Blood Th17 Research Articles

Interferon-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites

Type 1 T helper (Th1) cells generate an efficient antitumor immune response in multiple malignancies. The functions of Th1 cells in malignant ascites (MA) have not been elucidated. The distribution of helper T cells in peritoneal fluid and peripheral blood was determined in patients and animal models with malignant ascites. The effects of Th1-derived interferon-γ (IFN-γ) on the formation of malignant ascites were investigated. The mechanism underlying the recruitment of Th1 cells into peritoneal cavity was explored. In patients with malignant ascites and animal models of malignant ascites, the percentage of Th1 cells increased in peritoneal fluid compared with peripheral blood. Next, our experiment demonstrated that Th1 cells inhibited the growth of tumor cells by secreting IFN-γ in vitro. In murine models of malignant ascites, increased peritoneal fluid and shorter survival time were observed in IFN-γ−/− mice compared with wild-type (WT) mice. Then, the levels of C-X-C motif chemokine ligand (CXCL) 9/10 and the ratio of CXCR3+ Th1 cells indicated the involvement of CXCL9, 10/CXCR3 axis in the recruitment of Th1 cells into peritoneal cavity. As expected, in murine models of malignant ascites, the gradient between ascitic Th1 ratio and blood Th1 ratio decreased in CXCR3−/− mice compared with WT mice. IFN-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites. Hence, manipulation of Th1 cells or IFN-γ will provide a therapeutic candidate against malignant ascites.

Retracted: Clinical Significance of Peripheral Blood Th1 and Th17 Cell Content and Serum IL-35 and IL-17 Expression in Patients with Ankylosing Spondylitis.

[This retracts the article DOI: 10.1155/2022/6540557.].

Immune-Enhancing Effect of Sargassum horneri on Cyclophosphamide-Induced Immunosuppression in BALB/c Mice and Primary Cultured Splenocytes.

Sargassum horneri (SH) is a seaweed that has several features that benefit health. In this study, we investigated the immune-enhancing effect of SH, focusing on the role of spleen-mediated immune functions. Chromatographic analysis of SH identified six types of monosaccharide contents, including mannose, rhamnose glucose, galactose xylose and fucose. SH increased cell proliferation of primary cultured naïve splenocytes treated with or without cyclophosphamide (CPA), an immunosuppression agent. SH also reversed the CPA-induced decrease in Th1 cytokines. In vivo investigation revealed that SH administration can increase the tissue weight of major immune organs, such as the spleen and thymus. A similar effect was observed in CPA-injected immunosuppressed BALB/c mice. SH treatment increased the weight of the spleen and thymus, blood immune cell count and Th1 cytokine expression. Additionally, the YAC-1-targeting activities of natural killer cells, which are important in innate immunity, were upregulated upon SH treatment. Overall, our study demonstrates the immune-enhancing effect of SH, suggesting its potential as a medicinal or therapeutic agent for pathologic conditions involving immunosuppression.

003 Interleukin (IL)-26 drives pathogenic IL-17A responses through a TH17-keratinocyte crosstalk

Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions and is highly expressed in tissues of TH17-mediated inflammatory diseases including psoriasis. However, the expression of IL-26 with respect to IL-17A and its precise function in the context of pathogenic TH17 responses are still unclear. In this study, we used flow cytometry-based fluorescent in situ hybridization of blood TH17 cells along with single-cell and spatial transcriptomics of psoriatic skin lesions to analyze the dynamic of the regulation of IL-26 expression in TH17 cells. We show that blood TH17 cells contain a large population of IL-26-producing cells that do not produce IL-17A. Unlike IL-17A-producing cells, these IL-26-producing cells develop at early stages of TH17 differentiation and do not require TGF-β. However, when exposed to TGF-β, IL-26-producing cells transition into IL-17 producers, a process also observed in psoriatic skin lesions, where TGF-β is highly expressed by basal keratinocytes in close vicinity to IL-26-producing T cells. T cell-derived IL-26 was able to induce TGF-β expression in keratinocytes themselves, suggesting a mechanism by which TH17 cells control IL-17A responses in tissues via the expression of IL-26. Thus, our study identifies IL-26-producing cells as an early differentiation stage of TH17 cells that can further differentiate into IL-17A producing cells upon tissues infiltration via a paracrine loop involving TGF-β.

