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The Cre-LoxP conditional knockout strategy has been used extensively to study gene function in a specific cell-type. In this study, the authors tried to engineer mice in which the Dbc1 gene is conditionally knocked out in Treg cells. Unexpectedly, the conditional Dbc1 allele was completely deleted with a low frequency in some Foxp3YFP-Cre mice harboring floxed Dbc1 allele under specific settings. It was found that the germline recombination of floxed Dbc1 allele, which caused Dbc1 knock out mice, occurred in the male Foxp3YFP-Cre mice harboring floxed Dbc1 allele. Even though the authors documented that Foxp3 is expressed in the testis, the germline recombination was not caused by the germline expression of Cre, which was driven by the Foxp3 promoter. The germline recombination may be caused by the unspecific expression of Cre recombinase in the fetus, in which the floxed Dbc1 allele of some stem cells with development potential to germ cells may be recombined. Additionally, this study found that the floxed Dbc1 allele was recombined in non-T cells of some Foxp3CreDbc1fl mice, which need to be characterized. Our results also suggest that using male mice with a low frequency of recombined gene allele can reduce the risk of having full knock out mice. [ABSTRACT FROM AUTHOR]

Background and Purpose: Regulation of neural inflammation is considered as a vital therapeutic target in ischemic stroke. All-trans retinoic acid (atRA), a potent immune modulator, has raised interest in the field of stroke therapy. However, the immunological mechanisms for atRA-mediated neuroprotection remain elusive. The current study evaluated the impact of atRA on post-stroke neural inflammation and elucidated the mechanisms involved in the regulation of related neutrophil functions.Methods: atRA was prophylactically administered to mice 1 day before transient middle cerebral artery occlusion (tMCAO, 1 h) and repeated daily immediately after reperfusion for 3 days. Stroke outcomes, neutrophil polarization, and formation of neutrophil extracellular traps (NETs) in the stroke lesion were assessed. Neutrophil depletion was induced with anti-Ly6G antibodies. Primary neutrophil cultures were used to explore the mechanisms of atRA treatment.Results: Prophylactic atRA treatment reduced infarct volumes and neurological deficits at 1 day after tMCAO. Post-stroke neural inflammation was attenuated and neutrophil accumulation in lesion was downregulated. atRA treatment skewed neutrophil toward N2 phenotype which facilitated its clearance by macrophage and inhibited NETs formation. The functions of neutrophil were indispensable in the protective effects of atRA and were associated with suppression to STAT1 signaling by atRA. Administration of atRA after stroke still provided efficient protection to cerebral ischemia.Conclusion: atRA displays potent therapeutic efficacy in ischemic stroke by attenuating neural inflammation. Treatment of atRA impeded neutrophil accumulation, favored N2 polarization, and forbade NETs formation in ischemic lesion. STAT1 signaling played a decisive role in the mechanisms of atRA-afforded regulation to neutrophil. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren's syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases. [ABSTRACT FROM AUTHOR]

