Percentage Of Th17 Cells Research Articles

SFgl2 gene-modified MSCs regulate the differentiation of CD4+ T cells in the treatment of autoimmune hepatitis

BackgroundAutoimmune hepatitis (AIH) is a T-cell-mediated autoimmune liver disease that can lead to liver injury and has a poor long-term prognosis. Mesenchymal stromal cells (MSCs) have immunosuppressive effects and can treat AIH. CD4+ T cells express the unique inhibitory Fcγ receptor (FcγRIIB), which is the only receptor for the immunosuppressive factor soluble fibrinogen-like protein 2 (sFgl2). This study aimed to examine the therapeutic effect of sFgl2 gene-modified MSCs (sFgl2-MSCs) on AIH.MethodsMSCs were obtained from the inguinal fat of mice and cocultured with CD4+ T cells sorted from mouse spleens. FcγRIIB expression on CD4+ T cells was determined by flow cytometry. sFgl2 expression in MSCs transfected with lentiviral vectors carrying the Fgl2 gene and a green fluorescent protein-encoding sequence was determined by enzyme-linked immunosorbent assay. The percentages of Th1 cells Th17 cells and regulatory T cells (Tregs) were determined by flow cytometry And the levels of p-SHP2 and p-SMAD2/3 were detected by Western blotting after the cells were cocultured with MSCs for 72 h. After locating MSCs by in vivo imaging Con A-induced experimental AIH mice were randomly divided into 4 groups and administered different treatments. After 24 h histopathological scores liver function and cytokine levels were examined and the proportions of CD4+ T cells CD8+ T cells Tregs Th17 cells and Th1 cells in the spleen and liver were determined by flow cytometry. In addition immunohistochemical staining was used to detect the liver infiltration of T-bet-, Foxp3- and RORγ-positive cells.ResultsFcγRIIB expression on CD4+ T cells was upregulated after coculture with MSCs. After coculture with sFgl2-MSCs, the proportion of Tregs among CD4+ T cells increased, the proportion of Th17 and Th1 cells decreased, and the levels of p-SHP2 and p-SMAD2/3 increased. In vivo, sFgl2-MSCs significantly improved liver function, decreased liver necrosis area, decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 expression, increased IL-10 expression, reduced liver infiltration of CD4+ T and CD8+ T cells, increased the proportion of Tregs and reduced the proportions of Th17 and Th1 cells in mice.ConclusionBy promoting Tregs differentiation and inhibiting Th17 and Th1 cell differentiation, sFgl2 gene-modified MSCs have a more powerful therapeutic effect on Con A-induced experimental AIH and may represent a strategy for the clinical treatment of AIH.

Transcriptome analysis of T cells from Ldlr−/− mice and effects of in vitro vitamin D treatment

Vitamin D is known for its immunosuppressive effects on T cells, suppressing Th1 and Th17 and promoting Treg differentiation. Th1 cells contribute to inflammatory responses such as inflammatory cytokine production and macrophage activation, which accelerate the progression of atherosclerosis. However, the mechanisms underlying the modulation of T cell functions by vitamin D in atherosclerosis have not been investigated. This study analyzed the gene expression profiles of T cells, using RNA-seq transcriptome analysis, to investigate the effects of in vitro vitamin D treatment on T cell differentiation and signal transduction pathways in Ldlr knock-out (Ldlr−/−) mice. C57BL/6 mice were randomly assigned to two groups and fed a control diet (CON) or a Western diet (WD) for 16 weeks, while Ldlr−/- mice (LDLR−/−) were fed a Western diet. Splenic T cells were isolated and stimulated with anti-CD3e and anti-CD28 mAb for 48 h with or without 10 nM 1,25(OH)2D3. RNA sequencing was performed, followed by KEGG and GO enrichment analyses. Populations of T cell subsets and cytokine production were measured to assess T cell lineage differentiation. The JAK-STAT, HIF-1, and calcium signaling pathways of Ldlr−/− mice significantly differed from those of control mice, and 1,25(OH)2D3 treatment affected MAPKKK binding molecular function of Ldlr−/− mice. Percentages of Th1 cells and IL-17 production were significantly reduced by 1,25(OH)2D3 treatment in all three mouse groups. These results suggest that 1,25(OH)2D3 has anti-inflammatory effects in atherosclerosis and is involved in cell signaling pathways that could prevent disease progression by regulating T cell differentiation and effector functions.

