The intricate dance of non-coding RNAs in myasthenia gravis pathogenesis and treatment.

Myasthenia gravis (MG) stands as a perplexing autoimmune disorder affecting the neuromuscular junction, driven by a multitude of antibodies targeting postsynaptic elements. However, the mystery of MG pathogenesis has yet to be completely uncovered, and its heterogeneity also challenges diagnosis and treatment. Growing evidence shows the differential expression of non-coding RNAs (ncRNAs) in MG has played an essential role in the development of MG in recent years. Remarkably, these aberrantly expressed ncRNAs exhibit distinct profiles within diverse clinical subgroups and among patients harboring various antibody types. Furthermore, they have been implicated in orchestrating the production of inflammatory cytokines, perturbing the equilibrium of T helper 1 cells (Th1), T helper 17 cells (Th17), and regulatory T cells (Tregs), and inciting B cells to generate antibodies. Studies have elucidated that certain ncRNAs mirror the clinical severity of MG, while others may hold therapeutic significance, showcasing a propensity to return to normal levels following appropriate treatments or potentially foretelling the responsiveness to immunosuppressive therapies. Notably, the intricate interplay among these ncRNAs does not follow a linear trajectory but rather assembles into a complex network, with competing endogenous RNA (ceRNA) emerging as a prominent hub in some cases. This comprehensive review consolidates the landscape of dysregulated ncRNAs in MG, briefly delineating their pivotal role in MG pathogenesis. Furthermore, it explores their promise as prospective biomarkers, aiding in the elucidation of disease subtypes, assessment of disease severity, monitoring therapeutic responses, and as novel therapeutic targets.

Advanced in immunological monitoring of HIV infection: profile of immune cells and cytokines in people living with HIV-1 in Benin.

BACKGROUND: Immune cells and cytokines have been linked to viremia dynamic and immune status during HIV infection. They may serve as useful biomarkers in the monitoring of people living with HIV-1 (PLHIV-1). The present work was aimed to assess whether cytokines and immune cell profiles may help in the therapeutic follow-up of PLHIV-1. METHODS: Forty PLHIV-1 in treatment success (PLHIV-1s) and fifty PLHIV-1 in treatment failure (PLHIV-1f) followed at the University Hospital of Abomey-Calavi/Sô-Ava in Benin were enrolled. Twenty healthy persons were also recruited as control group. Circulating cytokines and immune cells were quantified respectively by ELISA and flow cytometry. RESULTS: PLHIV-1 exhibited low proportions of CD4 + T cells, NK, NKT, granulocytes, classical and non-classical monocytes, and high proportions of CD8 + T cells, particularly in the PLHIV-1f group, compared to control subjects. Eosinophils, neutrophils and B cell frequencies did not change between the study groups. Circulating IFN-γ decreased whereas IL-4 significantly increased in PLHIV-1s compared to PLHIV-1f and control subjects even though the HIV infection in PLHIV-1s downregulated the high Th1 phenotype observed in control subjects. However, Th1/Th2 ratio remained biased to a Th1 phenotype in PLHIV-1f, suggesting that high viral load may have maintained a potential pro-inflammatory status in these patients. Data on inflammatory cytokines showed that IL-6 and TNF-α concentrations were significantly higher in PLHIV-1s and PLHIV-1f groups than in control subjects. Significant high levels of IL-5 and IL-7 were observed in PLHIV-1f compared to controls whereas PLHIV-1s presented only a high level of IL-5. No change was observed in IL-13 levels between the study groups. CONCLUSION: Our study shows that, in addition to CD4/CD8 T cell ratio, NK and NKT cells along with IL-6, TNF-α, IL-5 and IL-7 cytokines could serve as valuable immunological biomarkers in the therapeutic monitoring of PLHIV-1 although a larger number of patients would be necessary to confirm these results.

Dimethyl itaconate inhibits antigen-specific Th17 cell responses and autoimmune inflammation via modulating NRF2/STAT3 signaling.

