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• The potential roles of IL-35-producing T and B cells and serum IL-35 levels in the pathogenesis of MGremain unclear. • The percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells were significantly lower in patients with AChR-MG than in HCs. Further, the proportions of IL-35-producing T cells and B cells and serum levels of IL-35 increased after treatment. • IL-35 may represent a potential biomarker for the clinical evaluation of MG. Interleukin 35 (IL-35) plays an anti-inflammatory in numerous autoimmune diseases. However, the potential roles of IL-35-producing T and B cells and serum IL-35 levels in the pathogenesis of myasthenia gravis (MG) and its association with disease activity in patients with MG remain unclear. The percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells among peripheral blood mononuclear cells were determined in 37 patients with anti-acetylcholine receptor (AChR) antibody-positive MG and 35 healthy controls (HCs) by performing a flow cytometry analysis. Serum IL-35 levels in participants were determined using an enzyme-linked immunosorbent assay. Further, the correlations between IL35 levels and disease activity were analysed. The percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells were significantly lower in patients with anti-AChR antibody-positive MG than in HCs (p = 0.001 and p = 0.002, respectively). Furthermore, patients with thymoma and patients with generalized MG had lower percentages of IL-35-producing CD4 + CD25 + T cells and CD19 + B cells than those without thymoma and those with ocular MG (p = 0.001 and p = 0.003; p = 0.008 and p = 0.001, respectively). Interestingly, the suppression of IL-35 secretion correlated negatively with the activities of daily living scores of patients with MG (r = -0.4774, p = 0.0028) and the quantitative MG scores (r = -0.4656, p = 0.0037). The proportions of IL-35-producing T cells and B cells and serum levels of IL-35 increased after treatment. IL-35 may represent a potential biomarker for the clinical evaluation of MG. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the relationship between tumour-necrosis factor-alpha (TNF-α), interleukin (IL)-18, IL-23, IL-35 and Heilcobacter (H) pylori infection with T2DM. A total of 25 healthy subjects and 102 confirmed T2DM patients were enrolled in this study. Diabetic patients were subdivided into six groups according to antidiabetic therapy. Diabetic non-treated patients exhibited a significant elevation in H. Pylori- Ig-G, TNF-α, IL-18, and IL-23 levels, but a noticeable decrease in IL-35 expression was observed compared to healthy controls. Antidiabetic therapy induced a significant decrease in the level of glycosylated hemoglobin (HbA1c), TNF-α, IL-18 and IL-23, while IL-35 expression was upregulated compared to diabetic controls. The results exhibited a positive correlation between H. pylori and HbA1c%, TNF-α, IL-18, and IL-23 values, and also between HbA1c% and TNF-α, IL-18 and IL-23 levels. Therefore, antidiabetic therapy decreases significantly the hyperglycemic state and circulating level of inflammatory cytokines which reflects their potential anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

To evaluate three subtypes of CD4+Foxp3+ T cells, interleukin-35 (IL-35) and IL-10 in systemic lupus eryhtematosus (SLE) patients and study their relation to disease activity. Fifty SLE patients were included and divided according to the SLE disease activity index (SLEDAI) into 2 equal groups with activity or in remission. Twenty healthy subjects were included as controls. All subjects underwent flow cytometric analysis of CD4, CD25, CXCR5 and Foxp3 expression on T cells. Serum IL-35 and IL-10 levels were measured by ELISA. Patients were 46 females and 4 males with a mean age of 38.0 ± 10.0 years, disease duration of 9.2 ± 6.0 years. The mean SLEDAI was 6.8 ± 3.7 in active ones. SLE patients especially those with activity had significantly reduced percents of CD4+CD25+Foxp3+ and CD4+CXCR5+Foxp3+ T cells, but increased percents of CD4+CD25−Foxp3+ T cells. This was accompanied by significant higher levels of serum IL-35 and IL-10 (p < 0.0001). The SLEDAI in active patients significantly correlated with CD4+CD25−Foxp3+ T cell percent, serum IL-35 and IL-10 levels (p < 0.05) and inversely with the CD4+CD25+Foxp3+ and CD4+CXCR5+Foxp3+ T cell percents (p < 0.05). At cut-off values of 3.29% for CD4+CD25+Foxp3+ T cell, 7.62% for CD4+CD25−Foxp3+ T cell, 1.77% for CD4+CXCR5+Foxp3+ T cell, 22.04 pg/ml for IL-35 level and 30.51 pg/ml for serum IL-10 level were found to be highly sensitive and specific for detecting lupus activity. CD4+Foxp3+ T cells, IL-35 and IL-10 showed high sensitivity and specificity for detecting SLE activity and may be considered as potentially promising therapeutic targets. [ABSTRACT FROM AUTHOR]

progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body's autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β ), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease. [ABSTRACT FROM AUTHOR]

Immune tolerance to both self-antigens and innocuous non–self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and suppressive molecules are involved in induction and maintenance of tolerance. In addition to their key function in the production of immunoglobulins, B cells can regulate immune responses through their surface molecules and secretion of cytokines. Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated through IL-10 secretion. However, IL-35 and TGF-β have also been associated with B cell–mediated immunosuppression. Several types of murine and human Breg cells have been described, such as mouse CD5 + CD1d hi B10 cells, CD21 hi CD23 hi CD24 hi transitional stage 2–like B cells, and CD138 + plasma cells and plasmablasts. Human Breg cell types include CD27 + CD24 high B10 cells, CD24 hi CD38 hi immature transitional B cells, and CD73 − CD25 + CD71 + B R 1 cells and a subset of plasma cells. Support for the in vivo existence of allergen-specific human Breg cells comes from direct detection of their increase during the course of allergen-specific immunotherapy, as well as their increased expression in nonallergic but high-dose allergen–exposed beekeepers. Human B R 1 cells selectively upregulate IgG 4 antibodies on differentiation to plasma cells. This suggests an additional immune regulatory role because of the noninflammatory and blocking antibody function of IgG 4 . Taken together, Breg cells appear to be involved in mediating allergen tolerance, but many open questions remain to be answered. [ABSTRACT FROM AUTHOR]