Interleukin-21 modulates balance between regulatory T cells and T-helper 17 cells in chronic hepatitis B virus infection

BackgroundChronic HBV infection is always accompanied by differences in the balance between regulatory T cells (Tregs) and T-helper 17 (Th17) cells in infection phases. IL-21 plays an important role in the progression of chronic HBV infection. Thus, the aim of our study was to investigate the role of the regulatory function of IL-21 in maintaining the balance between Tregs and Th17 cells in chronic HBV infection.MethodsTwenty-five chronic HBV-infected patients in the immune-tolerant (IT) phase and 23 chronic hepatitis B (CHB) patients were recruited in this study. Cytokines production was measured by ELISA. The mRNA expression levels were determined by qPCR. CD4+T cells were stimulated with or without IL-21. Tregs and Th17 cells were measured by flow cytometry. pSTAT3 and STAT3 expression was assessed by Western blotting.ResultsThe concentration of IL-21 in the serum of CHB were significantly higher than that in the serum from IT patients, and IL-21 and IL-21R levels in the PBMCs from CHB were higher than those from IT patients. IL-21 promoted Th17 cells differentiation and function but inhibited Treg cells differentiation and function by activating STAT3 signaling pathways, upregulating RORγt expression, downregulating Foxp3 expression, by increasing IL-17and IL-22 secretion, and decreasing TGF-β secretion in chronic HBV infection. The proportion of Tregs and TGF-β concentrations in CHB was significantly lower than that in IT patients. Furthermore, the percentage of Th17 cells and the IL-17 concentration in CHB was markedly higher than that in IT patients, causing a reduction in the Tregs/Th17 ratio in CHB patients.ConclusionsOur results suggest that IL-21 may contribute to inflammation in chronic HBV infection by modulating the balance between Treg and Th17 cells.

Aberrant Immune Features after Recovery from COVID-19 in Patients with Systemic Lupus Erythematosus and Other Autoimmune Diseases.

Considering the large number of individuals who have already been infected and may have reinfection, the post-infection effects of COVID-19 are of great importance for clinical practice and predicting disease trends. However, our understanding of the potential long-term effects, particularly on immunity, after recovering from COVID-19 remains limited. The aim of this study was to investigate the abnormal immunological factors that contribute to the prolonged immunological effects of COVID-19. Two groups of patients were enrolled in the study, including 11 individuals with various autoimmune diseases (AIDs) and 16 patients diagnosed with systemic lupus erythematosus (SLE). Detailed clinical symptoms were closely monitored, and peripheral mononuclear cells were analyzed using flow cytometry. The clinical status was evaluated using the SLE Disease Activity Index (SLEDAI) and the Clinical Global Impressions (CGI) index. The proportions of follicular T helper cells (Tfh) exhibited significant increases in both cohorts (AID: p = 0.03; SLE: p = 0.0008). Conversely, the percentages of Foxp3+ and CD4+ regulatory T cells (Treg) were reduced in patients following COVID-19 infection (AID: p = 0.009, 0.05, resp.; SLE: p = 0.02, 0.0009, resp.). The percentages of Th2 and Th17 cells were significantly increased in SLE patients (p < 0.05). Exacerbated conditions were observed in SLE patients two months after infection (SLEDAI, p < 0.05). Our findings show that COVID-19 infection increases Tfh cells and decreases Treg cells in patients of AIDs, worsening pathogenetic immune status in post-recovery populations.