Pyrroloquinoline Quinone Administration Alleviates Allergic Airway Inflammation in Mice by Regulating the JAK-STAT Signaling Pathway.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.

Correlation of acetyl-coenzyme A carboxylase 1 with Th17 and Th1 cells, serving as a potential prognostic biomarker for acute ischemic stroke patients.

BackgroundAcetyl‐coenzyme A carboxylase 1 (ACC1) regulates lipid homeostasis, T helper (Th) cell differentiation, oxidative stress, inflammation response, and neurological process, engaging in acute ischemic stroke (AIS) pathogenesis, while its clinical utility in AIS is unclear. Hence, this study intended to explore the correlation among blood ACC1, Th17, and Th1 cells, and ACC1’s potency as a prognostic biomarker for AIS management.MethodsACC1 in peripheral blood mononuclear cells (PBMCs) of 160 AIS patients and 30 controls were determined using RT‐qPCR; blood Th17 and Th1 cells in AIS patients were quantified by flow cytometry.ResultsACC1 was increased in AIS patients compared with controls (median (interquartile range): 2.540 (1.753–3.548) vs. 0.980 (0.655–1.743), p < 0.001), which exhibited a good value to reflect AIS risk with the area under the curve of 0.872 (95% CI: 0.805–0.939). Moreover, ACC1 was positively linked with Th17 (r = 0.374, p < 0.001) and Th1 (r = 0.178, p = 0.024) cells in AIS patients. Additionally, ACC1 (r = 0.328, p < 0.001), Th17 (r = 0.272, p = 0.001), and Th1 cells (r = 0.195, p = 0.014) were positively associated with the National Institutes of Health Stroke Scale score in AIS patients. ACC1 high vs. low (p = 0.038) and Th17 high vs. low (p = 0.026) were related to shortened recurrence‐free survival (RFS) in AIS patients, while Th1 cells (p = 0.179) were not correlated with RFS. Whereas ACC1 (p = 0.248), Th17 (p = 0.079), and Th1 cells (p = 0.130) were not linked with overall survival (OS) in AIS patients.ConclusionCirculating ACC1 overexpression correlates with increased Th17, Th1 cells, NIHSS score, and shortened RFS in AIS patients.

The changes in peripheral blood Th17 and Treg ratios in Hashimoto's thyroiditis are accompanied by differential PD-1/PD-L1 expression.

ObjectiveThe aim of this study was to analyze the percentages of T helper 17 cells (Th17s) and T regulatory cells (Tregs) in autoimmune Hashimoto’s thyroiditis (HT), and the expression of the checkpoint molecules programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) on these cells.MethodsThis is a case-control study involving 53 initially diagnosed HT patients (HT group) and 21 normal controls (NC group). The peripheral blood mononuclear cells from the individuals of the two groups were isolated and restimulated ex vivo; the percentage of Th17s, Tregs, PD-1+ Th17s, PD-L1+ Th17s, PD-1+ Tregs, and PD-L1+ Tregs was assessed by flow cytometric analysis.Results(1) The percentage of Th17s in the peripheral blood of the HT group was significantly higher than that of the NC group [(6.38 ± 1.32)% versus (3.12 ± 0.66)%; t = 14.110, P < 0.001], while the percentage of peripheral blood Tregs was significantly lower [(3.82 ± 1.48)% versus (5.61 ± 1.60)%; t = −4.599, P < 0.001]. (2) HT patients’ Th17s expressed PD-1 at a significantly lower frequency than their counterparts in the NC [(6.46 ± 2.77)% versus (18.51 ± 3.96)%; t = −14.842, P < 0.001], while no difference was observed for PD-L1 between the two groups. (3) In contrast, both PD-1 and PD-L1 were expressed at significantly higher frequency on HT patients’ Tregs than on NC [respectively: (17.01 ± 3.04)% versus (10.23 ± 2.77)%; t = 8.850, P < 0.001 for PD-1; (16.60 ± 9.58)% versus (11.36 ± 10.14)%; t = 2.089, P < 0.005, for PD-L1].Conclusion(1) The increased percentage of Th17s and decreased percentage of PD-1+ Th17s in the HT group suggest that a loss of control on Th17 activity through the checkpoint inhibitory axis PD-1/PD-L1 may participate in disease pathogenesis. (2) While the decreased percentage of Tregs in HT patients may explain a lack of regulatory functions able to prevent the autoimmune destruction of the thyroid, the significance of the increased frequency of Tregs expressing PD-1 and PD-L1, previously reported to boost Tregs differentiation, remains to be established. Elucidating this apparent contradiction may reveal important mechanisms underlying HT pathogenesis.