Background: Mounting evidence has shown that a novel subset of mesenchymal stem cells (MSCs) derived from human gingiva referred to as gingival mesenchymal stem cells (GMSCs) displays a greater immunotherapeutic potential and regenerative repair expression than MSCs obtained from other tissues. However, the safety of the use of transplanted GMSCs in humans remains unclear. Methods: In this study, we evaluated the safety of GMSCs transplanted into mouse, rat, rabbit, beagle dog, and monkey as well as two animal models of autoimmune diseases. Results: In short- and long-term toxicity tests, infused GMSCs had no remarkable adverse effects on hematologic and biochemical indexes, particularly on the major organs such as heart, liver, spleen, and kidney in recipient animals. It was also shown that GMSCs were well tolerated in other assays including hemolysis, vascular, and muscular stimulation, as well as systemic anaphylaxis and passive skin Arthus reaction in animal models. GSMC infusion did not cause any notable side effects on animal models of either autoimmune arthritis or lupus. Significantly, GMSCs most likely play no role in genotoxicity and tumorigenesis. The biological features remained stable for an extended period after cell transfer. Conclusions: GMSCs are safe in various animal models of autoimmunity, even during active disease episodes, especially in monkeys. This study paves a solid road for future clinical trials of GMSCs in patients with autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Kinases and transcriptional regulators are fundamental components of cell signaling that are expressed on many types of immune cells which are involved in secretion of cytokines, cell proliferation, differentiation, and apoptosis. Both play important roles in biological responses in health as well as in illnesses such as the autoimmune diseases which comprise at least 80 disorders. These diseases are caused by complex genetic and environmental interactions that lead to a breakage of immunologic tolerance and a disruption of the balance between self-reactive cells and regulatory cells. Kinases or transcriptional regulatory factors often have an abnormal expression in the autoimmune cells that participate in the pathogenesis of autoimmune disease. These abnormally expressed kinases or transcriptional regulators can over-activate the function of self-reactive cells to produce inflammatory cytokines or down-regulate the activity of regulatory cells, thus causing autoimmune diseases. In this review we introduce five kinds of kinase and transcriptional regulator related to autoimmune diseases, namely, members of the Janus kinase (JAK) family (JAK3 and/or tyrosine kinase 2 (TYK2)), fork head box protein 3 (Foxp3), the retinoic acid-related orphan receptor gamma t (RORγt), and T-box expressed in T cells (T-bet) factors. We also provide a mechanistic insight into how these kinases and transcriptional regulators affect the function of the immune cells related to autoimmune diseases, as well as a description of a current drug design targeting these kinases and transcriptional regulators. Understanding their exact role helps offer new therapies for control of the inflammatory responses that could lead to clinical improvement of the autoimmune diseases. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for maintaining immune tolerance and preventing autoimmune and inflammatory diseases. The activity and function of Tregs are in large part determined by various intracellular metabolic processes. Recent findings have focused on how intracellular metabolism can shape the development, trafficking, and function of Tregs. In this review, we summarize and discuss current research that reveals how distinct metabolic pathways modulate Tregs differentiation, phenotype stabilization, and function. These advances highlight numerous opportunities to alter Tregs frequency and function in physiopathologic conditions via metabolic manipulation and have important translational implications. [ABSTRACT FROM AUTHOR]

[Display omitted] • K/B × N arthritis model-derived sera and synovial fluid can stimulate NETs formation. • GMSCs inhibit both peripheral and synovial NETs formation by secreting manner. • GMSCs suppress NETs formation via PGE2-PKA-ERK signaling pathway. • GMSCs ameliorate arthritis by suppressing NETs formation. Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Vitamin A (VitA) is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. VitA is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. VitA is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes. VitA has demonstrated a therapeutic effect in the treatment of various infectious diseases. To better understand the relationship between nutrition and the immune system, the authors review recent literature about VitA in immunity research and briefly introduce the clinical application of VitA in the treatment of several infectious diseases. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated previously that induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) have immunosuppressive effects on activated T cells. However, the effects of iPSC-MSCs on quiescent T cells are still unknown. The aim of this study was to identify the immunomodulatory role of iPSC-MSCs on resting peripheral blood mononuclear cells (PBMCs) from allergic rhinitis (AR) patients. Methods: PBMCs were cocultured with iPSC-MSCs without any stimulation, following which lymphocyte proliferation, activation of T cells, TH1/TH2 and regulatory T (Treg) cell differentiation, and Treg cell function were analyzed. The roles of soluble factors and cell–cell contact were examined to investigate the mechanisms involved. Results: iPSC-MSCs promoted the proliferation of resting lymphocytes, activated CD4+ and CD8+ T cells, and upregulated and activated Treg cells without any additional stimulation. In addition, iPSC-MSCs balanced biased TH1/TH2 cytokine levels. Cell–cell contact was confirmed to be a possible mechanism involved. NF-κB was identified to play an important role in the immunomodulatory effects of iPSC-MSCs on quiescent T cells. Conclusions: iPSC-MSCs activate quiescent T cells and elevate regulatory T-cell response in AR patients, suggesting different immunomodulatory functions of iPSC-MSCs according to the phases of diseases. Therefore, iPSC-MSCs are a potential therapeutic candidate for treating allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation. Tr1 cell development and suppressive function of Itk deficient cells can be restored by the expression of the transcription factor interferon regulatory factor 4 (IRF4). Downstream of ITK, Ras activity is responsible for Tr1 cell induction, as expression of constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk−/− cells. We conclude that TCR/ITK signalling through the Ras/IRF4 pathway is required for functional development of Tr1 cells. [ABSTRACT FROM AUTHOR]