Contribution of T helper 17 cells and interleukin-17 to the pathogenesis of primary immune thrombocytopenia in Egyptian children

Though pathogenesis of primary immune thrombocytopenia (ITP) is still rendered unclear, yet there are many research efforts that have been directed to the role of T helper 17 (Th17) and interleukin 17 (IL-17) in the pathogenesis of this disease. The Th17 cell, which produces IL-17, is a subset of T helper cells. Interleukin 17 is pro-inflammatory cytokine that is recently proved to have a crucial role in the emergence of autoimmune diseases. We aimed to investigate the role of T helper17 cells and interleukin-17 in the pathogenesis of ITP in Egyptian children. This study was carried out on 100 children with ITP and 100 apparently healthy children as a control group. Patients were subjected to full medical history taking, thorough physical examination and routine investigations according to our local standards. Percentage of Th17 cells was measured by flow cytometry in study groups. Also, serum IL-17 was measured in in study groups by ELISA. Th 17 cells were significantly higher in patients compared to controls. Moreover, 3.1-fold increased serum levels of IL-17 were observed in patients with ITP compared to controls. Newly diagnosed patients had significantly higher percentage of Th-17cells as well as higher IL-17 levels than patients with either persistent or chronic ITP. Conclusion: We concluded that Th 17 cells and IL-17 seem to play an important role in the pathogenesis of ITP in Egyptian children.What is Known -- What is New:• The pathogenesis of ITP is heterogeneous A novel subset of CD4+ T cells, distinct from Th1 and Th2, was recently identified. It is characterized by the production of IL-17 and, therefore, designated as Th17 cells. Several studies support a pivotal role for serum cytokines in the pathogenesis of ITP and provide evidence to suggest that helper Tlymphocytes polarize into Th1 and Th2 immune response. we aimed to investigate the role of T helper17 cells and interleukin-17 in the pathogenesis of ITP in Egyptian children.

Curcumin alleviated dextran sulfate sodium-induced colitis by recovering memory Th/Tfh subset balance.

Restoration of immune homeostasis by targeting the balance between memory T helper (mTh) cells and memory follicular T helper (mTfh) cells is a potential therapeutic strategy against ulcerative colitis (UC). Because of its anti-inflammatory and immunomodulatory properties, curcumin (Cur) is a promising drug for UC treatment. However, fewer studies have demonstrated whether Cur can modulate the mTh/mTfh subset balance in mice with colitis. To explore the potential mechanism underlying Cur-mediated alleviation of colitis induced by dextran sulfate sodium (DSS) in mice by regulating the mTh and mTfh immune homeostasis. Balb/c mice were administered 3% and 2% DSS to establish the UC model and treated with Cur (200 mg/kg/d) by gavage on days 11-17. On the 18th d, all mice were anesthetized and euthanized, and the colonic length, colonic weight, and colonic weight index were evaluated. Histomorphological changes in the mouse colon were observed through hematoxylin-eosin staining. Levels of Th/mTh and Tfh/mTfh cell subsets in the spleen were detected through flow cytometry. Western blotting was performed to detect SOCS-1, SOCS-3, STAT3, p-STAT3, JAK1, p-JAK1, and NF-κB p65 protein expression levels in colon tissues. Cur effectively mitigates DSS-induced colitis, facilitates the restoration of mouse weight and colonic length, and diminishes the colonic weight and colonic weight index. Simultaneously, it hinders ulcer development and inflammatory cell infiltration in the colonic mucous membrane. While the percentage of Th1, mTh1, Th7, mTh7, Th17, mTh17, Tfh1, mTfh1, Tfh7, mTfh7, Tfh17, and mTfh17 cells decreased after Cur treatment of the mice for 7 d, and the frequency of mTh10, Th10, mTfh10, and Tfh10 cells in the mouse spleen increased. Further studies revealed that Cur administration prominently decreased the SOCS-1, SOCS-3, STAT3, p-STAT3, JAK1, p-JAK1, and NF-κB p65 protein expression levels in the colon tissue. Cur regulated the mTh/mTfh cell homeostasis to reduce DSS-induced colonic pathological damage, potentially by suppressing the JAK1/STAT3/SOCS signaling pathway.

Immune cell profiles of idiopathic inflammatory myopathy patients expressed anti-aminoacyl tRNA synthetase or anti-melanoma differentiation-associated gene 5 autoantibodies