Relation of CDC42, Th1, Th2, and Th17 cells with cognitive function decline in Alzheimer's disease.

ObjectiveCell division cycle 42 (CDC42) regulates neurite outgrowth, neurotransmitter, and T help (Th) cell‐mediated neuroinflammation, while its clinical implication in Alzheimer's disease (AD) is not clear. The present study aimed to investigate the correlation of CDC42 with Th1, Th2, and Th17 cells, as well as CDC42’ longitudinal change and relation to cognitive function decline in AD patients.Methods150 AD patients were enrolled, then their blood Th1, Th2, and Th17 cells were quantified by flow cytometry at baseline; CDC42 was detected by RT‐qPCR and MMSE score was assessed at baseline and during 3‐year follow‐up. Meanwhile, CDC42, Th1, Th2, and Th17 cells were quantified in 30 Parkinson's disease (PD) patients and 30 healthy controls (HCs).ResultsCDC42 (p < 0.001) and Th2 cells (p < 0.001) were lowest in AD patients, followed by PD patients, highest in HCs; but Th1 cells (p = 0.001) and Th17 cells (p < 0.001) showed opposite trends. CDC42 was not related to Th1 cells (p = 0.134), positively correlated with Th2 cells (p = 0.023) and MMSE (p < 0.001), while negatively associated with Th17 cells (p < 0.001) in AD patients. CDC42 was only related to Th17 cells (p = 0.048) and MMSE (p = 0.048) in PD patients; and it was not linked with Th1, Th2, Th17 cells, or MMSE in HCs (all p > 0.05). During a 3‐year follow‐up, CDC42 was gradually declined in AD patients (p < 0.001), its decline was positively correlated with MMSE decline at 1 year (p = 0.004), 2 years (p = 0.005), and 3 years (p = 0.026).InterpretationCDC42 might have the potency to serve as a biomarker for estimating AD risk and progression.

Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease involving a variety of immune cells, including adaptive T and B cells and innate lymphoid cells (ILCs). Understanding the pathogenic role of these immune cells in RA provides new insights into the intervention and treatment of RA.MethodsA total of 86 patients with RA (RA group) and 50 healthy controls (HC) were included in the study. The immune cells of CD4+, CD19+ B, NK, Th17, Treg, ILCs, and their subsets (i.e., ILC1s, ILC2s, and ILC3s) were characterized in peripheral blood mononuclear cells by flow cytometry. Cytokines (i.e., IFN-γ, IL-4, IL-10, IL-17A, IL-22, and IL-33) in sera were detected using ELISA. The above immune cells and cytokines were analyzed in patients with different disease activity status and positive ( +) or negative ( −) rheumatoid factor (RF)/anti-citrullinated protein antibodies (ACPA).ResultsPatients with RA had higher percentages of CD4+ T, CD19+ B, Th17, ILC2s, and ILC3s and lower percentages of Treg and ILC1s than HC. Patients with RA had elevated levels of IFN-γ, IL-4, IL-17A, and IL-22 and decreased level of IL-10. Compared with HC, patients with high disease activity had higher percentages of Th17, ILC2s, and ILC3s; lower percentages of ILC1s; and lower level of IL-10. The percentage of Treg cells in remission, low, moderate, and high disease activities decreased, whereas the level of IL-17A increased compared with HC. Furthermore, RF+ or ACPA+ patients exhibited elevated percentages of CD19+ B, ILC2s, and ILC3s and had decreased percentage of ILC1s and Treg cells than HC. The percentage of Th17 cells increased in RF−/ACPA− and RF+/ACPA+ patients. However, the above immune cells between RF or ACPA positive and negative patients were not significantly different.ConclusionTh17, Treg, and ILC subset dysregulations are present in patients with RA but may not be associated with conventionally defined seropositive RF and ACPA.Key Points• Th17, Treg, and ILC subset dysregulations are present in patients with RA but may reflect inflammation rather than specific diseases and stages.• No difference for the distribution of Th17, Treg, and ILC subsets between RF+and RF− patients and between ACPA+and ACPA− patients. The screening spectrum of RF and ACPA serology should be expanded to elucidate the role of immune cells in RA pathogenesis.