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Background: Interleukin (IL) 35 was recently identified as an additional anti-inflammatory and immunosuppressive cytokine. However, the role of IL-35 in allergic rhinitis is not well understood. The effect of IL-35 on other cytokines in allergic responses is also unclear. Objective: To investigate, in mice with allergic rhinitis, the effect of IL-35 on other cytokines associated with allergic rhinitis. Methods: A murine model of allergic rhinitis was established, and splenic cells were collected. Ovalbumin-specific allergic T-cell response was measured. The production of cytokines (T helper 1 interferon-gamma), Th2 (IL-4, IL-5, IL-13), Th17 (IL-17), IL-12 family (IL-12, IL-23, IL-27), IL-2, tumor necrosis factor-alpha, transforming growth factor-beta, and IL-10) stimulated with antigen was also measured in the presence or absence of IL-35. Results: IL-35 significantly inhibited the ovalbumin-specific T-cell response. It also significantly reduced the production of IL-4, IL-5, IL-13, IL-17, IL-23, and TNF-alpha, and significantly increased the production of IL-2, IL-10, and IL-27. Conclusion: This study showed that IL-35 inhibits allergic T-cell response and has the ability to modulate the production of IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-23, IL-27, and TNF-alpha in mice with allergic rhinitis. This study also indicated the possibility of a novel therapy with IL-35 for the control of allergic rhinitis. [ABSTRACT FROM AUTHOR]

Background Grass pollen–specific immunotherapy involves immunomodulation of allergen-specific T H 2 responses and induction of IL-10+ and/or TGF-β+CD4+CD25+ regulatory T cells (induced Treg cells). IL-35+CD4+CD25+ forkhead box protein 3–negative T (IL-35–inducible regulatory T [iT R 35]) cells have been reported as a novel subset of induced Treg cells with modulatory characteristics. Objective We sought to investigate mechanisms underlying the induction and maintenance of immunologic tolerance induced by IL-35 and iT R 35 cells. Methods The biological effects of IL-35 were assessed on group 2 innate lymphoid cells (ILC2s); dendritic cells primed with thymic stromal lymphopoietin, IL-25, and IL-33; and B and T H 2 cells by using flow cytometry and quantitative RT-PCR. Grass pollen–driven T H 2 cell proliferation and cytokine production were measured by using tritiated thymidine and Luminex MagPix, respectively. iT R 35 cells were quantified in patients with grass pollen allergy (seasonal allergic rhinitis [SAR] group, n = 16), sublingual immunotherapy (SLIT)–treated patients (SLIT group, n = 16), and nonatopic control subjects (NACs; NAC group, n = 16). Results The SAR group had increased proportions of ILC2s (P =.002) and IL-5+ cells (P =.042), IL-13+ cells (P =.042), and IL-5+IL-13+ ILC2s (P =.003) compared with NACs. IL-35 inhibited IL-5 and IL-13 production by ILC2s in the presence of IL-25 or IL-33 (P =.031) and allergen-driven T H 2 cytokines by effector T cells. IL-35 inhibited CD40 ligand–, IL-4–, and IL-21–mediated IgE production by B cells (P =.015), allergen-driven T-cell proliferation (P =.001), and T H 2 cytokine production mediated by primed dendritic cells. iT R 35 cells suppressed T H 2 cell proliferation and cytokine production. In addition, allergen-driven IL-35 levels and iT R 35 cell counts were increased in patients receiving SLIT (all, P <.001) and NACs (all, P <.001) compared with patients with SAR. Conclusion IL-35 and iT R 35 cells are potential novel immune regulators induced by SLIT. The clinical relevance of SLIT can be underscored by restoration of protective iT R 35 cells. Graphical abstract [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that IL-17 contributes to airway hyperresponsiveness (AHR); however, the mechanisms that suppress the production of this cytokine remain poorly defined. Objective: We sought to identify the regulatory cells and molecules that suppress IL-17–dependent allergic airways disease. Methods: Mice were sensitized by means of airway instillations of ovalbumin together with low levels of LPS. Leukocyte recruitment to the lung and AHR were assessed after daily challenges with aerosolized ovalbumin. Flow cytometry, quantitative PCR, and gene-targeted mice were used to identify naturally arising subsets of regulatory T (Treg) cells and their cytokines required for the suppression of established allergic airway disease. Results: Allergic sensitization through the airway primed both effector and regulatory responses. Effector responses were initially dominant and led to airway inflammation and IL-17–dependent AHR. However, after multiple daily allergen challenges, IL-17 production and AHR decreased, even though pulmonary levels of TH17 cells remained high. This loss of AHR was reversible and required the expansion of a Treg cell subset expressing both forkhead box protein 3 and inducible costimulator. These Treg cells also expressed the regulatory cytokines IL-10, TGF-β, and IL-35. Whereas IL-10 and TGF-β were dispensable for suppression of AHR, IL-35 was required. Conclusion: IL-35 production by inducible costimulator–positive Treg cells can suppress IL-17 production and thereby reverse established, IL-17–dependent AHR in mice. Targeting this pathway might therefore be of therapeutic value for treating allergic asthma in human subjects. [ABSTRACT FROM AUTHOR]