BackgroundPatients with idiopathic inflammatory myopathy (IIM) often express a different type of myositis-specific autoantibodies (MSAs), each associated with different clinical symptoms. Understanding the immunopathogenesis of various IIM subgroups can help improve the diagnosis and prognosis of IIM patients with different MSAs. However, the immune cell profiles of these IIM patients with anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies remain unclear. We focused on the immune cell profiles of IIM patients with anti-ARS or anti-MDA5 autoantibodies.ResultsThe peripheral blood from IIM patients with anti-MDA5 autoantibody (MDA5 + group, n = 24) or one of the anti-ARS autoantibodies (ARS + group, n = 40) autoantibodies, and healthy controls (HC group, n = 60) were collected and examined. We found that IIM patients had a lower CD3 T cell population compared to the HC group. IIM patients showed a significantly lower TN cell population and a higher TEMRA cell population. Higher Th17 and Treg cell populations were found in these IIM patients than in the HC group. In these IIM patients, the MDA5 + group exhibited the higher percentages of Th17 and Treg cells than the ARS + group. It is noteworthy that the percentage of Th1 cells in the survival subgroup was higher than in the death subgroup in IIM patients with ARS + or MDA5 + . Furthermore, in the MDA5 + group, the percentage of Treg cells was higher in the survival subgroup compared to the death subgroup.ConclusionsOur study demonstrated that elevated Th1 may be a good prognostic indicator in IIM patients with ARS + or MDA5 + . Elevated Treg may also help predict a good prognosis in MDA5 + IIM patients. However, more large-scale studies and clinical samples are needed to verify the significance of Th1 and Treg cell subsets in clinical outcomes for these IIM patients with ARS + or MDA5 + . These data may help design a therapeutic approach that specifically targets the pathogenic immune molecular responsible for autoimmune attacks in IIM.

Elevated profiles of peripheral Th22, Th17, Th2 cells, and decreased percentage of Th1 cells in breast cancer patients.

Th22 subset is a particular type of CD4+ T helper cells subset. Our study aimed to explore the expression level of circulating Th22, Th17, Th1, and Th2 cells and the possible mechanism of these cells in breast cancer (BC) with different pathological features. Our study enrolled 43 newly diagnosed BC patients and 30 healthy controls. Frequencies of peripheral Th22, Th17, Th1, and Th2 cells were tested by flow cytometry. Concentrations of IL-22 cytokine in plasma were examined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was done to test aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) gene expression. Frequencies of Th22, Th17, Th2 subsets, and the plasma IL-22 level was obviously higher in the BC patients. A positive correlation between Th22 frequency and IL-22 concentration in plasma was detected in BC patients. Furthermore, the percentage of Th22, Th2 subsets in peripheral blood of HER2 positive BC was higher than that in HER2 negative BC patients. A negative correlation between Th1 subset and Ki-67% as well as a positive correlation between Th2 subset and Ki-67% was found in BC patients. The proportion of Th1 cells in BC patients was significantly lower than that of the control group. Expression of AHR and RORC transcription factors were also observed to be upregulated in the BC patients. Furthermore, Th22 cells were positively correlated with BC tumor stage and clinical outcomes. The BC patients with a higher percentage of Th22, Th17, Th1 cells or a lower percentage of Th1 cells showed a decreased trend of survival rate. Th22, Th17, Th1, and Th2 subsets may play an essential role in BC patients. Th22, Th17, Th1, and Th2 cells may have potential significance to be used as clinical markers in BC patients with different molecular classification. Th22 cells may have potential value in BC patients' outcomes prediction, providing clinical value.

Targeting PRMT1 prevents acute and chronic graft-versus-host disease

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.

Circulating Th17/Treg as a promising biomarker for patients with rheumatoid arthritis in indicating comorbidity with atherosclerotic cardiovascular disease.

Immune and inflammatory responses have a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and atherosclerotic cardiovascular disease (ASCVD). This study aims to explore the change of peripheral lymphocytes, especially the absolute and relative changes in peripheral T cells in RA patients with and without ASCVD. The changes in the lymphocyte subsets were assessed to provide a novel insight in diagnosing and preventing ASCVD in patients with RA. A propensity score matching system (1:1) was conducted to perform a matched case-control study with 169 pairs RA-ASCVD and RA participants. Univariate and multivariate analyses were performed to determine the association between peripheral lymphocytes and RA-ASCVD. Multivariate logistic regression analysis demonstrated that Th17 cell absolute, Th17 cell Ratio, Th17/Treg were associated with a significantly higher risk of ASCVD after model adjustment. Then we focused on Th17/Treg, multivariate logistic analyses in tri-sectional Th17/Treg groups showed that the odds of ASCVD is gradually increasing with Th17/Treg rank's rising after model adjustment. Finally, the restricted cubic spline of Th17/Treg and odds ratio of RA-ASCVD was conducted. Interestingly, we found a critical point of Th17/Treg (critical point = 0.2399). Th17/Treg shows a protective role in the odds of ASCVD when Th17/Treg < 0.2399. With smaller Th17/Treg, the protective efficiency is more obvious when Th17/Treg < 0.2399. Our study suggested that increasing absolute and percentage of Th17 cells in the peripheral blood of patients with RA was associated with the development of ASCVD. And Th17/Treg may be a promising biomarker for patients with RA in indicating comorbidity with ASCVD.