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis

ObjectiveMALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA.MethodsTotally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4+ T cells were isolated from RA patients, followed by MALT1 overexpression or knockdown lentivirus transfection and Th1/2/17 polarization assay. In addition, IMD 0354 (NF-κB antagonist) and SP600125 (JNK antagonist) were also added to treat CD4+ T cells.ResultsMALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4+ T cells; while MALT1 knockdown exhibited the opposite effect. Besides, IMD 0354 and SP600125 addition attenuated MALT1’s effect on Th2 and Th17 differentiation.ConclusionMALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA.

Effects of Modified Jianpi Qushi Heluo Decoction on Scores of TCM Syndromes, 24 h Urinary Albumin, and Plasma Albumin in IMN of Spleen-Kidney Qi Deficiency.

Objective To explore the effects of modified Jianpi Qushi Heluo decoction on scores of TCM syndromes, 24 h urinary albumin (UA), and plasma albumin (Alb) in idiopathic membranous nephropathy (IMN) of spleen-kidney qi deficiency. Methods A total of 84 patients with IMN of spleen-kidney qi deficiency type admitted to the hospital were enrolled between November 2019 and September 2021. According to the random number table method, they were divided into the observation group (42 cases) and control group (42 cases). The control group was treated with routine Western medicine, while the observation group was additionally treated with modified Jianpi Qushi Heluo decoction. All were continuously treated for 2 months. The clinical curative effect between the two groups was compared. Before and after treatment, scores of TCM syndromes, biochemical indexes (24 h UA, plasma Alb, serum triglyceride (TG), and serum cholesterol (TC)), and T lymphocyte subsets (Th1, Th2, Th1/Th2, and Th17) were compared between the two groups. The occurrence of adverse reactions in both groups during treatment was recorded. Results The difference in the total response rate of treatment between the observation group and control group was not statistically significant (90.48% vs. 73.81%) (P > 0.05). After 2 months of treatment, scores of TCM syndromes in the observation group were significantly lower than those in the control group, levels of 24 h UA, TG, and TC were significantly lower than those in the control group, and Alb was significantly higher than that in the control group (P < 0.05). After 2 months of treatment, levels of peripheral blood Th1 and Th17 in the observation group were significantly lower than those in the control group, while Th2 and Th1/Th2 were higher than those in the control group (P < 0.05). The difference in incidence of adverse reactions between the observation group and control group was not statistically significant (4.76% vs. 14.29%) (P > 0.05). Conclusion The modified Jianpi Qushi Heluo decoction can reduce UA, increase Alb, and improve clinical symptoms and immune function of patients with IMN of spleen-kidney qi deficiency.

Blood Th17 cells and IL-17A as candidate biomarkers estimating the progression of cognitive impairment in stroke patients.

BackgroundT helper (Th) cells regulate immunity and inflammation to engage in cognitive impairment in several neurological diseases, while their clinical relevance in stroke patients is not clear. The current study intended to assess the relationship of Th1 cells, Th17 cells, interferon‐gamma (IFN‐γ), and interleukin (IL)‐17A with cognitive function in stroke patients.MethodsOne hundred twenty stroke patients and 40 controls were enrolled in this muticenter study. Th1 and Th17 cells in peripheral blood were assessed by flow cytometry; meanwhile, IFN‐γ and IL‐17A in serum were detected by enzyme‐linked immunosorbent assay. Cognitive function of stroke patients was evaluated by Mini‐Mental State Examination (MMSE) score at enrollment (baseline), year 1, year 2, and year 3.ResultsTh1 cells (p = 0.037) and IFN‐γ (p = 0.048) were slightly increased, while Th17 cells (p < 0.001) and IL‐17A (p < 0.001) were greatly elevated in stroke patients compared with controls. Th17 cells (r s = −0.374, p < 0.001) and IL‐17A (r s = −0.267, p = 0.003) were negatively correlated with MMSE score at baseline, but Th1 cells and IFN‐γ were not. Meanwhile, Th17 cells (p = 0.001) and IL‐17A (p = 0.024) were increased in patients with cognitive impairment compared to those without cognitive impairment. Notably, Th17 cells were positively associated with 1‐year (r s = 0.331, p < 0.001), 2‐year (r s = 0.261, p = 0.006), and 3‐year (r s = 0.256, p = 0.011) MMSE decline; IL‐17A was positively correlated with 1‐year (r s = 0.262, p = 0.005), 2‐year (r s = 0.193, p = 0.045), but not 3‐year MMSE decline. However, both Th1 cells and IFN‐γ were not linked with MMSE decline.ConclusionTh17 cells and IL‐17A estimate the progression of cognitive impairment in stroke patients.

