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BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response. METHODS: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1-/-mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion. RESULTS: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1-/-mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PDL1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PDL1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH. CONCLUSIONS: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH. [ABSTRACT FROM AUTHOR]

IFNγ-producing ex-Th17 cells ['Th1/17'] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of patients with Crohn's disease [CD]. Human Th17 cells expressing CCR5 ['pTh17'] co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17 cells. pTh17 cells, but not Th1/17 cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5[-]Th17 cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17 cells in the intestine. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli [AIEC], but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from dendritic cells [DC]. Intestinal CCR5+Th1/17 cells responded instead to cytomegalovirus and were reduced in ulcerative colitis [UC], suggesting an unexpected protective role. In conclusion, we identified an IL-23–inducible subset of human intestinal Th17 cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role. [ABSTRACT FROM AUTHOR]

Background The development of Crohn's disease [CD] involves immune cell signalling pathways regulated by epigenetic modifications. Aberrant DNA methylation has been identified in peripheral blood and bulk intestinal tissue from CD patients. However, the DNA methylome of disease-associated intestinal CD4+ lymphocytes has not been evaluated. Materials and Methods Genome-wide DNA methylation sequencing was performed from terminal ileum CD4+ cells from 21 CD patients and 12 age- and sex-matched controls. Data were analysed for differentially methylated CpGs [DMCs] and methylated regions [DMRs]. Integration was performed with RNA-sequencing data to evaluate the functional impact of DNA methylation changes on gene expression. DMRs were overlapped with regions of differentially open chromatin [by ATAC-seq] and CCCTC-binding factor [CTCF] binding sites [by ChIP-seq] between peripherally derived Th17 and Treg cells. Results CD4+ cells in CD patients had significantly increased DNA methylation compared to those from the controls. A total of 119 051 DMCs and 8113 DMRs were detected. While hypermethylated genes were mostly related to cell metabolism and homeostasis, hypomethylated genes were significantly enriched within the Th17 signalling pathway. The differentially enriched ATAC regions in Th17 cells [compared to Tregs] were hypomethylated in CD patients, suggesting heightened Th17 activity. There was significant overlap between hypomethylated DNA regions and CTCF-associated binding sites. Conclusions The methylome of CD patients shows an overall dominant hypermethylation yet hypomethylation is more concentrated in proinflammatory pathways, including Th17 differentiation. Hypomethylation of Th17-related genes associated with areas of open chromatin and CTCF binding sites constitutes a hallmark of CD-associated intestinal CD4+ cells. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) has various causes, including chromosomal abnormalities, a prethrombotic state, and abnormal uterine anatomical factors. However, in about 50% of cases, the cause remains unknown and is referred to as unexplained recurrent spontaneous abortion (URSA). The fetus is protected from rejection by the maternal system, acting as an allogeneic gene, and immune tolerance serves as a crucial mechanism. The Th17/Treg cell paradigm's emergence as a new subpopulation of CD4+ T cells, interacting with one another, plays an essential role in the immune microenvironment and the body's defense system. This Th17/Treg cell model helps to explain the pathology of recurrent miscarriage that could not be accounted for by the original immune mechanism based on the Th1/Th2 model. Furthermore, the plasticity of Th17 and Treg cells holds innovative significance in autoimmunity and abortion. This paper reviews the role of Th17/Treg cellular immune response in the maintaining normal pregnancy and understanding unexplained recurrent spontaneous abortion. • Th17/Treg cell balance in unexplained recurrent spontaneous abortion. • The plasticity of Th17 and Treg cells has innovative significance in abortion. • The immune cascade amplification regulatory network formed by immune cells. • Clinical application and treatment of unexplained recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Periodontitis is a multifactorial inflammatory disease mediated by the host immune response to dental plaque. Periodontitis is characterized by periodontal bone loss and loss of tooth support. Several studies have corroborated the infiltration of T lymphocytes in periodontitis and correlated the infiltration with chronic inflammation in a dysregulated T cell-mediated immune response. The complexity of the disease has prompted multiple studies aiming to understand T cell-mediated pathogenesis. Recent findings have demonstrated the pivotal role of helper T cells in many autoimmune diseases, such as rheumatoid arthritis, which has been conventionally correlated with periodontal bone loss. In contrast, the roles of helper T subsets, Th1, Th2, and particularly Th17, have not been explored. Th17-mediated pathogenesis is a significant aspect of the progression and therapy of periodontitis. In this review, we highlight the complex role of Th17 in the underlying pro-inflammatory cascades mediated by a repertoire of Th17-released molecules and their role in aggravated inflammation in periodontitis. We also summarize recent therapeutics targeting Th17 and related molecules, primarily to ameliorate inflammation and maintain periodontal care. • The significant role of Th17 cell subtype in periodontitis. • Cytokines and chemokines' role in pathogenesis. • Th17-targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections. [Display omitted] • GSH-regulated IL-22, but not IL-17 from Th17 cells, is vital for gut barrier integrity • GCLC expression in IBD patients correlates with gut integrity gene expression • Gclc controls mROS and mitochondrial ATP linked to PI3K/mTOR-driven IL-22 translation • ROS scavenging or T cell's IL-22 saves mutant mice from infection-induced lethality Bonetti et al. show that glutathione's (GSH) control of mitochondrial reactive oxygen species (ROS) in Th17 cells is critical to maintain intestinal barrier integrity during bacterial gastrointestinal infections. They highlight the connection between mitochondrial function and intestinal barrier integrity and identify a Th17 cell-intrinsic GSH/mitochondrial-IL-22 signaling axis as crucial for host protection. [ABSTRACT FROM AUTHOR]

• Strictosamide alleviates acute lung injury. • Strictosamide regulating Th17/Treg cells and gut microbiota. • The close relationship between gut microbiota and immune function in acute lung injury model mice. Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)- β. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors- γ t (ROR γ t) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota. [Display omitted] [ABSTRACT FROM AUTHOR]

Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in T H 17 cells may be beneficial in psoriasis. We found that Ca v 1.4, encoded by CACNA1F , was the only Ca v 1 calcium channel expressed in T H 17 cells. We sought to investigate the role of Ca v 1.4 expression in early T H 17-activation events and effector functions, as well as its association with T H 17 signature genes in lesional psoriatic (LP) skins. Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Ca v 1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Ca v 1.4 in T H 17 activation and effector functions in a 3-dimensional skin reconstruction model. CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4+ and CD4− cells from LP biopsies. Nicardipine, a Ca v 1 channel antagonist, markedly reduced inflammatory cytokine production by T H 17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Ca v 1.4 in T H 17 cells impaired cytokine production. Finally, Ca v 1 inhibition reduced the expression of the keratinocyte genes characteristic of T H 17-mediated psoriasis inflammation in human skin equivalents. Ca v 1.4 channels promote T H 17-cell functions both at the periphery and in inflammatory psoriatic skin. [ABSTRACT FROM AUTHOR]

Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated T H 17 cell immune responses. T H 17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of T H 17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is one of the most common noninfectious respiratory diseases caused by immunoglobulin E (IgE) response. Objective: The study sought to explore the relationship between lncRNA MIAT and miR-10b-5p and their interaction in the regulation of allergic phenotypes in allergic rhinitis (AR) mice. Methods: A mice model of AR was constructed using ovalbumin (OVA) sensitization. AR mice were treated with miR-10b-5p agomiR and LNA mediated lncRNA MIAT. The targeting relationship between MIAT and miR-10b-5p was analyzed by the ENCORI website and dual-luciferase reporter assay. The numbers of rubbing and sneezing of mice were counted. Hematoxylin-eosin (HE) staining visualized the eosinophils infiltration in nasal mucosa tissues of mice. The percentage of Th17 cells was quantitated by flow cytometry analysis. ELISA was used to detect the levels of serum OVA-specific IgE, the Th12 cytokine IL-4, and inflammatory cytokines (IL-6, IL-17). Results: MIAT was up-regulated in the nasal mucosa of AR mice, while miR-10b-5p was down-regulated. MIAT directly suppressed miR-10b-5p expression in AR mice. The numbers of rubbing and sneezing, the percentage of Th17 cells, and the levels of OVA-specific IgE, IL-4, IL-6, and IL-17 in AR mice were decreased by miR-10b-5p overexpression, which was reversed by MIAT overexpression. The eosinophils infiltration in AR mice was inhibited by miR-10b-5p overexpression, which was also reversed by MIAT overexpression. Conclusion: The present study demonstrates that MIAT overexpression Promotes allergic inflammation and symptoms by activating Th17 immune response via miR-10b-5p inhibition. [ABSTRACT FROM AUTHOR]

The uterus is an organ for raising the fetus, and its lumen is lined by the endometrium. The endometrium is an important site for the implantation and maturation of fertilized eggs. The endometrium undergoes repetitive proliferation, maturation (decidualization), and exfoliation changes every menstrual cycle. At the same time, the number and type of endometrial immunocompetent cells vary during the menstrual cycle. At the implantation stage, the immunocompetent cells occupy approximately half of the endometrial cells. Immunocompetent cells normally eliminate pathogenic microorganisms to protect the body; however, they also promote immune tolerance to accept the fetus during pregnancy. The immunocompetent cells in the uterus can perform both these functions. With the establishment of pregnancy, stimuli from the trophoblast (placenta) and fetus can also change the immune environment of the uterus, and pregnancy can be maintained only when the immune system is well adapted to the stimuli of some hormones and the fetus. Immunity for the establishment of pregnancy is not simple because multiple immunocompetent cells are involved in establishing and maintaining pregnancy. To understand the immune mechanisms associated with the establishment of pregnancy, we have to learn about each immune cell. This review, therefore, discusses the roles and distribution of the immunocompetent cells inside the uterus during menstruation and early pregnancy. [ABSTRACT FROM AUTHOR]

Background and Aims Dysregulated T cell responses contribute to the pathogenesis of inflammatory bowel disease [IBD]. Because vitamin D [vitD] deficiency is a risk factor for adverse disease outcomes, we aimed to characterize the impact of vitD on intestinal and peripheral T cell profiles. Methods T cells were isolated from peripheral blood and intestinal biopsies of IBD patients, incubated with vitD and characterized by flow cytometry. To translate these in vitro findings to the clinic, serum vitD concentrations and clinical outcomes were correlated with T cell phenotype and function in a prospective patient cohort. Results Incubation of peripheral and intestinal T cells with 1,25(OH)2-vitD resulted in strongly reduced frequencies of pro-inflammatory CD4+ and CD8+ T cells producing interferon γ [IFNγ], interleukin-17 [IL-17], IL-22, IL-9 and tumour necrosis factor [TNF]. Univariable analysis of 200 IBD patients revealed associations of vitD deficiency with non-compliant vitD intake, season of the year and anaemia in Crohn's disease [CD] as well as disease activity in ulcerative colitis [UC]. Ex vivo immunophenotyping revealed that CD4+ and CD8+ T cell subsets were not substantially altered in vitD-deficient vs vitD-sufficient patients while regulatory T cell frequencies were reduced in UC and non-smoking CD patients with vitD deficiency. However, normalization of serum vitD concentrations in previously deficient CD patients resulted in significantly reduced frequencies of CD4+ T cells producing IFNγ, IL-17 and IL-22. Conclusion vitD exerts profound anti-inflammatory effects on peripheral and intestinal CD4+ and CD8+ T cells of IBD patients in vitro and inhibits TH1 and TH17 cytokine production in CD patients in vivo. [ABSTRACT FROM AUTHOR]

The purpose of the investigation was to evaluate whether the application of compression forces exerted on the periodontal ligament during orthodontic movement is reflected at the level of interleukin (IL)-17 and IL-23. The gingival crevicular fluid (GCF) samples from the compression sites of 32 molars from 16 patients prescribed with modified Hyrax appliance were collected. The GCF were analyzed for IL-17, IL-23, and IL-1β (Control) at baseline and at 1, 7, and 14 days of active wear of the appliance. Orthodontic forces resulted in increased levels of IL-17 and IL-23 in the GCF, which were statistically significant at 7 days of force application at compression sites. At day 14, levels decreased to baseline; IL-1β levels (positive control) were more elevated at all times after force application. IL-17 and IL-23 levels were significantly lower than IL-1β, and undetectable in some samples. Upregulation of IL-17 and IL-23 occurred in response to the force application in compression sites. Monitoring the levels of inflammatory mediators might be a clinically useful procedure, as they may help to define optimal forces to produce the most rapid tooth movement. [ABSTRACT FROM AUTHOR]

Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H 2 S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H 2 S production. Here, we show that apoptosis-deficient MRL/ lpr (B6.MRL-Faslpr/J) and Bim−/− (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H 2 S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H 2 S. Moreover, apoptotic cells and vesicles (apoVs) express key H 2 S-generating enzymes and generate a significant amount of H 2 S, indicating that apoptotic metabolism is an important source of H 2 S. Mechanistically, H 2 S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H 2 S homeostasis and the unique role of H 2 S in regulating Th17 cell differentiation via sulfhydration of Sep15C38. [Display omitted] • Apoptotic cells are an important resource providing endogenous H 2 S • Apoptotic-cell-generated H 2 S maintains immune homeostasis • H 2 S inhibits the aberrant Th17 cell differentiation via sulfhydration of Sep15 • H 2 S from apoptotic cells ameliorates murine systemic lupus erythematosus phenotypes H 2 S is an important endogenous regulator of the immune system. Ou et al. demonstrate that apoptotic cells and vesicles produce H 2 S to maintain immune homeostasis and inhibit Th17 cell differentiation via sulfhydration of Sep15C38. [ABSTRACT FROM AUTHOR]

Background and Aims Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn's disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. Results CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells Conclusions CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course. [ABSTRACT FROM AUTHOR]

• The serum levels of IL-33 are significantly increased in myasthenia gravis patients. • The frequency of Th17 cells is higher in MG patients. • The expression levels of TSLP are decreased significantly in myasthenia gravis patients. • Increased serum IL-33 levels positively correlate with the upregulation of IL-17A levels. • IL-33 is a potential biomarker for myasthenia gravis. Myasthenia gravis (MG) is an archetypal autoimmune disorder of the neuromuscular junction. The imbalance of inflammatory cytokines are involved in the pathogenesis of MG. IL-33, a member of the IL-1 family, plays a key immune-modulation role in several autoimmune disease. However, its regulatory role in MG remains unclear. Here, we demonstrated that IL-33 expression in the serum of MG patients was significantly increased. We further proved that the serum levels of IL-33 were significantly negative correlated with the expression levels of TSLP. Increased serum IL-33 levels positively correlated with the upregulation of IL-17A levels and the quantitative myasthenia gravis (QMG) score in MG patients. Our findings indicate that IL-33 plays a potent immuno- enhancing role in the pathogenesis of MG by downregulating TSLP, consequently affecting the development of Th17 cells in MG. [ABSTRACT FROM AUTHOR]

CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of specific master transcription factors, and the resulting effector cell phenotypes as defined by expression of signature cytokines. However, recent studies assessing the expression of gene modules in single CD4 T cells, rather than expression of one or a few signature genes, have provided a more complex picture in which the canonical model does not fit as cleanly as proposed. Here, we review the concepts of lineage commitment, plasticity and functional heterogeneity in the context of this greater complexity. We then apply our current understanding of CD4 T cell subsets to discuss outstanding questions regarding follicular helper T cells and follicular regulatory T cells with respect to their shared features with other known CD4 T cell subsets. [ABSTRACT FROM AUTHOR]

Purpose: Sodium chloride (NaCl) has been proposed as a driving factor in autoimmune diseases through the induction of pathogenic CD4+ T helper cells that produce interleukin-17 (Th17 cells). This study investigated the effects of NaCl on inflammatory arthritis in mice and humans. Materials and Methods: Collagen-induced arthritis (CIA) mice were fed a normal or high-salt diet ad libitum, and clinical and histologic features of arthritis were evaluated. The proportion of Th17 cells in the spleens of CIA mice fed a normal or high-salt diet was evaluated by flow cytometry, and the expression of IL-17 in joints and intestines was determined by immunohistochemical staining. We also analyzed the effect of NaCl on Th17 differentiation from peripheral blood monocytes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and evaluated the contents of sodium and IL-17 in the synovial fluid of RA and OA patients. Results: NaCl increased murine and human Th17 cell differentiation in a dose-dependent manner. Clinical and histological arthritis was more severe in the high-salt-fed CIA mice, compared to control CIA mice. The proportion of Th17 cells among splenocytes was higher in CIA mice fed a high-salt diet. Expression of synovial and intestinal IL-17 was also higher in high-salt-fed CIA mice. Comparison of synovial fluid between RA patients and OA patients revealed that Na+ and IL-17 were more abundant in RA synovial fluid. Conclusion: This study suggests that NaCl can aggravate arthritis by affecting Th17 differentiation. Accordingly, limiting salt intake may be helpful for treating inflammatory arthritis, such as RA. [ABSTRACT FROM AUTHOR]

Cytokines and chemokines have a fundamental role in the maintenance of inflammation and bone response, which culminate in the development of chronic periapical lesions. Regulatory (Treg) and Th17 cytokines play a key role in regulating the immune response involved in this process. The aim of this study was to investigate the role of Treg and Th17 cells in chronic inflammatory periapical disease, by comparing the expression of the immunoregulatory mediators TGF-β, IL-10, CCL4, and the proinflammatory IL-17 and CCL20 in the periapical tissue of teeth with pulp necrosis, with and without associated chronic lesions. Eighty-six periapical tissue samples were obtained from human teeth. The samples were divided into three groups: pulp necrosis with a periapical lesion (n=26); pulp necrosis without a periapical lesion (n=30), and control (n=30). All samples were submitted to histopathological analysis and cytokine and chemokine measurement through ELISA. Statistical analyses were done with Kruskal-Wallis and Mann-Whitney tests and Spearman correlation. The group with pulp necrosis and a periapical lesion showed a higher expression of CCL4 and TGF-β in comparison with pulp necrosis without a lesion. CCL20 was higher in the group with a periapical lesion when compared to the control. In all groups there was a weak positive correlation between IL-17/CCL20, IL-10/CCL4, and IL-17/TGF-β. Both types of cytokines, pro-inflammatory and immunoregulatory, occur simultaneously in periapical tissue. However, a rise in immunosuppressive cytokines and chemokines (CCL4 and TGF-β) in periapical lesions suggests a role of these cytokines in stable periapical disease. [ABSTRACT FROM AUTHOR]

Abstract Given the impossibility to study the lung immune response during Mycobacterium tuberculosis -latent infection, and consequently, the mechanisms that control the bacterial load, it is reasonable to determine the activation of local immunity in the early phase of the infection. The phosphatidylinositol-3-kinase gamma enzyme (PI3Kγ) is involved in the leukocyte recruitment, phagocytosis and cellular differentiation, and therefore, it is considered a promising target for the development of immunotherapies for chronic inflammatory diseases. Mice genetically deficient in PI3Kγ (PI3Kγ−/-) or WT (Wild Type) were evaluated 15 days post-infection. The enzyme deficiency improved the resistance against infection, increased the frequency of CD4+IL-17+ cells, the production of IL-17 as well as the gene and protein expression of molecules associated with Th17 cell differentiation and neutrophil recruitment. Our findings show, for the first time, the participation of the PI3Kγ in vivo in the M. tuberculosis -infection, and suggest an association of Th17 cells with protection in the early phase of tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatoryskindiseaseswith a central role of T-cell-derived IL-22 in their pathogenesis. Although prostaglandin (PG) E2 is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. Objectives: We sought to investigate whether PGE2 has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. Methods: T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE2 in IL-22 production. The involvement of PGE2 receptors and their downstream signals was also examined. The effects of PGE2 were evaluated by using the oxazolone-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated by using genomic profiling in human lesional AD skin. Results: PGE2 induces IL-22 from T cells through its receptors, E prostanoid receptor (EP) 2 and EP4, and involves cyclic AMP signaling. Selective deletion of EP4 in T cells prevents hapteninduced IL-22 production in vivo, and limits atopic-like skin inflammation in the oxazolone-induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately upregulated in human AD lesional skin but were at less than significant detection levels after corticosteroid or UVB treatments. Conclusions: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells. [ABSTRACT FROM AUTHOR]

Background Multiple reports have described the proportion of Th17 cells in peripheral blood and serum levels of Th17-related cytokines in patients with multiple sclerosis (MS). To clarify the status of Th17 cells and Th17-related cytokines in MS patients, we did a meta-analysis of the results published previously to assess the levels of peripheral Th17 cells and serum Th17-related cytokines in patients with MS. Methods We searched Embase, PubMed, Cochrane, Web of Knowledge, FDA.gov, and Clinical Trials.gov systematically for studies reporting the proportion of Th17 cells and the serum levels of Th17-related cytokines (IL-17, IL23) in MS patients. Our main endpoints were the proportion of Th17 cells among CD4 + T cells in peripheral blood (PB), serum IL-17 levels, and serum IL-23 levels. We assessed pooled data by using a random-effects model. It has been registered at International Prospective Register of Systematic Reviews (PROSPERO) (number CRD42017059113). Results Of 560 identified studies, a total of 12 studies were selected in our analysis. Compared with control subjects, MS patients had a higher proportion of Th17 cells [1.37, (0.53, 2.21)] in PB, an elevated levels of serum IL-17 [2.48, (1.25, 3.71)] and an increased IL-23 levels in serum [2.29, (0.58, 4.00)]. Conclusion Under random effect model of meta-analysis, the data showed that the proportion of Th17 cells in PB and levels of serum IL-17 and IL-23 increased among MS patients compared to control subjects. This result demonstrated that Th17 cells and Th17-related cytokines may be involved in the pathogenic mechanisms of MS. [ABSTRACT FROM AUTHOR]