Background The immunomodulatory and anti-inflammatory functions of mesenchymal stem cells (MSCs) have been demonstrated in several autoimmune/inflammatory diseases, but their contribution to allergic conjunctivitis and underlying antiallergic mechanisms remain elusive. Objective We sought to explore the clinical application of MSCs to experimental allergic conjunctivitis (EAC) and its underlying antiallergic mechanisms. Methods Culture medium from TNF-α–stimulated, bone marrow–derived MSCs (MSC-CMT) was administered topically to mice with EAC, and the related allergic symptoms and biological changes were evaluated. Murine spleen-derived B cells, bone marrow–derived mast cells (MCs), and lung vascular endothelial cells were cultured in vitro to investigate the antiallergic MSC-CMT mechanisms. Results Topical instillation of MSC-CMT significantly attenuated the clinical symptoms of short ragweed pollen–induced EAC, with a significant decrease in inflammatory cell frequency, nuclear factor κB p65 expression, and TNF-α and IL-4 production. In vitro MSC-CMT significantly inhibited the activation of MCs and B-cell IgE release and reduced histamine-induced vascular hyperpermeability. During EAC, MSC-CMT treatment also decreased IgE production, histamine release, enrichment and activation of MCs, and conjunctival vascular hyperpermeability. The MSC-CMT–mediated inhibition of B cells, MCs, and histamine and its antiallergic effects during EAC were abrogated when MSCs were pretreated with COX2 small interfering RNA. Conclusions Our findings provide compelling evidence that MSC-CMT inhibits EAC through COX2-dependent multiple antiallergic mechanisms and support the use of MSC-CMT as a novel strategy for treating allergic conjunctivitis. [ABSTRACT FROM AUTHOR]

Background: Induced CD4+ forkhead box protein 3–positve regulatory T (iTreg) cells are a promising source for cell-based therapies of established inflammatory and autoimmune diseases. However, their relationship to mast cell (MC) function and MC-driven diseases remains unknown. Objective: We sought to explore the roles of iTreg cells on MC function and the established MC-driven disease contact hypersensitivity (CHS). Methods: In vitro coculture studies were carried out to investigate the interaction between iTreg cells in murine or human MCs by using both direct cell-cell contact and transwell systems to separate cell-cell contact. In vivo mice iTreg cells were administered to mice with established CHS, and innate immunologic responses, such as MC infiltration and inflammatory cytokine expression at contact sites, were evaluated. Results: In vitro coculture under direct cell-cell contact resulted in indirect suppression of IgE-independent activation of MCs by murine or human iTreg cells. Mechanistically, iTreg cells suppressed proinflammatory cytokine levels by modulating nuclear factor κB p65 activation in MCs through T cell–derived TGF-β1. Injection of iTreg cells but not natural CD4+CD25+ regulatory T cells into animals with established CHS resulted in the suppression of infiltration and functions of MCs and also led to decreased production of inflammatory cytokines at allergic contact areas. iTreg cell–mediated immunosuppressive effects were abrogated when iTreg cells were pretreated with TGF-β1 small interfering RNA. Conclusions: Our study demonstrates that iTreg cells suppress MC function and attenuate established MC-driven CHS through TGF-β1–dependent mechanisms. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23–2, an inhibitor of the mRNA m6A demethylase FTO , inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO -overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A- IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23–2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO -mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA. [Display omitted] • Increased FTO promotes the migration, invasion and inflammatory response of RA FLS. • FTO controls RA FLS functions by enhancing ADAMTS15 mRNA stability in an m6A-IGF2BP1dependent manner. • The FTO-mediated m6A modification plays an important role in regulating synovial inflammation and joint damage in RA. [ABSTRACT FROM AUTHOR]