JNK pathway-associated phosphatase in acute ischemic stroke patients: Its correlation with T helper cells, clinical properties, and recurrence risk.

ObjectiveJKAP modifies T‐cell immune response and inflammation, also involves in cardia‐cerebrovascular disease etiology. This study intended to explore JKAP's relation with T‐helper 1 (Th1), T‐helper 17 (Th17) cell levels, clinical properties, and recurrence‐free survival (RFS) in acute ischemic stroke (AIS) patients.MethodsA total of 155 AIS patients were analyzed. Serum JKAP, interferon‐gamma (IFN‐γ), and interleukin‐17A (IL‐17A) were detected by ELISA; then blood Th1 and Th17 cells were quantified by flow cytometry. Besides, 30 healthy subjects were enrolled as controls to detect JKAP, Th1, and Th17 cells.ResultsJKAP level was lower (p < 0.001), Th1 cells were not differed (p = 0.068), but Th17 cells were elevated in AIS patients versus controls (p < 0.001). Meanwhile, JKAP was negatively correlated with Th1 cells (p = 0.038), Th17 cells (P<0.001), IFN‐γ (p = 0.002), and IL‐17A (p < 0.001) in AIS patients. JKAP was negatively associated with the National Institutes of Health Stroke Scale (NIHSS) score (p < 0.001), but Th17 cells (p = 0.001), IFN‐γ (p = 0.035), and IL‐17A (p = 0.008) levels were positively associated with NIHSS score. Additionally, accumulating RFS was numerically longer in patients with JKAP Quantile (Q) 4 than patients with JKAP Q1–Q3 (p = 0.068), and numerically better in patients with JKAP Q3–Q4 than patients with JKAP Q1–Q2 (p = 0.069), but without statistical significance.ConclusionJKAP correlates with lower Th1 and Th17 cell percentages as well as milder disease severity.

T helper cell subsets and related target cells in acute COVID-19

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 24 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells basophiles and eosinophils were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased regulatory Tfh1 cell and increased pro-inflammatory Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of nave and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24 plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

Cell division control protein 42 correlates with lower disease risk and its elevation predicts better treatment response, and inhibits T-helper 17 cell differentiation in rheumatoid arthritis.

Previous research reports that cell division control protein 42 (CDC42) is dysregulated in rheumatoid arthritis (RA). This study aimed to further explore the linkage of CDC42 with T-helper (Th) 1 and Th17 cell differentiation, and its implication in RA management. After enrolling 80 RA patients, their blood CDC42, Th1 and Th17 cells were detected by RT-qPCR and flow cytometry, respectively, IFN-γ and IL-17A were detected by ELISA. Based on the treatment response at week 12, the patients were classified as response patients and no response patients. In addition, blood CDC42 was also detected after enrolling 40 healthy controls. Subsequently, naïve CD4+ T cells from RA patients were transfected with control, CDC42 overexpression and knockdown lentivirus, followed by differentiation assay. CDC42 was reduced in RA patients versus healthy controls (P < 0.001). In RA patients, CDC42 was negatively correlated with IFN-γ (P = 0.023), Th17 cells (P = 0.011) and IL-17A (P = 0.003) but not Th1 cells (P = 0.200). CDC42 presented an increasing trend after treatment (P < 0.001); besides, CDC42 at week 8 (P = 0.027) and week 12 (P < 0.001) were increased in response patients versus no response patients. Subsequent experiment showed that in RA CD4+ T cells, CDC42 overexpression reduced IFN-γ and IL-17A (both P < 0.05), while CDC42 knockdown elevated IL-17A (P < 0.05) but not IFN-γ (P > 0.05). Moreover, CDC42 overexpression inhibited, while CDC42 knockdown increased Th17 cell percentage (P < 0.05) but not Th1 cell percentage (P > 0.05). CDC42 negatively correlates with disease risk and its elevation predicts better treatment response; it also inhibits Th17 but not Th1 cell differentiation in RA.