Objective Increasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive. Methods We looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients. A wide array of ex vivo , in vitro , and in silico methods were employed to study enzyme activity, gene expression, subcellular localization, protease identification, surface expression, and protein–protein interactions. Results We show that circulating immune cells, particularly CD4+ T cells, served as an important source for the increase in plasma DPP4 activity in T2DM. Moreover, we found kallikrein-related peptidase 5 (KLK5) as the enzyme responsible for cleaving DPP4 from the cell surface by directly interacting with the extracellular loop. Expression and secretion of KLK5 is induced in CD4+ T cells of T2DM patients. In addition, KLK5 shed DPP4 from circulating CD4+ T helper (Th)17 cells and shed it into the plasma of T2DM patients. Similar cleavage and shedding activities were not seen in controls. Conclusions Our study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM. [ABSTRACT FROM AUTHOR]

Résumé L’artérite à cellules géantes (ACG) et l’artérite de Takayasu sont deux vascularites granulomateuses affectant les vaisseaux de gros calibre dont la cause exacte n’est pas connue. Néanmoins, les mécanismes physiopathologiques impliqués au cours de l’ACG sont de mieux en mieux identifiés et ont permis l’émergence de nouvelles cibles thérapeutiques comme le blocage de la signalisation de l’interleukine-6 (IL-6). Le facteur déclenchant de ces vascularites n’est pas connu mais l’hypothèse, jamais confirmée à ce jour, d’un agent infectieux activant les cellules dendritiques de l’adventice est privilégiée. Cette activation de la réponse immunitaire innée permet le recrutement et l’activation des lymphocytes T CD4 qui se polarisent en lymphocytes Th1 et Th17. Par la suite, sont recrutés des lymphocytes T CD8 et des monocytes/macrophages qui vont amplifier la réponse inflammatoire locale et contribuer, avec les cellules résidentes de la paroi artérielle, à la destruction et au remodelage de la paroi artérielle conduisant in fine à l’occlusion de la lumière vasculaire à l’origine des complications ischémiques de ces pathologies. Cette revue décrit les récentes avancées dans la connaissance de la physiopathologie de l’ACG et les similitudes entre ACG et pseudopolyarthrite rhizomélique (PPR). Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are two granulomatous vasculitis affecting large arteries. Their exact pathogenesis is not fully understood but major progresses have been done last years, especially in the knowledge of the pathogenesis of GCA, thus providing new therapeutic targets like the inhibition of the interleukin-6 (IL-6) pathway. The trigger of these diseases is not clearly identified but it is thought that an infectious agent could activate and lead to the maturation of dendritic cells that are localized in the adventitia of arteries. Then, CD4 T cells are recruited and polarize into Th1 and Th17 cells that produce IFN-γ and IL-17, respectively. Following IFN-γ secretion, CD8 T cells and monocytes are recruited, monocytes differentiate into macrophages that form giant cells. With the contribution of resident cells, immune cells trigger the destruction and the remodeling of the arterial wall, thus leading to the progressive occlusion of the arterial lumen which is responsible for ischemic symptoms of GCA. In this paper, we review recent progresses in the knowledge of the pathogenesis of GCA with a particular focus on the links with polymyalgia rheumatica. [ABSTRACT FROM AUTHOR]

Ten years ago, we discovered that microbiota composition controls intestinal T cell homeostasis and alters T cell responses of mice in different animal facilities. Here I discuss how these discoveries, reported in Cell Host & Microbe in 2008, came to be and contributed to our understanding of microbiota immune effects. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We conducted this study to analyze the effects of nucleoside analogues in the treatment of hepatitis B cirrhosis and its effect on Th17 cells. PATIENTS AND METHODS: 120 patients were randomly divided into lamivudine combined with adefovir dipivoxil group (combined group) and entecavir group. There were 59 cases in the combined group and 59 cases in entecavir group. The combined group was administered lamivudine 100 mg/d + adefovir dipivoxil 10 mg/d and entecavir group was administered entecavir 0.5 mg/d. The treatment was continued until there was virus negativity and it maintains for at least 3 months. RESULTS: The treatment effects were compared. We compared the average rate of viral clearance time and virus clearance of two groups of patients; the difference was not statistically significant (p>0.05). The relapse rate after a negative test of entecavir group was lower than that of the combined group (p<0.05). Before and after treatment, the levels of TBIL, ALT and ALB in the two groups were compared; the differences were not statistically significant (p>0.05). The Th17 cell proportion and the level of IL-17 after treatment of the entecavir group were lower than those before treatment. The combined group exhibited no change, and the entecavir group was lower than combined group; the differences were statistically significant (p<0.05). CONCLUSIONS: Therefore, the effects of the combination of lamivudine and adefovir dipivoxil is the same as single entecavir treatment of hepatitis B cirrhosis suppression of viral replication. It does not increase liver injury and the antiviral effects of entecavir may be related to inhibition of the expression of Th17 cells and effector molecules IL-17. [ABSTRACT FROM AUTHOR]

The process involved in periapical lesions, which occur as an outcome of pulpal necrosis, is regulated by the immune system including regulatory T cells (Treg) and T helper 17 cell (Th17) responses. The objective of this study was to conduct a frequency systematic review to determine the presence of Treg/Th17 responses and the influence of these cells in the progression of chronic inflammatory periapical lesions in humans. A systematic computerized search was carried out in Pubmed, Medline, Web of Science and Scopus electronic databases from their date of inception through the first week of May 2017. In addition, the reference lists of the included articles and the grey literature were hand-searched. Articles that evaluated the presence and influence of Treg/Th17 in the progression of human periapical lesions were included. Study selection and the quality assessment of the included articles (using the Newcastle-Ottawa scale) were carried out by two authors. Fifty-seven titles/abstracts were screened and eight studies met the eligibility criteria and were included in this systematic review. The included studies showed large variation in the type of periapical lesion assessed, mean age, age range, type of experiment and findings regarding the participation of Th17 and Treg in the status of inflammatory periapical lesions. The studies showed the involvement of Treg in the modulation of the inflammatory response in radicular cysts and periapical granulomas. This systematic review highlights the relationship between Treg and Th17 acting in a subtle balance inhibiting or promoting the progression of human periapical lesions. [ABSTRACT FROM AUTHOR]

In healthy individuals and in patients with invasive aspergillosis, Aspergillus-specific T-cells in peripheral blood display mainly a Thelper1 phenotype. Although in other fungal infections Thelper17 immunity is important, it was suggested that in aspergillus infection Thelper17 cells do not play a role or may even be detrimental.Objectives: To compare the cytokine profiles of Aspergillus-specific CD4+ T-cells in peripheral blood and in the lung. To investigate the Thelper phenotype at the primary location of A. fumigatus exposure.Methods: Lung-derived T-cells and peripheral blood T-cells from COPD-patients were stimulated with overlapping peptides of 6 A. fumigatus proteins. Aspergillus-specific T-cells were identified on the basis of the activation marker CD154 and production of TNFα. In addition, production of the cytokines IFNγ, IL-17, IL-4 and IL-5 by the Aspergillus-specific T-cells was measured.Results: The majority of lung-derived Aspergillus-specific T-cells displayed a Thelper17 phenotype, and only low percentages of cells produced IFNγ. In contrast, in the peripheral blood of COPD patients Aspergillus-specific T-cells displayed a Thelper1 phenotype, similar as peripheral blood-derived Aspergillus-specific T-cells from healthy individuals.Conclusions: These data demonstrate that in A. fumigatus infection, similar as in other fungal infections, Thelper17 cells may play a more important role in the immune response than was appreciated until now. [ABSTRACT FROM AUTHOR]