Pathogenic Th17 cells play a crucial role in autoimmune diseases like uveitis and its animal model, experimental autoimmune uveitis (EAU). Dimethyl itaconate (DMI) possesses potent anti-inflammatory effects. However, there is still a lack of knowledge about the role of DMI in regulating pathogenic Th17 cells and EAU. Here, we reported that intraperitoneal administration of DMI significantly inhibited the severity of EAU via selectively suppressing Th17 cell responses. In vitro antigen stimulation studies revealed that DMI dramatically decreased the frequencies and function of antigen-specific Th17, but not Th1, cells. Moreover, DMI hampered the differentiation of naive CD4+ T cells toward pathogenic Th17 cells. DMI-treated DCs produced less IL-1ß, IL-6, and IL-23, and displayed an impaired ability to stimulate antigen-specific Th17 activation. Mechanistically, DMI activated the NRF2/HO-1 pathway and suppressed STAT3 signaling, which subsequently restrains p-STAT3 nuclear translocation, leading to decreased pathogenic Th17 cell responses. Thus, we have identified an important role for DMI in regulating pathogenic Th17 cells, supporting DMI as a promising therapy in Th17 cell-driven autoimmune diseases including uveitis.

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Serum autophagy-related gene 5 level in stroke patients: correlation with CD4+ T cells and cognition impairment during a 3-year follow-up.

Autophagy-related gene (ATG) 5 regulates blood lipids, chronic inflammation, CD4+ T-cell differentiation, and neuronal death and is involved in post-stroke cognitive impairment. This study aimed to explore the correlation of serum ATG5 with CD4+ T cells and cognition impairment in stroke patients. Peripheral blood was collected from 180 stroke patients for serum ATG5 and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cell detection via enzyme-linked immunosorbent assays and flow cytometry. The Mini-Mental State Examination (MMSE) scale was completed at enrollment, year (Y)1, Y2, and Y3 in stroke patients. Serum ATG5 was also measured in 50 healthy controls (HCs). Serum ATG5 was elevated in stroke patients compared to HCs (P<0.001) and was positively correlated to Th2 cells (P=0.022), Th17 cells (P<0.001), and Th17/Treg ratio (P<0.001) in stroke patients but not correlated with Th1 cells, Th1/Th2 ratio, or Treg cells (all P>0.050). Serum ATG5 (P=0.037), Th1 cells (P=0.022), Th17 cells (P=0.002), and Th17/Treg ratio (P=0.018) were elevated in stroke patients with MMSE score-identified cognition impairment vs those without cognition impairment, whereas Th2 cells, Th1/Th2 ratio, and Treg cells were not different between them (all P>0.050). Importantly, serum ATG5 was negatively linked with MMSE score at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), and Y3 (P=0.001); moreover, it was positively related to 2-year (P=0.024) and 3-year (P=0.012) MMSE score decline in stroke patients. Serum ATG5 was positively correlated with Th2 and Th17 cells and estimated cognitive function decline in stroke patients.

Coexisting Th1 and Th2 cytokines in patients with collagenous gastritis and implications for its pathogenesis.

OBJECTIVES: Collagenous gastritis (CG) is a rare cause of refractory dyspepsia and anemia that frequently affects children and young adults and whose histological hallmark is chronic mucosal inflammation with a subepithelial collagen band. The etiology remains obscure, and no established treatments exist. We investigated the pathogenesis of CG by determining the expression profiles of genes related to immunity and inflammation in index biopsies. METHODS: Gastric biopsies from 10 newly diagnosed patients with CG were evaluated using the NanoString nCounter assay. Gastric biopsies from 14 normal individuals served as controls. The gene expression ratios for CG versus controls were determined in pooled samples and confirmed in individual samples by quantitative reverse transcription polymerase chain reaction. The results were compared with previously reported expression data from a cohort of patients with collagenous colitis, a colonic disorder with similar morphology, including subepithelial collagen band. RESULTS: CG biopsies featured enhanced expression of key genes encoding both Th1 (IFNγ, TNF-α, IL-2, IL-10, IL-12A, IL-12B, and IL-18) and Th2 cytokines (IL-3, IL-4, IL-5, IL-6, and IL-13). In contrast, biopsies from patients with CC exhibited upregulated Th1 cytokines only. CONCLUSIONS: We show in this first published gene expression profiling study that CG involves simultaneous upregulation of Th1 and Th2 cytokines. This finding is unique, contrasting with other types of chronic gastritis as well as with collagenous colitis, which shares the presence of a collagen band. Involvement of Th2 immunity in CG would support further investigation of potential dietary, environmental, or allergic factors to guide future therapeutic trials.