Effects of retinoic acid on immunity and inflammation in patients with &lt;i&gt;Psoriasis vulgaris&lt;/i&gt;

Purpose: To investigate the effect of retinoic acid on immune and inflammatory factors in patients with psoriasis vulgaris, and its underlying mechanism of action.Methods: A total of 20 P. vulgaris (PV) patients from Dongtai People's Hospital were divided into two groups, with 10 patients receiving retinoic acid and 10 receiving calcipotriol. The patients' clinical parameters, psoriasis area and severity index were evaluated after one month of treatment. Enzymelinked immunosorbent assay (ELISA) was used to measure the concentrations of interleukin-10 and interleukin-17 in the patients' peripheral blood, while the proportion of T helper immune cells that expressed IL-17a and regulatory T immune cells were determined via flow sorting. Expressions of Notch1 in psoriatic lesions and CD4+T cells were determined by quantitative real time-polymerase chain reaction (qRT-PCR).Results: Retinoic acid significantly reduced psoriasis area and severity index. Furthermore, retinoic acid decreased the concentration of IL-17, increased the concentration of IL-10, lowered the percentage of Th17 cells, but elevated the percentage of Treg immune cells (p &lt; 0.05). Expression of Notch1 in skin lesions and CD4+T cells was lower in the retinoic acid group than in the calcipotriol group (p &lt; 0.05).Conclusion: Expression of Notch1 is decreased in skin tissue lesions of PV patients receiving oral retinoic acid treatment. Thus, retinoic acid influences Th17/Treg immune balance by regulating Notch1 signaling pathway in PV patients, and therefore can potentially be developed for the treatment of psoriasis.

Percentage of Th1 and Th17 cells and serum level of IL-17 and IFN-γ cytokines in COVID-19-associated mucormycosis.

The considerable number of the 2019 coronavirus disease (COVID-19) patients who developed mucormycosis infections in West and Central Asia urged a need to investigate the underlying causes of this fatal complication. It was hypothesized that an immunocompromised state secondary to the excessive administration of anti-inflammatory drugs was responsible for the outburst of mucormycosis in COVID-19 patients. Therefore, we aimed to study the implication of two major subsets of adaptive immunity T helper (Th)-1 and Th17 cells in disease development. Thirty patients with COVID-19-associated mucormycosis, 38 with COVID-19 without any sign or symptom of mucormycosis, and 26 healthy individuals were included. The percentage of Th1 and Th17 cells in peripheral blood, as well as the serum levels of interleukin (IL)-17 and interferon-gamma (IFN-γ), were evaluated using flow cytometry and ELISA techniques, respectively. Th17 cell percentage in patients with COVID-19-associated mucormycosis was significantly lower than in COVID-19 patients (P-value: <0.001) and healthy subjects (P-value: 0.01). In addition, the serum level of IL-17 in COVID-19 patients was significantly higher than that of healthy individuals (P-value: 0.01). However, neither the frequency of Th1 cells nor the serum level of IFN-γ was different between the study groups. Given the critical role of Th17 cells in the defense against mucosal fungal infections, these findings suggest that low numbers of Th17 and insufficient levels of IL-17 might be a predisposing factor for the development of mucormycosis during or after COVID-19 infection.

HLA-DR Helps to Differentiate Erythrodermic Cutaneous T-cell Lymphoma from Erythrodermic Inflammatory Dermatoses in Flow Cytometry.