To discuss the expression of T helper cell 17 (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in peripheral blood (PB) of patients with acute leukemia (AL), and to explore the relationship between them and disease prognosis. 40 patients diagnosed with acute leukemia in The First Affiliated Hospital of Zhengzhou University from July 2012 to August 2014 were selected as the observation group. Meanwhile, 40 healthy people were taken as the control group. Flow Cytometry Method (FCM) was used to detect the level of Th17 cells and CD4+ CD25+ Foxp3+ cells in peripheral blood of the two groups, and enzyme-linked immuno sorbent assay (ELISA) method was used to test the level of IL17 and TGF-β in peripheral blood of two groups; reverse transcription-polymerase chain reaction (RT-PCR) was adopted to analyze the mRNA levels of RORγT and Foxp3 in peripheral blood. In addition, we examined the levels of Th17 and CD4+ CD25+ Foxp3+ cells and associated factor levels in patients with remission after AL chemotherapy. the Th17 cells (CD3+ CD4+ IL-17+) in acute leukemia patients accounted for (1.51±0.27)%, which was significantly higher than that of control group (0.36±0.23)%, with statistical significance (t=20.51, P<0.001); the percentage of CD4+ CD25+ Foxp3+ cells in AL patients was (3.37±0.48)%, which was significantly higher than that of control group of (1.26±0.27)%, with statistical significance (t=24.23, P<0.001); the serum levels of IL-17 and TGF-β in AL patients were (28.12±6.33) pg/ml and (38.41±8.44) pg/ml respectively, which were all significantly higher than that of control group of (14.41±6.21) pg/ml and (24.49±7.42) pg/ml, with statistical significance (t=7.83, P<0.001; t=7.83, P<0.001); the RORγT mRNA and Foxp3 mRNA levels in AL patients were all significantly higher than that of control group, with statistical significance (t=12.27, P<0.001; t=7.89, P<0.001). In addition, compared with before chemotherapy, the levels of Th17 cells and CD4+ CD25+ Foxp3+ cells, and the serum levels of IL-17 and TGF-β in acute leukemia patients all decreased significantly after 6 months of chemotherapy, and the difference was statistically significant (P<0.001). Th17 cells, CD4+ CD25+ Foxp3+ cells and their secretory proteins IL-17, TGF-β and transcription factors were significantly increased in AL patients. Therefore, regular detection of peripheral blood Th17 and Treg cells, as well as their secretory proteins are useful for monitoring the immune status and prognosis of patients. [ABSTRACT FROM AUTHOR]

Takayasu's arteritis (TA) is a granulomatous large vessel vasculitis more common in India. We review recently published literature in this field over the past year. Multiple reports based on genetic data and studies in peripheral blood of patients with TA suggest perturbation of the Th17-IL17 axis in these patients, which may be amenable to targeted therapy. Abnormal pro-atherogenic lipid profiles in TA (increased LDL-C and Apo A1, decreased HDL-C and Apo-B) may drive disease process in TA. Clinically inactive TA at diagnosis has been shown to relapse and progress angiographically on follow-up. TA seems to be associated with poorer pregnancy outcomes. Recent papers on 18 fluoro-deoxyglucose positron emission tomography and contrast-enhanced magnetic resonance angiographic scoring of TA suggest the need to incorporate these techniques into clinical assessment tools to delineate the actual extent of vascular involvement in TA. Recent advances in therapeutics indicate that leflunomide may be an effective disease-modifying agent in TA, whereas a large retrospective French cohort suggests relatively safety and efficacy of biologic agents targeting tumour necrosis factor alpha or interleukin-6 in patients with TA. [ABSTRACT FROM AUTHOR]

Purpose: The ketogenic diet (KD) is an effective treatment for intractable epilepsy (IE), however the therapeutic mechanism is still unclear. This study was designed to investigate T helper type 17/regulatory T cell (Th17/Treg) levels in children with IE and age-matched healthy controls following KD.Method: Circulating levels of Th17/Treg cells were analyzed by flow cytometry. Plasma concentration of interleukin (IL)-17 was measured by cytometric bead array assay. Real-time PCR was performed to measure mRNA levels of mTOR, HIF1α and Th17/Treg associated factors in purified CD4(+)CD25(+) T and CD4(+)CD25(-) T cells.Results: By one-way ANOVA, the proportion of circulating Th17 cells and expression of IL-17A and RORγt were significantly higher (P<.05), while the proportion of circulating Tregs and expression of Foxp3, GITR, CTLA-4 were significantly lower (P<.05) in IE patients than healthy subjects. However, these alternations were reversed following KD (P<.05). In CD4(+)CD25(+) T and CD4(+)CD25(-) T cells mTOR and HIF1α expression were significantly higher in IE patients (P<.05), however KD reduced mTOR and HIF1α expression (P<.05). The plasma IL-17A concentrations were higher in IE patients than controls (P<.05). KD partially reduced IL-17A levels (P<.05).Conclusion: Our results suggest that Th17/Treg imbalance is characteristic of childhood IE, and may contribute to IE pathogenesis. KD treatment is able to correct this imbalance, probably via inhabiting the mTOR/HIF-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The prevalence of psychological symptoms such as anxiety and depression among patients with asthma is high. Both asthma and psychological symptoms are characterized by immune inflammation in which CD4+ T cells play a role. Objective: To investigate whether T-helper (Th) 1, Th2, and Th17 cells imbalance exists in patients with asthma and with and in patients without psychological symptoms. Methods: The messenger RNA (mRNA) expression of T-box 21 (T-bet), GATA binding protein 3 (GATA-3), and RAR-related orphan receptor C (RORC) in peripheral CD4+ T cells of 20 patients with asthma and with psychological symptoms, 30 patients with asthma and without psychological symptoms, and 30 healthy subjects were detected by real-time polymerase chain reaction. A Luminex-based approach quantified the levels of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL) 4, and IL-17A cytokines in serum. Results: The mRNA expressions of T-bet, GATA-3 and RORC were significantly different among the three groups. Significant elevations of the expressions of T-bet, GATA-3, and RORC mRNA were found in patients with asthma and with psychological symptoms than in healthy subjects, along with the higher levels of IFN-γ, TNF-α, and IL-17A. Increased expressions of T-bet mRNA were found in patients with asthma and with psychological symptoms but not in those without psychological symptoms. However, the ratio of T-bet to GATA-3 was in balance in patients with asthma and with psychological symptoms. Conclusion: Analysis of our data revealed Th1 and Th2 cells activated in balance in the peripheral blood of patients with asthma and with psychological symptoms, along with activated Th17 cells. This finding provided an improved understanding of the immune-inflammation responses in patients with asthma and with psychological symptoms, and offered information for new targeted therapy to patients with asthma and with psychological symptoms. [ABSTRACT FROM AUTHOR]

Aim of the work To investigate the role of T-helper 17 (Th17) cells in peripheral blood and serum interleukin-17 (IL-17) in rheumatoid arthritis (RA) patients, and their correlation with disease activity and joint destruction. Patients and methods This study included forty RA patients and twenty matched healthy controls. Disease activity score in 28 joints (DAS-28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-CCP, tumor necrosis factor alpha (TNF-α), serum IL-17 and Th17 cells in peripheral blood were measured. Radiological assessment using modified Sharp/van der Heijde (mSvH) score for hand and feet in addition to MRI score for the wrist and metacarpophalangeal (MCP) joints were performed for detection of synovitis and bone erosion. Results The patients were 38 females and 2 males with a mean of 41.15 ± 5.85 years and disease duration of 15.6 ± 4.62 years. Serum IL-17 and Th17 cells in peripheral blood were found to be significantly increased in RA patients (204.1 ± 33.8 pg/ml and 4.62 ± 1.13%) than in controls (25.36 ± 5.39 pg/ml and 0.7 ± 0.021%) ( p < 0.001). Th17 cells significantly correlated with serum IL-17 (r 0.88, p < 0.001). Both Th17 cells and serum IL-17 significantly correlated with DAS-28, ESR, CRP, TNF-α, Van der Heijde modification score and MRI scores for wrist and MCP joints for synovitis and bone erosion (all with a p < 0.001). Conclusion This study demonstrates an important role for Th-17 cells and serum IL-17 in the pathogenesis of the inflammatory and destructive pattern characteristic of RA. [ABSTRACT FROM AUTHOR]

Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant. A patient with Sjögren syndrome and features of AD-HIES with this mutation is described and the molecular consequences are further characterized. This study provides a clinical and immunological description of the patient. STAT phosphorylation in primary patient cells was studied and A4 cells transfected with the patient allele were used to study phosphorylation kinetics, transcriptional activity, and target-gene induction. The hybrid clinical features of the patient were associated with normal T H 17 cells. Enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon IL-6 stimulation, but reduced IL-6–induced SOCS3 production were all observed. The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype that dismantles the classical antithetic dualism of gain- versus loss-of-function. Germline STAT3 mutation–related disease represents a pathological spectrum with the p.R335W associated phenotype locating between the 2 recognized clinical disease patterns. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease, which brings increasing threaten for human health and is still lacking of satisfied treatment. Recently, numerous studies have also demonstrated the effect of particular subsets of CD4+ T cells on PD pathology. Th17 cells played an important role in the pathogenesis of PD. Traditional Chinese medicine has been widely used to treat PD clinically, and has a tremendous potential in clinical drug development.Purpose: The aim of this study was to verify the therapeutic effects of DHY on PD mice model, and investigate the underlying molecular mechanisms.Methods: Herein, we verified the effects of a traditional Chinese medicine formula, named DiHuangYin (DHY), on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD through behavioral and histopathological tests. High-resolution mass spectrometry combined with molecular networking was applied for substance profiling of DHY. Based on the chemical compositions of DHY, network pharmacology was performed. Immunofluorescence and ELISA were used to evaluate the expressions of cytokines in peripheral immune system. qPCR and immunofluorescence were used to detect the inflammation infiltration of central nervous system.Results: DHY improves the motor function and prevents the loss of dopaminergic neurons in the MPTP induced mouse model of PD. 118 components of DHY were identified or tentatively characterized based on the MS/MS data and molecular networking. Network pharmacology suggested IL-17 signaling pathway and neuroactive ligand-receptor interaction as the important targets. Compared to the MPTP-intoxicated mice, the DHY group showed a decreased number of Th17 cells from splenocytes and a decreased level of IL-17A in the serum. On the other hand, less inflammatory infiltration was found in the midbrain of DHY treatment mice which might be associated with the attenuated peripheral inflammation.Conclusions: Though the underlying pharmacological mechanism of DHY is still lacking, we provided evidence that DHY decoction could protect dopaminergic neurons by mitigating peripheral inflammation. [ABSTRACT FROM AUTHOR]

Summary Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4 + cells. Moreover, cPTH enhances the sensitivity of naive CD4 + cells to TNF via GαS/cAMP/Ca 2+ signaling. Accordingly, conditional deletion of GαS in CD4 + cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Objective To assess the role of Th9 and Th17 cells in malignant ascites (MA). Methods MA from 30 hepatic carcinoma patients and benign ascites from 30 cirrhotic patients were collected. Corresponding peripheral blood samples from these hepatic carcinoma and cirrhotic patients as well as 30 healthy subjects were collected. The frequency of Th9 and Th17 cells was tested by flow cytometry. Serum levels of interleukin (IL)-9 and IL-17 were examined by ELISA. Results The observed frequency of Th9 and Th17 cells, and the IL-9 and IL-17 serum levels were significantly higher in MA patients than those in cirrhotic patients and healthy control samples ( P < 0.05). Moreover, the Th9 cells demonstrated positive correlation with Th17 cells as well as IL-9 in MA patients; however, this positive correlation was not observed in the cirrhotic patients or healthy control samples. The frequency of Th9 and Th17 cells was distinctly higher in MA patients presenting with stage III or IV malignancy and with lymph node or distant metastasis than those in patients in stage I or II and without distant metastasis ( P < 0.05). Conclusions The increased frequency of Th9 and Th17 cells in MA patients suggests that these two T cell subsets play a synergistic role in MA pathogenesis. This study also demonstrated that Th9 and Th17 cells may perform their biological functions in conjunction with IL-9 production. [ABSTRACT FROM AUTHOR]

Objective To study the correlation between miR-21 and Treg/Th17 ratio in the microenvironment of rats with hepatocellular carcinoma. Methods Diethylnitrosamine was used to build the hepatocellular carcinoma model of rats; the content of Treg cells and Th17 cells and the expression of miR-21 in the peripheral blood of rats with hepatocellular carcinoma were detected. The statistical analysis was performed on the correlation between miR-21 expression and Treg/Th17 ratio. Results Hepatocellular carcinoma model of rats was successfully constructed. The proportion of Th17 cells among all CD4 + T cells in the peripheral blood of rats with hepatocellular carcinoma was 5.319%, which was higher than the control group; while the proportion of Treg cells was 9.472%, which was higher than the control group. Treg/Th17 ratio in the model group was 1.781, compared with 1.478 in the control group. The expression of miR-21 was increased in the peripheral blood of rats with hepatocellular carcinoma and it showed a positive correlation with the ratio of Treg/Th17. Conclusions There is a positive correlation between the expression level of miR-21 and the ratio of Treg/Th17. [ABSTRACT FROM AUTHOR]

Female spontaneously hypertensive rats (SHR) have more regulatory T cells (Tregs) in their kidneys than males. The goal of this study was to determine the impact of blood pressure (BP) on the renal immune profile. We hypothesize that increases in BP promote a proinflammatory renal T cell and cytokine profile in SHR, although females will have greater hormone-dependent increases in Tregs and males will have greater increases in Th17 cells. Renal T cell and cytokine profiles were assessed in male and female Wistar-Kyoto rats and male and female SHR treated with vehicle or hydrochlorothiazide and reserpine (HCTZ) from 6 to 12 (6-HCTZ) or 11 to 13 weeks of age (2-HCTZ). Regardless of sex, SHR had a more proinflammatory renal immune profile than Wistar-Kyoto rats. 6-HCTZ attenuated age-related increases in BP and 2-HCTZ reversed hypertension compared with vehicle-treated SHR. Neither 6-HCTZ nor 2-HCTZ altered CD3(+), CD4(+), or CD8(+) T cells in either sex. Both treatments decreased Tregs only in female SHR abolishing sex differences in Tregs. 6-HCTZ has no impact on Th17 cells in either sex and 2-HCTZ had a minimal impact on renal Th17 cells. To further assess mechanisms mediating sex differences in the renal immune profile, male and female SHR were gonadectomized to determine the impact of sex hormones. Gonadectomy increased proinflammatory markers in both sexes, suggesting that both male and female sex hormones are anti-inflammatory. In conclusion, BP contributes to sex differences in the renal T-cell profile of SHR; female SHR increase renal Tregs in response to increases in BP. [ABSTRACT FROM AUTHOR]