Fluvoxamine inhibits Th1 and Th17 polarization and function by repressing glycolysis to attenuate autoimmune progression in type 1 diabetes.

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULT: Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved ß cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. CONCLUSION: Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Long-acting anti-inflammatory injectable DEX-Gel with sustained release and self-healing properties regulates TH1/TH2 immune balance for minimally invasive treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a prevalent immune-related allergic disease, and corticosteroid nasal sprays serve as the primary treatment for this patient population. However, their short duration of efficacy and frequent administration pose challenges, leading to drug wastage and potential adverse effects. To overcome these limitations, we devised a novel approach to formulate DEX-Gel by incorporating dexamethasone (DEX) into a blend of Pluronic F127, stearic acid (SA), and polyethylene glycol 400 (PEG400) to achieve sustained-release treatment for AR. RESULTS: Following endoscopic injection into the nasal mucosa of AR rats, DEX-Gel exhibited sustained release over a 14-day period. In vivo trials employing various assays, such as flow cytometry (FC), demonstrated that DEX-Gel not only effectively managed allergic symptoms but also significantly downregulated helper T-cells (TH) 2 and TH2-type inflammatory cytokines (e.g., interleukins 4, 5, and 13). Additionally, the TH1/TH2 cell ratio was increased. CONCLUSION: This innovative long-acting anti-inflammatory sustained-release therapy addresses the TH1/TH2 immune imbalance, offering a promising and valuable approach for the treatment of AR and other inflammatory nasal diseases.

Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response.

Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1ß secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs' capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.

Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype.

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.

A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection.

Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains (T cell helper) TH1 cell proliferation and promotes host-protective type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris. Accordingly, T cell-specific deletion of the TFF3 receptor, leucine-rich repeat and immunoglobulin containing nogo receptor 2 (LINGO2), impairs TH2 cell commitment, allows proliferative expansion of interferon (IFN)g+ cluster of differentiation (CD)4+ TH1 cells and blocks normal worm expulsion through an IFNg-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between TH1/TH2 subsets.

Characterization of human CD4+EOMES+GzmK+ T-cell subsets unveils an uncoupling of suppressive functions from IL-10-producing capacities.

Human CD4+EOMES+ T cells are heterogeneous and contain Th1-cells, Tr1-cells, and CD4+CTL. Tr1- cells and non-classical EOMES+ Th1-cells displayed, respectively, anti- and pro-inflammatory cytokine profiles, but both expressed granzyme-K, produced IFN-γ, and suppressed T-cell proliferation. Diffusion map suggested a progressive CD4+T-cell differentiation from naïve to cytotoxic cells and identified EOMES+Th1-cells as putative Tr1-cell precursors (pre-Tr1).

A comprehensive review on the role of T cell subsets and CAR-T cell therapy in Aspergillus fumigatus infection.

