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Recent findings have shown that the level of interleukin‐35 (IL‐35) is abnormal in several autoimmune diseases. Nonetheless, whether IL‐35 participates in the pathogenesis of immune thrombocytopenia (ITP) remains unclear. The current study investigates whether IL‐35 modulates megakaryopoiesis. The results show that IL‐35 receptors are progressively expressed on bone marrow megakaryocytes during the in vitro differentiation of CD34+ progenitors. IL‐35 increases the number of megakaryocyte colony‐forming units through the Akt pathway. The level of bone marrow IL‐35 is reduced in ITP patients, and the decreased level of IL‐35 may inhibit megakaryopoiesis. Then, the potential causes of decreased IL‐35 in ITP patients are explored. The primary type of cell that secretes IL‐35, known as IL‐35‐producing regulatory T cells (iTr35), is reduced in ITP patients. Bone marrow mesenchymal stem cells (MSCs) from ITP patients exhibit an impaired capability of inducing iTr35 due to enhanced apoptosis, which may contribute to the reduced level of bone marrow IL‐35 in ITP patients. Iguratimod promotes megakaryocyte development and differentiation by elevating the expression of IL‐35 receptors on megakaryocytes. Iguratimod improves response rates and reduces bleeding symptoms in corticosteroid‐resistant ITP patients. [ABSTRACT FROM AUTHOR]

Objective To evaluate the role of induced immunosuppressive T regulatory (iTr) 35 cells in SSc-related inflammation and fibrosis. Methods Sixty-eight SSc patients were enrolled in this study. Subsets of iTr35 and Tr1 were measured by flow cytometry. IL-35 and IL-10 levels were measured using ELISA. Expressions of iTr35, Tr1, fibrosis-related genes and proteins associated with signalling pathways were determined using immunofluorescence, western blot and immunohistochemistry assays. Results In peripheral blood, the proportions of the iTr35 cells were higher and Tr1 cells were lower than the control group. Similarly, IL-35 expression was increased, while IL-10 levels were decreased. In fibroblasts from skin tissue, the expression levels of EBI3, IL-12Ap35, Foxp3 and IL-10 were decreased, but collagen I, TGF-β, alpha smooth muscle actin (α-SMA) and fibronectin levels were increased. Phosphorylated STAT3/6 were increased, but iTr35 and Tr1 cell levels were significantly decreased. When CD4+ cells were incubated with both recombinant human (rh)IL-35 and rhIL-10, the cell numbers of iTr35 and Tr1 were greater than the same type of cells treated with rhIL-35 or rhIL-10 alone. However, the viability of conventional CD4+ T cells was decreased by gradually increasing iTr35 cells. Moreover, iTr35 cells affected α-SMA expression through the STAT3/6 signalling pathway. Conclusion Both iTr35 and Tr1 cells are involved in SSc-related inflammation and fibrosis. IL-35 can induce iTr35 cells, showing a synergistic effect with IL-10. We also found that iTr35 cells can inhibit T cell proliferation and differentiation via the STAT3/6 signalling pathway, thereby causing fibrosis. [ABSTRACT FROM AUTHOR]

Inflammation is a hallmark of many airway diseases. Improved understanding of the cellular and molecular mechanisms of airway disease will facilitate the transition in our understanding from phenotypes to endotypes, thereby improving our ability to target treatments based on pathophysiologic characteristics. For example, allergic asthma has long been considered to be driven by an allergen-specific T helper 2 response. However, clinical and mechanistic studies have begun to shed light on the role of other cell subsets in the pathogenesis and regulation of lung inflammation. In this review, we discuss the importance of different lymphocyte subsets to asthma and other airway diseases, while highlighting the growing evidence that asthma is a syndrome that incorporates many immune phenotypes. [ABSTRACT FROM AUTHOR]

Pemphigus is an autoimmune disease that causes blistering and is life-threatening if left untreated. Nowadays, finding a promising treatment for pemphigus remains a serious challenge. Various treatments are currently recommended to treat this disease, but they rarely lead to complete and durable remission. Regulatory cells appear to have a critical role in numerous autoimmune diseases, so it is possible that promotion of these cells may induce remission. This study presents a new approach to treating pemphigus that has not been discussed to date. This approach introduces interleukin (IL)-35 as a new treatment for pemphigus. This cytokine could induce two different types of regulatory cell, including IL-35-that produces induced regulatory T cells and IL-35 + regulatory B cells, which could suppress both effector T cells and effector B cells. It seems that IL-35 may act as an efficient therapeutic strategy for pemphigus. It probably limits progression of the disease and may even contribute to long-lasting remission. However, further study is required to evaluate the efficacy and safety of treating pemphigus with IL-35. [ABSTRACT FROM AUTHOR]