Differential diagnosis of erythroderma is challenging in dermatology, especially in differentiating erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. This study retrospectively reviewed the peripheral blood flow cytometric results of 73 patients diagnosed with erythroderma at Peking University First Hospital from 2014 to 2019. The flow cytometry antibody panel included white blood cell markers, T-cell markers, B-cell markers, T-cell activation markers, and T helper cell differentiation markers. Features of the cell surface antigens were compared between 34 patients with erythrodermic cutaneous T-cell lymphoma and 39 patients with erythrodermic inflammatory dermatoses. The percentage of HLA-DR+/CD4+T cells was the most pronounced marker to distinguish erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses, with a threshold of 20.85% (sensitivity 96.77%, specificity 70.37%, p = 0.000, area under the curve (AUC) 0.882), suggesting its potential capability in the differential diagnosis of erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. Moreover, in contrast to erythrodermic inflammatory dermatoses, the percentage of Th17 cells was significantly downregulated in erythrodermic cutaneous T-cell lymphoma (p = 0.001), demonstrating a dysregulated immune environment in erythrodermic cutaneous T-cell lymphoma.

Serum IL-17 levels correlate with urinary albumin in systemic lupus erythematosus (SLE) pregnant mice model

Women of reproductive age are more likely to have systemic lupus erythematosus (SLE), which frequently results in health issues, particularly during pregnancy. A normal pregnancy's first trimester shows a marked increase in the percentage of Th17 cells, which then steadily declined in the second and third trimesters. Meanwhile, IL-17 level increases in SLE-affected pregnant women. This study aimed to analyze the correlation between serum IL-17 and pregnancy outcome (fetus weight, blood pressure, urinary albumin) in SLE pregnant animal models. Twenty mice were randomly divided into two groups, including the normal pregnant group and SLE-pregnant group. The SLE pregnant mice was made by intraperitoneally induction of 0.5 mL pristane. Serum IL-17 was assayed by enzyme-linked immunosorbent assay (ELISA) method. The serum IL-17 level, the blood pressure and urinary albumin were significantly higher in the SLE pregnant mice group than those of the normal pregnant group (p&lt; 0.05). The weight of fetus was significantly smaller in the group of SLE pregnant mice group than the normal pregnant group (p&lt; 0.05). There was a significantly positive correlation between the serum IL-17 level and urinary albumin (p = 0.042; r = 0.459). In conclusion, serum IL-17 levels correlate with urine albumin in SLE pregnant models, but do not correlate with fetus weight and blood pressure.

Kuijieling decoction regulates the Treg/Th17 cell balance in ulcerative colitis through the RA/RARα signaling pathway

Ethnopharmacological relevanceUlcerative colitis (UC) is an idiopathic intestinal disease characterized by chronic inflammation with unknown etiology. Kuijieling decoction is a traditional Chinese Medicine with unique therapeutic efficacy for UC. Aim of the studyTo validate the effects of Kuijieling decoction on vitamin A metabolism and retinoic acid (RA) production, along with evaluation of its immunomodulatory activity, and further clarify the upstream mechanisms underlying Treg/Th17 regulation that contribute to therapeutic effects against UC. Materials and methodsNetwork pharmacology and molecular docking analyses were employed to predict the potential anti-UC targets of Kuijieling and associated pathways. A rat model of UC was generated by treatment with trinitrobenzene sulfonic acid (TNBS) to induce inflammation. T lymphocytes were induced to differentiate into Th17 via combined stimulation with the cytokines TGF-β1, IL-6 and IL-23. Expression levels of RA/RARα-related factors (RARα, CRABPII, Smad3, IL-6R and IL-23R) and Treg/Th17 cell-related factors (Foxp3, RORγt) were measured via western blot (WB), quantitative real-time PCR (RT-qPCR), and immunohistochemistry analyses. Components of the vitamin A metabolic pathway (vitamin A, retinol, retinoic acid) and Treg/Th17 cell-related cytokines (IL-10, IL-17, IL-21) were evaluated using ELISA. Flow cytometry was performed to determine the percentages of Treg and Th17 cells. ResultsThe action targets of Kuijieling were significantly associated with T cell activation, Th17 cell differentiation and the immune response. IL-2, IL-6, STAT3 and RARα displayed strong binding affinities with the main components of Kuijieling, suggesting an important role in its therapeutic efficacy. Kuijieling promoted vitamin A metabolism and RA/RARα signaling in UC rats and T lymphocytes. Moreover, Kuijieling effectively regulated the Treg/Th17 cell balance in UC rats and T lymphocytes and relieved inflammation. The protective effect of Kuijieling was weakened after inhibition of the RA/RARα signaling pathway. ConclusionsKuijieling promotes vitamin A metabolism and RA synthesis, enhances interactions between RA, intracellular binding protein CRABPII and nuclear receptor RARα, and upregulates Smad3 and Foxp3, thus promoting Treg differentiation. Simultaneously, Kuijieling inhibited expression of IL-6R and IL-23R genes and production of RORγt, leading to suppression of Th17 differentiation, and ultimately, reduction of the Th17/Treg cell ratio.

Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1

In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets.The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis.Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.

The decreased of peripheral blood natural killer cell is associated with serum IL-2 level in the renal tubular acidosis in patients with primary sjogren’s syndrome

BackgroundPrimary Sjogren’s Syndrome (pSS) is a lymphoproliferative disease with autoimmune characteristics, which is characterized by lymphocyte infiltration of exocrine glands and involvement and dysfunction of extraglandular organs. Renal tubular acidosis (RTA) is a common renal involvement in pSS. This study investigated the phenotypic characteristics of peripheral blood lymphocyte subsets and cytokines in pSS patients complicated with RTA (pSS-RTA).MethodThis retrospective study included 25 pSS patients complicated with RTA and 54 pSS patients without RTA (pSS-no-RTA). To examine the level of peripheral lymphocytes subsets, flow cytometry analysis was used. The level of serum cytokines were detected by flow cytometry bead array(CBA). The influencing factors related to the occurrence of pSS-RTA were identified through logistic regression analyze.ResultsThe absolute number of CD4 + T cells and Th2 cells in peripheral blood were decreased in pSS-RTA patients than pSS-no-RTA patients. Moreover, the absolute number of NK cells and Treg cells were also decreased in pSS-RTA patients than pSS-no-RTA. The level of serum IL-2 was higher in pSS-RTA patients than pSS-no-RTA patients, and is negatively correlated with the number of NK cells, the number and percentage of Th17 cells, and Th17/Treg. Serum IL-2 level is also correlated with various cytokines. Multivariate logistic analysis proved that elevated ESR and ALP were risk factors for pSS complicated with RTA, while Treg was a protective factor.ConclusionThe increase of serum IL-2 level and the decrease of peripheral blood NK cells and Treg cells may be the immune mechanism of the development of pSS-RTA disease.

Vitamins A and D Enhance the Expression of Ror-γ-Targeting miRNAs in a Mouse Model of Multiple Sclerosis.

Autoreactive T cells, particularly those characterized by a Th17 phenotype, exert significant influence on the pathogenesis of multiple sclerosis (MS). The present study aimed to elucidate the impact of individual and combined administration of vitamin A and D on neuroinflammation, and microRNAs (miRNAs) involved in T helper (Th)17 development, utilizing a murine model of experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice, and 3 days prior to immunization, intraperitoneal injections of vitamins A and D or their combination were administered. Th17 cell percentages were determined in splenocytes utilizing intracellular staining and flow cytometry. Furthermore, the expression of Ror γ-t, miR-98-5p and Let-7a-5p, was measured in both splenocytes and spinal cord tissues using RT-PCR. Treatment with vitamin A and D resulted in a reduction in both disease severity in EAE mice. Treated mice showed a decreased frequency of Th17 cells and lower expression levels of IL17 and Ror γ-t in splenocytes and spinal cord. The spinal cord tissues and splenocytes of mice treated with vitamins A, D, and combined A+D showed a significant upregulation of miR-98-5p and Let-7a-5p compared to the EAE group. Statistical analysis indicated a strong negative correlation between miR-98-5p and Let-7a-5p levels in splenocytes and Ror-t expression. Our findings indicate that the administration of vitamins A and D exerts a suppressive effect on neuroinflammation in EAE that is associated with a reduction in the differentiation of T cells into the Th17 phenotype and is mediated by the upregulation of miR-98-5p and Let-7a-5p, which target the Ror γ-t.

Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy

Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4+ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4+cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTORDC−/− AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH.

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.