Understanding the immune response to Aspergillus fumigatus, a common cause of invasive fungal infections (IFIs) in immunocompromised individuals, is critical for developing effective treatments. Tcells play a critical role in the immune response to A. fumigatus, with different subsets having distinct functions. Th1 cells are important for controlling fungal growth, while Th2 cells can exacerbate infection. Th17 cells promote the clearance of fungi indirectly by stimulating the production of various antimicrobial peptides from epithelial cells and directly by recruiting and activating neutrophils. Regulatory T cells have varied functions in A.fumigatus infection. They expand after exposure to A. fumigatus conidia and prevent organ injury and fungal sepsis by downregulating inflammation and inhibiting neutrophils or suppressing Th17 cells. Regulatory T cells also block Th2 cells to stop aspergillosis allergies. Immunotherapy with CAR T cells is a promising treatment for fungal infections, including A. fumigatus infections, especially in immunocompromised individuals. However, further research is needed to fully understand the mechanisms underlying the immune response to A. fumigatus and to develop effective immunotherapies with CAR-T cells for this infection. This literature review explores the role of Tcell subsets in A.fumigatus infection, and the effects of CAR-T cell therapy on this fungal infection.

hsa_circ_0087100/hsa-miR-6743-5p affects Th1 cell differentiation by regulating STAT1 in diabetic retinopathy.

Objective: To elucidate the role of the competitive endogenous RNA (ceRNA) network in immune infiltration of diabetic retinopathy (DR). Methods: We obtained differentially expressed (DE) circRNAs, miRNAs and mRNAs from the Gene Expression Omnibus database. Then, we identified immune infiltration by CIBERSORT and single-sample gene set enrichment analysis and discovered co-expression genes by weighted gene co-expression network analysis. Furthermore, STAT1-mediated Th1 differentiation was determined in DR cell models, DR patients and DR mouse models. Results: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 was involved in immune infiltration of Th1 cells. Aberrant expression of the ceRNA network and STAT1-mediated Th1 differentiation was thus verified in vitro and in vivo. Conclusion: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 may affect Th1 cell differentiation in DR.

Recurrent implantation failure and inflammatory markers in serum and follicle fluid of women undergoing assisted reproduction.

It has been shown previously that the immune system plays a role in implantation and embryo development. The objective was therefore to evaluate cytokine levels and Th1/Th2 ratio in women with recurrent implantation failure in this nested case-control study. Women with no implantation after ≥ 3 embryo transfers were included in the recurrent implantation failure group (n = 29) and were compared with women with successful pregnancy after the first embryo transfer, with an indication of male factor (n = 26). Cytokines analyzed with the Meso scale discovery (MSD) technology Proinflammatory Human Kit 1 and calculated Th1/Th2 ratios were the main outcome measures. In serum there was a difference between the recurrent implantation failure group and the control group in ratios for IFN-γ/IL-10 (p = 0.01), IL-1ß/IL-10 (p = 0.04), IL-2/IL-10 (p = 0.00), TNF-α/IL-10 (p = 0.02), IFN-γ/IL-13 (p = 0.01), IL-12/IL-13 (p = 0.02), IL-2/IL-13 (p = 0.00), and TNF-α/IL-13 (p = 0.00), where the control group had higher ratios, i.e. a shift towards a Th1 pro-inflammatory profile before treatment start. In follicular fluid there were differences in ratios between IL-2/IL-10 (p = 0.02), IL-8/IL-10 (p = 0.02), TNF-α/IL-10 (p = 0.02), IFN-γ/IL-13 (p = 0.01), and TNF-α/IL-13 (p = 0.03). The recurrent implantation failure group had higher ratios except for IFN-γ/IL-13, indicating a shift towards a Th1 pro-inflammatory profile in their follicular fluid. Pro-inflammatory activity in both serum and follicle fluid differs in recurrent implantation failure patients and patients with successful assisted reproduction treatment. Women at risk of immune-related recurrent implantation failure could be identified proactively. Because it is taken at a timepoint closer to implantation, ratios in follicular fluid are specifically interesting as risk markers.

Emedastine Inhibits Th1 and Th2 Cell Differentiation Mediated by Mast Cells.