Background: The differentiation of TH17 cells, which promote pulmonary inflammation, requires the cooperation of a network of transcription factors. Objectives: We sought to define the role of Etv5, an Ets-family transcription factor, in TH17 cell development and function. Methods: TH17 development was examined in primary mouse T cells wherein Etv5 expression was altered by retrovirai transduction, small interfering RNA targeting a specific gene, and mice with a conditional deletion of Etv5 in T cells. The direct function of Etv5 on the Il17 locus was tested with chromatin immunoprecipitation and reporter assays. The house dust mite-induced allergic inflammation model was used to test the requirement for Etv5-dependent TH17 functions in vivo. Results: We identify Etv5 as a signal transducer and activator of transcription 3-induced positive regulator of TH17 development. Etv5 controls TH17 differentiation by directly promoting Il17a and Il17f expression. Etv5 recruits histone-modifying enzymes to the Il17a-Il17f locus, resulting in increased active histone marks and decreased repressive histone marks. In a model of allergic airway inflammation, mice with Etv5-deficient T cells have reduced airway inflammation and IL-17A/F production in the lung and bronchoalveolar lavage fluid compared with wild-type mice, without changes in TH2 cytokine production. Conclusions: These data define signal transducer and activator of transcription 3-dependent feed-forward control of TH17 cytokine production and a novel role for Etv5 in promoting T cell-dependent airway inflammation. [ABSTRACT FROM AUTHOR]

Background: A T-helper 17 (Th17)/regulatory T (Treg) imbalance has been suggested recently to play a role in the development of periodontitis. All-trans retinoic acid (ATRA) has been reported to modulate Th17/Treg imbalances in some diseases. However, the effect of ATRA on periodontitis remains unknown. This study observes the effect of ATRA on Th17/Treg imbalance modulation in experimental periodontitis. Methods: Experimental periodontitis was induced in mice by oral infection with Porphyromonas gingivalis (P. gingivalis). ATRA was orally administered every other day. Alveolar bone resorption (ABR) was estimated by measuring the distance from the cemento-enamel junction to the alveolar bone crest. CD4+ T-cell subsets in the cervical lymph nodes (CLNs) and spleen were analyzed by flow cytometry. Th17/Treg cell-related cytokine messenger ribo-nucleic acid expression was quantified by real-time reverse transcription-polymerase chain reaction. Results: The present data shows that ATRA suppressed ABR and inhibited inflammatory cell infiltration into periodontal tissues. These effects were closely associated with reduced CD4+ retinoid-related orphan receptor γτ+ cells and increased CD4+ forkhead box P3+ cells in the CLNs. Furthermore, ATRA downregulated interleukin (IL)-17A expression and upregulated IL-10 and transforming growth factor-(31 expression in both the CLNs and P. gingivalis-infected gingival tissues. Conclusions: These results suggest that ATRA modulation of the Th17/Treg imbalance provides protection against periodontitis by enhancing Treg cell activation and inhibiting Th17 cell activation. These results indicate the potential for clinical prevention of periodontitis. [ABSTRACT FROM AUTHOR]

Aim: Ma Huang Tang (Ephedra decoction, MHT) is a famous classical formula from Shang Han Lun by Zhang Zhongjing in the Han Dynasty. The anti-asthmatic effects of MHT and the possible mechanisms were tested. Method: An asthma model was established by ovalbumin (OVA)-induction in mice. A total of forty-eight mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg·kg−1) and MHT (5, 10, and 20 mg·kg−1). Airway resistance (Raw) was measured by the forced oscillation technique, histological studies were evaluated by hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and Th17 cells were evaluated by flow cytometry (FCM). Results: This study demonstrated that MHT inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4 and IL-17 levels were recovered in bronchoalveolar lavage fluid, increased IFN-γ level in bronchoalveolar lavage fluid. Histological studies demonstrated that MHT substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry studies demonstrated that MHT substantially inhibited Th17 cells. Conclusion: These findings suggest that MHT may effectively ameliorate the progression of asthma, and could be further investigated for potential use as a therapy for patients with allergic asthma. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggested that maternal farm exposure during pregnancy modulates early immune development toward an allergy-protective status potentially mediated by TH1 or regulatory T (Treg) cells. However, the underlying mechanisms might involve immune modulation of additional T-cell populations, such as TH17 cells, influenced by genetic predisposition. Objective: We examined the role of maternal farm exposure and genetic predisposition on TH17 cell responses to innate and adaptive immune stimulation in cord blood. Methods: Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming mother, 22 farming mothers, and 2 exclusions) assessed farming exposures. Cord blood was stimulated with lipid A, peptidoglycan (Ppg), or PHA. TH17 lineage (retinoic acid receptor–related orphan receptor C [RORC], retinoic acid receptor–related orphan receptor α [RORA], IL-23 receptor [IL23R], IL17, IL17F, and IL22) and Treg cell markers (forkhead box protein 3 [FOXP3], lymphocyte activation gene 3 [LAG3], and glucocorticoid-induced TNF receptor [GITR]) were assessed at the mRNA level. TH17/Treg/TH1/TH2 cytokines and 7 single nucleotide polymorphisms within the TH17 lineage (RORC, IL23R, and IL17) were examined. Results: TH17 lineage mRNA markers were expressed at birth at low concentrations independent of maternal farm exposure. A positive correlation between TH17 lineage markers and FOXP3 (mRNA) was observed on stimulation (nonfarming mothers: lipid A, Ppg, and PHA; farming mothers: Ppg and PHA), influenced by maternal farming. Specific single nucleotide polymorphisms within the TH17 lineage genes influenced gene expression of TH17 and Treg cell markers and cytokine secretion. Conclusions: Gene expression of TH17 lineage markers in cord blood was not influenced by maternal farming. Yet TH17 and Treg cell markers were positively correlated and influenced by maternal farm exposure. Our data suggest that prenatal exposures and genetic predisposition play a role during early TH17 immune maturation, potentially regulating the development of immune-mediated diseases, such as childhood asthma. [Copyright &y& Elsevier]

BACKGROUND: Inflammatory bowel disease (IBD) is a common disease in human resulted from a various of factors including genetic background, immune system and environment factors. OBJECTIVES: Recent studies suggest pro-inflammatory cytokine IL-17 producing cell subset was involved in the disease development and the maintenance of IBD. And the differentiated and activation of IL-17 producing cells were mostly dependent on the cytokines profile secreted by innate cells in intestinal tissues. In this study, we examined the functions of IL-6 signal in regulatory of IL-17 production in acute IBD model. MATERIALS AND METHODS: Wildtype mice were treated with anti-IL-6 neutralizing antibodies to block IL-6 signal And then treated with DSS to induce acute IBD. RESULTS: Mice treated with anti-IL-6 neutralizing antibodies show severe colitis and high level of pro-inflammatory cytokine IL-17 production in DSS-induced acute IBD model when compared with control group. Our research suggested blockade of IL-6 signal pathways in acute colitus model resulted in specifical activation of IL-17 producing cell population. Furthermore, CD44+ activated Th17 cell population and CD44- IL-17 producing T cells exhibited different susceptibility to IL-6 signal in our model. CONCLUSIONS: Blockade of IL-6 signal in DSS-induced acuted IBD model increased IL-17 production level specifically in CD44- T cells and reduced CD44+ Th17 cell population. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases. [Display omitted] • GLUT3 controls the effector function of pathogenic Th17 cells • Ablation of GLUT3 in T cells prevents Th17-cell-mediated autoimmunity • GLUT3-dependent acetyl-CoA production controls the epigenetic program of T cells • Pharmacological inhibition of acetyl-CoA generation ameliorates autoimmunity Hochrein et al. report that inflammatory T cells express high levels of GLUT3. Ablation of GLUT3 curtailed Th17-cell-mediated immune responses and protected mice from autoimmune colitis and encephalomyelitis. GLUT3-dependent glucose metabolism controls the generation of nucleo-cytosolic acetyl-CoA and the epigenetic regulation of cytokine responses through histone acetylation. [ABSTRACT FROM AUTHOR]