Cytokines coordinate the activities of innate and adaptive immune systems and the Interleukin 12 (IL-12) family of cytokines has emerged as critical regulators of immunity in infectious and autoimmune diseases. While some members (IL-12 and IL-23) are associated with the pathogenesis of chronic inflammatory diseases, others (IL-27 and IL-35) mitigate autoimmune diseases. Unlike IL-12, IL-23 and IL-27 that are produced mainly by antigen presenting cells, IL-35 is predominantly secreted by regulatory B (i35-Bregs) and T (iTR35) cells. The discovery that IL-35 can induce the conversion or expansion of lymphocytes to regulatory B and T cells has considerable implications for therapeutic use of autologous regulatory B and T cells in human diseases. Although our current understanding of the immunobiology of IL-35 or its subunits (p35 and Ebi3) is still rudimentary, our goal in this review is to summarize what we know about this enigmatic cytokine and its potential clinical use, particularly in the treatment of CNS autoimmune diseases. [ABSTRACT FROM AUTHOR]

The importance of regulatory T cells in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-β are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible regulatory T cells. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible regulatory T cells.

Interleukin ( IL)-35, a recently identified cytokine of the IL-12 family, is a potent immunosuppressive cytokine secreted by regulatory T (Treg) cells and the newly reported regulatory B (Breg) cells. IL-35 functions as a crucial immunosuppressive factor in immune-mediated diseases, and the predominant mechanism of suppression is its ability to suppress T cell proliferation and effector functions. The pathogenic processes of the non-cytopathic hepatitis B virus ( HBV) infection-related liver diseases are immune-mediated, including liver damage and viral control. It has been found that IL-35 is detectable in peripheral CD4+ T cells in chronic HBV-infected patients, whereas it is undetectable in healthy individuals. There is growing evidence that cytokine-mediated immune responses play a pivotal role in determining the clinical outcome during HBV infection. It is particularly important to investigate the effects of IL-35 in the immunopathogenesis of chronic HBV infection. In this study, the recent understanding of this issue is discussed. [ABSTRACT FROM AUTHOR]

The importance of regulatory T cells in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of antitumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-β are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible regulatory T cells. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible regulatory T cells. [ABSTRACT FROM AUTHOR]

Background and Objectives: Mycobacterium tuberculosis (Mtb) harbors immune evasion that impairs immune responses and prevents optimal immunity against Mtb. However, little is known about mechanisms of immune evasion in Mtb infected individual. In this study, the relationship among the IL-35 level, IL-35-producing regulatory T cells (iTr35) subset, the bacterial burden and lung lesions in mice infected with Mtb were investigated to assess the impact of immune evasion on the infected mice. Methods: A total of twenty C57BL/6 male 6-7 weeks old mice, were injected with 1 × 105 colony-forming units (CFU) of attenuated H37Ra strain of Mtb in a volume of 200µL, to prepare mouse tuberculosis infection models. Colony forming units in left lung, body mass index and spleen coefficient were determined followed by histology and morphometry, quantitative RT-PCR for mRNA, Western blot analysis, cytokine IL-35 detection and flow cytometry of fork head box protein P3-expressing T cells. Results: Compared with the control mice, the mRNA expressions of the p35 and EBI3 of IL-35 were significantly increased in the spleen of 8-week infected mice, and their protein expressions were not only increased in 8-week but in lungs of 4-week infected mice, accompanied with an elevated level of serum IL-35. In addition, iTr35 subset was increased in the spleen of 8-week infected mice compared with the control mice. Importantly, the high bacterial burden, lung lesions, and low mouse weight were found in the 8-week infected mice. Conclusions: The mice infected with Mtb H37Ra strain resulted in elevated IL-35 levels and iTr35 subset. There were increased bacterial burden and lung lesions, suggesting that IL-35 and iTr35 cells play an immune evasion role in chronic Mtb infected mice. [ABSTRACT FROM AUTHOR]