[Display omitted] • NFIL3 deficiency alleviated MOG35-55 induced EAE along with lower clinical scores, milder neuroinflammation and demyelination. • NFIL3 deficiency decreased Th17 cells within the CNS of EAE. • Th17, Th1 and Treg cells did not change obviously in the spleens and lymph nodes in NFIL3-/- EAE. • In the periphery, the expressions of PD-1 and ICOS on CD4+T cells increased, whereas GM-CSF+CD4+T cells, Th2 cells, Th9 cells and CD8+CD103+T cells decreased in NFIL3-/- EAE. • NFIL3 deficiency affected CD11c+ dendritic cells both in vivo and in vitro. The anti-inflammatory capacity of NFIL3 knock out CD11c+ DCs increased while their pro-inflammatory capacity decreased. The transcription factor NFIL3 exerts comprehensive effects on the immune system. Previous studies revealed that NFIL3 is related to the function and development of different immune cell subsets. Experimental autoimmune encephalomyelitis (EAE) is mediated by immune cells which results in inflammatory demyelination in the central nervous system (CNS). However, how NFIL3 affects EAE has not been thoroughly studied. The current study aimed to investigate how NFIL3 affects EAE, especially the changes of T cells and dendritic cells as well as the crosstalk between them. We used NFIL3-/- mice and C57BL/6J mice (wildtype) to establish MOG35-55-induced EAE. The clinical scores were recorded daily. The immune cells within and outside the CNS of EAE mice were analyzed by flow cytometry. Histology was used to evaluated the neuroinflammation and demyelination in the CNS. Besides, CD11c+ dendritic cells (DCs) were cocultured with T cells and the interplay was measured. At the peak of EAE, Th17 cells decreased within the CNS accompanying with lower clinical scores and milder neuroinflammation and demyelination in NFIL3 knockout EAE mice. Outside the CNS, PD-1 and ICOS on CD4+T cells increased, whereas Th2, Th9, CD8+CD103+T cells and GM-CSF+CD4+T cells decreased. Besides, the pro-inflammatory capacity of NFIL3-/- CD11c+ dendritic cells was impaired while the anti-inflammatory capacity was promoted. This study suggests that NFIL3 deficiency could alleviate MOG35-55-induced EAE through regulating different immune cell subsets, which is not only related with adaptive immunity and innate immunity, but also related with the cross-talk between them, especially CD4+ T cells and CD11c+ dendritic cells. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren''s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential. [Copyright &y& Elsevier]

• IRF4 is a member of IRF transcription factor family (9 members) exerting the regulation of interferon (IFN). • IRF4 is restrictively expressed on immune cells and participates in the complicated immune system development and function. • IRF4 is recognized to be critical in the initiation and progress of SLE. • Targeted on IRF4 supplies the potential therapeutic approaches to treating patients with SLE. Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factors which mainly regulates the transcription of IFN. IRF4 is restrictively expressed in immune cells such as T and B cells, macrophages, as well as DC. It is essential for the development and function of these cells. Since these cells take part in the homeostasis of the immune system and dysfunction of them contributes to the initiation and progress of systemic lupus erythematosus (SLE), the roles of IRF4 in the SLE development becomes an important topic. Here we systemically discuss the biological characteristics of IRF4 in various immune cells and analyze the pathologic effects of IRF4 alteration in SLE and the potential targeting therapeutics of SLE. [ABSTRACT FROM AUTHOR]