Abstract: Prostaglandin I2 (PGI2) is an important immunoregulatory lipid mediator. In this study, we analysed the effects of the PGI2 analogue (Iloprost) on the differentiation of Th17 cells and Tregs from human naïve CD4+ T cells. PGI2 receptors (IP) are expressed on human naïve CD4+ T cells. Via IP binding, the PGI2 analogue decreased the proportion of Tregs and Foxp3 mRNA expression but increased the percentage of Th17 cells, RORC mRNA and IL-17A production. The regulatory effects of Iloprost correlated with elevated intracellular cAMP levels. The effects were mimicked by a cAMP agonist (db-cAMP) but attenuated by a protein kinase A inhibitor (H-89). STAT3 and STAT5 signalling play direct and crucial roles in the development of Th17 and Tregs, respectively. The PGI2 analogue enhanced the activation of STAT3 in response to IL-6, whereas it decreased STAT5 activation in response to IL-2. Moreover, db-cAMP imitated the above effects of Iloprost, which were weakened by H-89. These results demonstrate that the PGI2-IP interaction promoted the phosphorylation of STAT3 and reduced the phosphorylation of STAT5, likely via the upregulation of cAMP-PKA signalling, thus facilitated Th17 differentiation and suppressed Treg differentiation. Together with previous results, these data suggest that prostanoids play an important role in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis. [Copyright &y& Elsevier]

abstract: Importance: Accumulating evidence suggests that IL-17 A has broad pathogenic roles in multiple autoimmune and immune-mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). The development of new therapies that inhibit IL-17 pathway signaling is of clinical significance. Objectives: This review aims to summarize the current preclinical evidence on the role of Th17 cells and IL-17 and related cytokines in immune-mediated disease pathophysiology, with a focus on psoriasis and rheumatoid arthritis, as well as to summarize recent clinical trials in these indications with newly developed IL-17 pathway inhibitors. Methods: A systematic literature search was conducted of PubMed using relevant keywords. Studies were assessed according to recent relevance to IL-17-mediated pathophysiology and clinical IL-17 inhibition. Experimental animal models of autoimmune disease and clinical studies that focused on IL-17 pathway inhibitors were included. Results: Preclinical studies suggest that IL-17A is an attractive therapeutic target. Several IL-17A inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibodies, secukinumab and ixekizumab, and the anti-17RA monoclonal antibody brodalumab. Each has shown variable and sometimes favorable results in proof-of-concept and phase II clinical trials and is currently undergoing further clinical evaluation in a range of immune-mediated diseases. Conclusion: Targeting the IL-17 pathway shows promise as strategy to treat immune-mediated diseases ranging from skin to joints. [Copyright &y& Elsevier]

Abstract: Introduction: Different cell types and cytokines have been identified as contributors to the formation of periapical lesions. In this perspective, this study aimed to evaluate the immunoexpression of interleukin (IL)-17, transforming growth factor (TGF)-β1, and the forkhead box P3 (FoxP3) in periapical lesions, correlating them with the type of lesion, the intensity of the inflammatory infiltrate, and the thickness of the cystic epithelial lining. Methods: Twenty periapical granulomas (PGs), 20 radicular cysts (RCs), and 20 residual radicular cysts (RRCs) were submitted to immunohistochemical analysis using anti-IL-17, anti-TGF-β1, and anti-FoxP3 antibodies. Results: In comparison with PGs and RCs, RRCs exhibited a lower immunoexpression of IL-17 and TGF-β1 (P = .021 and P < .001, respectively). The number of FoxP3+ cells increased in this order: RRCs, RCs, and PGs (P < .001). In comparison with lesions with inflammatory infiltrates grades I and II, lesions with inflammatory infiltrate grade III exhibited a higher number of FoxP3+ cells (P = .002). Similarly, in comparison with lesions with inflammatory infiltrates grades II and III, lesions with inflammatory infiltrate grade I showed a tendency for a lower expression of IL-17 and TGF-β1 (P = .085 and P = .051, respectively). For all groups, there was a positive correlation between the immunoexpressions of IL-17 and TGF-β1 (P < .05). Positive correlations between the number of FoxP3+ cells and the immunoexpressions of IL-17 and TGF-β1 (P < .05) were found only in PGs. Conclusions: Th17 and Treg cells seem to interact at the site of injury, suggesting the involvement of proinflammatory and immunoregulatory cytokines in the pathogenesis of periapical lesions. [Copyright &y& Elsevier]

Summary: Although it is curable, tuberculosis continues to be is a major global public health problem, especially in developing countries. Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis. It has been well documented that CD4+ T lymphocytes are dominant leukocytes present in TPE. Traditionally, CD4+ T cells have been classified into two functionally distinct subsets, helper T-cell type 1 (Th1) and Th2 cells, based on their cytokine production profiles. Recently, regulatory T cells, Th17 cells, Th9 cells, and Th22 cells have been added to the ‘portfolio’ of Th cells. In this review, we summarize recent findings regarding the phenotypic characteristics of the above Th cells, the mechanisms of differentiation and recruitment of Th cells into pleural space, and the immune regulation of Th cells in TPE environment. We also describe the interplay between different Th cells, as well as between Th cells and other type of cells, such as pleural mesothelial cells in TPE. Further studies should be directed at identifying the mediators and mechanisms involved in the immunoregulatory properties of pleural Th cells in tuberculosis infection. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Th17 cells, a subset of CD4+ T cells that produce interleukin (IL)-17A, IL-17F, IL-21, IL-22, IL-26, and the chemokine CCL20 are critically involved in the mucosal inflammation observed in Crohn''s disease (CD). However, their role as mediators of inflammation in CD has been questioned by a recent clinical trial in which anti-IL-17A (secukinumab) treatment was ineffective. Besides being pro-inflammatory, Th17-related cytokines mediate mucosal protective functions. We aimed to investigate the role of Th17 cells in CD inflammation. Methods: Blood samples from 26 patients with active CD and 10 healthy controls (HC) were analyzed for levels of IL-17A-, IL-21- and IL-22-producing CD45RO+CD4+ T cells using multicolor flow cytometry. Samples were analyzed before and during adalimumab treatment to compare intra-individual changes during active and quiescent disease. Results: CD patients had statistically significantly higher levels of IL-17-A-, IL-21- and IL-22-producing CD45RO+CD4+ T cells in both active and quiescent disease compared with HC. Baseline levels of IL-21 and IL-22 producing CD45RO+CD4+ T cells correlated inversely with mucosal inflammation estimated by fecal calprotectin. Patients who responded to adalimumab treatment demonstrated a 2- to 3-fold increase in levels of IL-17A- and IL-21-producing CD45RO+CD4+ T cells in quiescent disease compared with active disease. Conclusion: Our data support the involvement of Th17 cells and IL-21- and IL-22-producing CD45RO+CD4+ T cells in CD. Because patients had higher levels in quiescent disease compared with active CD, we question whether Th17 cells are promoters of inflammation. Instead, Th17 cells may counterbalance inflammation and maintain gut homeostasis. [Copyright &y& Elsevier]