and autoantibody production triggering inflammation of, and damage to, multiple organs. Continuing research efforts focus on how gut microbes trigger systemic autoimmunity and SLE. The gut microbial communities of mice and humans with lupus have been investigated via high-throughput sequencing. The Firmicutes-to-Bacteroidetes ratio is consistently reduced in SLE patients, regardless of ethnicity. The relative abundance of Lactobacillus differs from the animal model used (MRL/lpr mice or NZB/W F1 mice). This may indicate that interactions between gut microbes and the host, rather than the enrichment of certain gut microbes, are especially significant in terms of SLE development. Enterococcus gallinarum and Lactobacillus reuteri, both of which are possible gut pathobionts, become translocated into systemic tissue if the gut epithelial barrier is impaired. The microbes then interact with the host immune systems, activating the type I IFN pathway and inducing autoantibody production. In addition, molecular mimicry may critically link the gut microbiome to SLE. Gut commensals of SLE patients share protein epitopes with the Ro60 autoantigen. Ruminococcus gnavus strain cross-reacted with native DNA, triggering an anti-double-stranded DNA antibody response. Expansion of R. gnavus in SLE patients paralleled an increase in disease activity and lupus nephritis. Such insights into the link between the gut microbiota and SLE enhance our understanding of SLE pathogenesis and will identify biomarkers predicting active disease.