Autoantibodies are abnormal antibodies which are generated by pathogenic B cells when targeting an individual's own tissue. Autoantibodies have been identified as a symbol of autoimmune disorders and are frequently considered a clinical marker of these disorders. Autoimmune diseases, including system lupus erythematosus and rheumatoid arthritis, consist of a series of disorders that share some similarities and differences. They are characterized by chronic, systemic, excessive immune activation and inflammation and involve in almost all body tissues. Autoimmune diseases occur more frequently in women than men due to hormonal impacts. In this review we systemically introduce and summarize the latest advances of various autoantibodies in multiple autoimmune diseases. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) are recently reported to play a more critical role in allergic diseases. We previously identified that mesenchymal stromal cells (MSCs) elicited therapeutic effects on allergic airway inflammation. Small extracellular vesicles (sEV) derived from MSCs possess striking advantages including low immunogenicity and high biosafety, and is extremely promising cell-free therapeutic agents. However, the effects of MSC-sEV on ILC2s are still unclear. Additionally, scalable isolation protocols are required for the mass production of homogenous MSC-sEV especially in clinical application. We previously reported that induced pluripotent stem cells-derived MSCs were the ideal cellular source for the large preparation of MSC-sEV. Here we developed a standardized scalable protocol of anion-exchange chromatography for isolation of MSC-sEV, and investigated the effects of MSC-sEV on ILC2 function from patients with allergic rhinitis and in a mouse ILC2-dominant asthma model. The characterization of MSC-sEV was successfully demonstrated in terms of size, morphology and specific markers. Using flow cytometry and human Cytokine Antibody Array, MSC-sEV but not fibroblasts-sEV (Fb-sEV) were found to significantly inhibit the function of human ILC2s. Similarly, systemic administration of MSC-sEV but not Fb-sEV exhibited an inhibition of ILC2 levels, inflammatory cell infiltration and mucus production in the lung, a reduction in levels of T helper 2 cytokines, and alleviation of airway hyperresponsiveness in a mouse model of asthma. Using RNA sequencing, miR-146a-5p was selected as the candidate to mediate the above effects of MSC-sEV. We next revealed the uptake of ILC2s to MSC-sEV, and that transfer of miR-146a-5p in MSC-sEV to ILC2s in part contributed to the effects of MSC-sEV on ILC2s in vitro and in a mouse model. In conclusion, we demonstrated that MSC-sEV were able to prevent ILC2-dominant allergic airway inflammation at least partially through miR-146a-5p, suggesting that MSC-sEV could be a novel cell-free strategy for the treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) are an important immune cell population, playing a crucial role in regulating immune tolerance and preventing autoimmune diseases. These cells consist of various cell sub-populations and generally have an immunoregulatory or suppressive role against immune responses. They also have a different cell heterogeneity and each populations has own biological characteristics. Treg deficiency, reduction, instability, reduced vitality and dysfunction all account for multiple autoimmune diseases. In this review, we have systemically reviewed Treg classification, phenotypic features, regulation of Foxp3 expression, plasticity and stability of Treg as well as their relationship with several important autoimmune diseases. We particularly focus on why and how inflammatory and diet environments affect the functional capacity and underlying mechanisms of Treg cell populations. We also summarize new advances in technologies which help to analyze and dissect these cells in molecular levels in-depth. We also clarify the possible clinical relevance on application of these cells in patients with autoimmune diseases. The advantages and weaknesses have been carefully discussed as well. We also propose the possible approaches to overcome these weaknesses of Treg cells in complicate environments. Thus, we have displayed the updated knowledge of Treg cells, which provides an overall insight into the role and mechanisms of Treg cells in autoimmune diseases. • Regulatory T cells(Treg) play a crucial role in regulating immune tolerance and preventing autoimmune diseases. • Clarify Treg classification, phenotypes, plasticity, stability and their relevance with autoimmune diseases is important. • New advances in technologies help to analyze and dissect Treg in molecular levels in-depth. [ABSTRACT FROM AUTHOR]

• IL-33 and its receptors have convincing clinical value for autoimmune diseases. • IL-33/ST2 axis mainly plays a detrimental role in a wide range of autoimmune diseases, although it has anti-autoimmune bioeffects. • IL-33/ST2 axis promotes autoimmune diseases by regulating the balance between Th1/Th17 cells and Tregs. • IL-33/ST2-mediated type 2 immune responses are equally important for the regulation of disease development. Autoimmune diseases (ADs), which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T effector (Th)1/Th17 cells and T regulatory cells. Interleukin (IL)-33, a member of the IL-1 family, induces inflammatory disease development by mediating type 2 immune responses. Recently, IL-33/ST2 axis was reported to induce autoimmunity involving Th1 and Th17 cells. In this review, we focus on the expression, regulation and function of IL-33/ST2 pathway in the context of autoimmune disorders. We discuss the clinical potential of this signaling pathway in predicting disease activity and severity and offer possible future therapeutic alternatives. [ABSTRACT FROM AUTHOR]