Blood T-helper 17 cells and interleukin-17A correlate with the elevated risk of postpartum depression and anxiety.

BackgroundT‐helper (Th) cells regulate inflammation and immunity, which is implicated in psychological disorders. The current study aimed to explore the clinical role of blood Th1, Th2, and Th17 cells and their main secreted cytokines in postpartum depression (PPD) and postpartum anxiety (PPA).MethodsA total of 226 postpartum women were included. At 6 weeks postpartum, Edinburgh Postnatal Depression Scale (EPDS) and State Trait Anxiety Inventory 6 item version (STAI6) scores were assessed; meanwhile, blood Th1, Th2, and Th17 cells were detected by flow cytometry, serum interferon‐gamma (IFN‐γ), interleukin‐4 (IL‐4), and IL‐17A were detected by enzyme‐linked immunosorbent assay.ResultsThe incidence of PPD and PPA were 24.3% and 27.9%, respectively. Th17 cells and IL‐17A were positively correlated with EPDS score and STAI6 score (all p < 0.001). Besides, Th17 cells (p < 0.001) and IL‐17A (p = 0.002) were increased in PPD cases vs. non‐PPD cases, and they were also elevated in PPA cases vs. non‐PPA cases (both p < 0.05). However, Th1 cells, Th2 cells, IFN‐γ, and IL‐4 were not linked with EPDS score or STAI6 score (all p > 0.05); besides, they did not vary in PPD cases vs. non‐PPD cases or in PPA cases vs. non‐PPA cases (all p > 0.05). Multivariate logistic regression model analysis showed that Th17 cells were independently associated with an elevated risk of PPD (odds ratio [OR] = 1.600, p = 0.001) and PPA (OR = 1.371, p = 0.022).ConclusionBlood Th17 cells and IL‐17A are positively linked with the risk of PPD and PPA, indicating which may be involved in the development of PPD and PPA.

7-DAYS HIGH SALT DIET AFFECTS THE PRODUCTION OF PRO- AND ANTI-INFLAMMATORY CYTOKINES IN YOUNG HEALTHY INDIVIDUALS

Objective: This study aimed to investigate the earliest immunomodulatory effects of NaCl during pre-hypertensive phase of acute salt loading in humans. Thus we have investigated serum levels of systemic pro- and anti-inflammatory cytokines in relation to peripheral Th17 and regulatory T cell abundance following 7-day high-salt (HS) loading in young salt-resistant healthy individuals. Design and method: 30 young healthy individuals adhered to a 7-day low-salt (LS) diet (3.5 g salt/day) followed by a 7-day high-salt (HS) diet (~14.7 g salt/day) protocol. Serum pro- and anti-inflammatory cytokines (INF-gamma, TNF-alpha, IL-6, IL-9, IL-17A, IL-23, IL-10, IL-21, IL-22, TGF-beta1), complement component C3a, as well as frequencies of peripheral blood Th17 and regulatory T cells (Treg), Th17/Treg ratio and the level of enzymes involved in their activation and differentiation (SGK1 and p38/MAP kinase) were measured before and after 7-day HS diet protocol. Results: Short-term HS diet significantly increased serum level of pro-inflammatory cytokines INF-gamma, TNF-alpha, IL-9 and IL-17A level, but also serum concentration of anti-inflammatory cytokines IL-10 and TGF-beta1. In addition, serum INF-gamma and IL-9 levels positively correlated to 24-h urine natriuresis. Relative amount of total and phosphorylated p38/MA kinase remained unchanged, while relative amount of total SGK1 significantly increased following 7-day HS diet compared to LS values. Conclusions: Result of the present study provided evidence of acute salt-loading induced changes in the immune status of young healthy individuals. The increase in relative amount of total SGK1 in peripheral mononuclear cells suggests lymphocyte (re)activation in response to hyperosmotic stress resulting in enhanced production of proinflammatory (IL-17, INF-gamma), but also anti-inflammatory cytokines (IL-10 and TGF-beta1). Still, which effect is prevailing remains elusive and warrants further studies.

Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk.