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression. [Display omitted] • ITK activation is elevated in RA patients. • The ITK inhibitor alleviates collagen-induced arthritis and reduces antigen-specific antibody production. • ITK inhibition interferes with Tfh cell generation. • ITK inhibition rebalance Th17 and Treg cells by regulating Foxo1 translocation. • Dihydroartemisinin is identified as a potential ITK inhibitor that holds promise for treating RA. [ABSTRACT FROM AUTHOR]

• IL-37 exhibits protective effect in allergic diseases, such as asthma, allergic rhinitis and allergic dermatitis. • IL-37 is a likely target for the treatment of allergic diseases. • IL-37 functions extracellular effect by forming a complex with IL-18Rα and relies on Smad3 to exert intracellular effect. • IL-37 plays an anti-allergic role by regulating the balance between Th1 and Th2 cells. Allergic diseases are ubiquitous diseases with detrimental effects on the quality of life of people worldwide. Common allergic diseases include asthma, allergic rhinitis (AR) and allergic dermatitis (AD). Recently, studies have shown that interleukin (IL)-37, a novel cytokine in the IL-1 family, exhibits broad protective properties in various diseases, such as autoimmune diseases and cancer. IL-37 displays its anti-inflammatory effect on diseases by curbing innate and acquired immunity as well as inflammatory reactions. IL-37 functions by forming a complex with IL-18Rα and IL-1R8 extracellularly and can be translocated to the nucleus upon forming a complex with mothers against decapentaplegic homolog 3 (Smad3) intracellularly, thereby affecting gene transcription and signaling pathway activation. In addition, increasing evidence confirms that IL-37 expression is aberrant in asthma, AR and AD, which indicates that IL-37 may also play essential roles in allergic diseases. Furthermore, accumulating data obtained from recombinant IL-37 (rIL-37)-treated mice and from IL-37 transgenic (IL-37tg) mice suggest a protective role for IL-37. This review will detail the role of IL-37 in the occurrence and development of allergic diseases and discuss the potential of IL-37 as a therapeutic target in allergic diseases. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • IL-13 is not a pure Th2 cytokine, but that it is also produced by Th1, Th17, ILC2 cells, etc. and acts on a variety of immune and non-immune cells. • IL-13 not only regulates the balance of Th1, Th17 and Treg cells but also takes an important role in immunity, inflammation and fibrosis. • It is important to understand the role of IL-13 in autoimmune and non-Th2 inflammatory diseases in which the source might not be the Th2 cells. • IL-13 exerts a key role in the development and pathogenesis of autoimmune disease, and may be a promising therapeutic target. Abstract Interleukin-13 (IL-13) was previously thought to be a redundant presence of IL-4, but in recent years its role in immunity, inflammation, fibrosis, and allergic diseases has become increasingly prominent. IL-13 can regulate several subtypes of T helper (Th) cells and affect their transformation, including Th1, Th2, T17, etc. , thus it may play an important role in immune system. Previous studies have revealed that IL-13 is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), ulcerative colitis (UC), type 1 diabetes (T1D), sjogren's syndrome (SS), etc. In this review, we will briefly discuss the biological features of IL-13 and summarize recent advances in the role of IL-13 in the development and pathogenesis of autoimmune diseases. This information may provide new perspectives and suggestions for the selection of therapeutic targets for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14 days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas. Furthermore, NaB treatment decreased the frequency and number of Th17 cells and increased the frequency and number of T regulatory (Treg) cells in both draining lymph nodes and spleens of EAU mice. In vitro , NaB treatment directly converted the differentiation of naive T cells from Th17 cells toward Treg cells. Mechanistically, the NaB-mediated inhibition of Th17 cell differentiation may occur via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/interleukin-6 receptor pathway. Moreover, the NaB-mediated inhibition on Th17 cell differentiation and uveitis were abrogated when an HO-1 inhibitor, SnPP, was used. These findings suggest that NaB inverts the differentiation of Th17 cells toward Treg cells and attenuates experimental autoimmune uveitis by modulating the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Allergic diseases, which affect up to 20–30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro . Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. In vivo , our results demonstrated that treatment with doxycycline significantly attenuated clinical symptoms of mouse models of experimental allergic conjunctivitis (EAC) with a significant decrease in inflammatory cell frequency, IgE production, histamine release, and a decrease in TNF-α and IL-4 production. Using mouse models of MCs-dependent passive systemic anaphylaxis (PSA), we further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Furthermore, our results showed that doxycycline significantly attenuate histamine-induced systemic anaphylaxis-like reaction (HISA) with a significantly downregulation of PI3K/Akt/eNOS/VE-cadherin pathway. The doxycycline-mediated anti-allergy effects during EAC, PSA and HISA were abrogated when an Akt activator, SC79, was administered. These findings suggest that doxycycline inhibits B cell, MC and histamine function and attenuates experimental allergic conjunctivitis and systemic anaphylaxis by possible modulating the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Abstract: B cell-activating factor belonging to the TNF family (BAFF) exerts its pathogenic role in supporting the survival and proliferation of B cells, regulating class switch recombination as well as the selection of autoreactive B cells. Overexpression of BAFF induces a dramatic expansion of activated B cells, particularly marginal zone B cells, as well as hypergammaglobulinemia, autoantibody production and immune complex deposition. However, in addition to its effect on B cells, recent work has also demonstrated that BAFF can promote T cell activation, proliferation and differentiation. In this review, we have discussed the recent progress on the function and role of BAFF on T cells and T cell-mediated diseases. [Copyright &y& Elsevier]

Abstract: CD4(+) T helper (Th) cells are central to the modulation of immune responses, with distinct effector subsets defined by their lineage-specific transcription factor expression, cytokines production and immune function. Th9, one of the recently defined subsets of Th cells, are identified by the potent production of interleukin-9 (IL-9). Recent studies have indicated that Th9 cells and IL-9 are closely associated with several autoimmune diseases, such as systemic lupus erythematosus (SLE), experimental autoimmune encephalitis (EAE) and systemic sclerosis (SSc). In the present review, we will briefly discuss the biological features of Th9/IL-9 and summarize recent advances focusing on the role of Th9/IL-9 in the pathogenesis and possible treatment in autoimmune diseases using anti-Th9 target. [Copyright &y& Elsevier]

Retinal ischemia-reperfusion injury (IRI) is one of the main pathogenic mechanisms of glaucoma, which are largely unknown, including neuroinflammation and neuronal death in the pathological process. In our previous studies, mesenchymal stem cells (MSCs) have been reported to play anti-inflammatory and neuroprotective roles. Additionally, conditioned culture medium (CM) of MSCs stimulated by TNF-α have achieved better antiallergic effects in an experimental allergic conjunctivitis mouse model. However, there is an urgent need for cell-free therapy approaches, like exosomes, to reduce the side effects of autoimmunity. The present study aimed to elucidate the pathways involving TNF-α-stimulated gingival MSC (GMSC)-exosomes (TG-exos), in modulating inflammatory microglia and alleviating apoptosis. In this study, exosomes from the CM of GMSCs were isolated by ultracentrifugation and were injected into the vitreous of mice. The results showed that intraocular injection of TG-exos into mice with IRI notably reduced inflammation and cell loss than that with G-exos (GMSC-exosomes). Similar results were observed in vitro. Additionally, with the microRNA (miR) arrays, it was found that miR-21-5p acted as a crucial factor in TG-exos for neuroprotection and anti-inflammation. Following target prediction and dual-luciferase assay suggested that miR-21-5p played a role by combining with programmed cell death 4 (PDCD4), which was regulated by the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) as a competing endogenous RNA (ceRNA). This study demonstrates a new therapeutic pathway for neuroprotection against IRI by delivering miR-21-5p-enriched exosomes through MEG3/miR-21-5p/PDCD4 axis and paves the way for the establishment of a cell-free therapeutic approach for glaucoma. [ABSTRACT FROM AUTHOR]