In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)2D3), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)2D3 than Th17 cells, as reflected by lower vitamin D receptor (VDR) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)2D3 exposure. Upon T-cell activation, VDR levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)2D3-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. In activated Th17.1 cells, 1,25(OH)2D3 amplified the suppressive effects of methylprednisolone (MP) on proliferation, MDR1 surface levels, secretion of IFN-γ and granzyme B, as well as expression of brain-homing markers CCR6 and VLA-4. The addition of P4 to 1,25(OH)2D3 further enhanced MP-mediated reduction in proliferation, CD25, CCR6 and CXCR3. Overall, this study indicates that glucocorticoid sensitivity of Th17.1 cells can be enhanced by treatment with 1,25(OH)2D3 and further improved with P4. Our observations implicate steroid hormone crosstalk as a therapeutic avenue in Th17.1-associated inflammatory diseases including MS.

Clinical Significance of Peripheral Blood Th1 and Th17 Cell Content and Serum IL-35 and IL-17 Expression in Patients with Ankylosing Spondylitis.

Objective To evaluate the clinical significance of peripheral blood T helper cell 1 (Th1) and T helper cell 17 (Th17) cell content and serum (interleukin) IL-35 and IL-17 expression in patients with ankylosing spondylitis (AS). Methods In this retrospective study, we included and assigned 60 cases of AS patients enrolled in our hospital from January 2019 to January 2020 to an active group (ankylosing spondylitis disease activity score (ASDAS) ≥2.1, n = 28) and a static group (ASDAS<2.1, n = 32) according to the degree of disease activity. The logistic propensity score matching method was used to include 60 healthy individuals after a physical examination during the same period in the control group. The peripheral blood Th1 and Th17 cell content and the levels of serum IL-35 and IL-17 were determined and analyzed. Results Statistically significant differences were found in the Th1 cell ratio and Th17 cell ratio between the control group and the other two groups (P < 0.05), and the static group yielded a higher Th1 cell ratio and a lower Th17 cell ratio than the active group (P < 0.05). Statistically significant differences were also observed in the serum IL-35 and IL-17 levels between the control group and the other two groups (P < 0.05), and the static group had a higher IL-35 level and a lower IL-17 level than the active group (P < 0.05). Conclusion The imbalance of Th17/Th1 cell content of AS patients is characterized by high expression of IL-17 and low expression of IL-35. The increased activity of AS was associated with a dominant state of Th17 cells and a significant increase in IL-17 expression, indicating that Treg/Th17 imbalance is closely related to the development of AS, which may provide new ideas for the prevention and treatment of AS.

Longitudinal Variations of CDC42 in Patients With Acute Ischemic Stroke During 3-Year Period: Correlation With CD4+ T Cells, Disease Severity, and Prognosis.

ObjectiveCell division cycle 42 (CDC42) modulates CD4+ T-cell differentiation, blood lipids, and neuronal apoptosis and is involved in the pathogenesis of acute ischemic stroke (AIS); however, the clinical role of CDC42 in AIS remains unanswered. This study aimed to evaluate the expression of CDC42 in a 3-year follow-up and its correlation with disease severity, T helper (Th)1/2/17 cells, and the prognosis in patients with AIS.MethodsBlood CDC42 was detected in 143 patients with AIS at multiple time points during the 3-year follow-up period and in 70 controls at admission by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, blood Th1, Th2, and Th17 cells and their secreted cytokines (interferon-γ (IFN-γ), interleukin-4 (IL-4), and interleukin-17A (IL-17A)) in patients with AIS were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively.ResultsCompared with controls (p < 0.001), CDC42 was reduced in patients with AIS. CDC42 was negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score (p < 0.001), whereas, in patients with AIS (all p < 0.050), it was positively associated with Th2 cells and IL-4 but negatively correlated with Th17 cells and IL-17A. CDC42 was decreased from admission to 3 days and gradually increased from 3 days to 3 years in patients with AIS (P<0.001). In a 3-year follow-up, 24 patients with AIS recurred and 8 patients died. On the 3rd day, 7th day, 1st month, 3rd month, 6th month, 1st year, 2nd year, and 3rd year, CDC42 was decreased in recurrent patients than that in non-recurrent patients (all p < 0.050). CDC42 at 7 days (p = 0.033) and 3 months (p = 0.023) was declined in reported deceased patients than in survived patients.ConclusionCDC42 is used as a biomarker to constantly monitor disease progression and recurrence risk of patients with AIS.