We have previously clarified that emedastine, a second-generation antihistamine drug, inhibits T helper 1(Th1)/Th2 cell differentiation mediated by Langerhans cells (LCs). In addition, although we have recently found that mast cells also function as antigen-presenting cells (APCs) and induce Th1/Th2 cell differentiation, any influence of emedastine on this function remained unclear. Here we investigated the influence of emedastine on Th1/Th2 cell differentiation via mast cells. Mast cells were obtained by long-term culture of murine splenocytes in medium supplemented with tumor necrosis factor (TNF)-α. The mast cells were then incubated in the presence or absence of emedastine, and cultured with naïve CD4+ T cells in the presence of ovalbumin (OVA) peptide. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was examined by enzyme-linked immunosorbent assay. When mast cells treated with emedastine were used as APCs, production of interferon (IFN)-γ and interleukin (IL)-4 from activated Th cells was significantly suppressed. This suppression was associated with inhibition of CD86 expression on mast cells, and mast cells treated with emedastine were shown to obstruct the differentiation of both Th1 and Th2 cells by down-regulating their cell surface expression of CD86. The present data provide additional information that topical application of emedastine to the lesional skin of patients with atopic dermatitis (AD) would reduce not only LC- but also mast cell-mediated skin inflammation.

Correlation analysis of vaginal flora and immune function Th1/Th2 imbalance in women with high-risk HPV infections in the female reproductive tract.

The purpose of this study was to analyze the correlation between vaginal flora and immune function Type 1 helper T cells/Type 2 helper T cells imbalance in females having HPV infections at high risk within the female reproductive tract. We selected 150 female patients who visited our hospital for reproductive tract inflammation between March 2019 and March 2021. They were divided into high-risk HPV-positive and high-risk HPV-negative groups according to the results of the HPV tests. Vaginal flora composition, density, diversity, and Th1/Th2 immune cell cytokine expression were assessed, and their correlations were analyzed. Compared to the HPV-negative group at high risk, the HPV-positive group at high risk exhibited significantly higher rates of Lactobacillius abnormalities, Chlamydia trachomatis and Mycoplasma urealyticum positivity(P<0.05). However, no statistically significant differences in the rates of Neisseria gonorrhoeae, bacterial vaginosis, mould, and trichomonad positivity were observed in both groups (P>0.05). The high-risk HPV-positive group displayed significantly higher rates of abnormal vaginal flora density and diversity compared to the HPV-negative group at high risk (P < 0.05). Compared to the HPV-negative group at high risk, the HPV-positive group at high risk exhibited significantly lower expression levels of Th1, Th1/Th2, IFN-γ, and IL-2 and higher expression levels of Th2, IL-4, and IL-10(P<0.05). Among patients having HPV infections at high risk, those with abnormal vaginal flora had lower expression levels of Th1, Th1/Th2, IFN-γ, and IL-2 and higher expression levels of Th2, IL-4, and IL-10 compared to those with normal vaginal flora, all of which were statistically significant(P<0.05). Vaginal flora dysbiosis was correlated with Th1/Th2 imbalance (P<0.05). Women with high-risk HPV infections in the female reproductive tract exhibit abnormal vaginal flora and immune function Th1/Th2 imbalance, characterized by a shift from Th1 to Th2. Moreover, there is a close correlation between vaginal flora dysbiosis and immune function Th1/Th2 imbalance.

Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells.

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7-18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4+ Tregs' percentage was decreased. Interestingly, a higher proportion of OB CD4+ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4+ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery.

Radical S-adenosyl methionine domain-containing 2, a potential target of D-tryptophan in asthma treatment, regulates T helper cell type 1/2 balance.

Asthma is a common chronic respiratory disease. D-tryptophan (D-TRP) can inhibit allergic airway inflammation and T helper cell type 2 (Th2) immune response. RNA-sequencing results have indicated that radical S-adenosyl methionine domain-containing 2 (RSAD2) might be a potential molecular target of D-TRP in asthma treatment. Herein, we established a mouse model of asthma using ovalbumin (OVA) via intraperitoneal injection and inhalational challenge. Gain- and loss-of-function studies of RSAD2 were performed in mice following the intratracheal delivery of lentiviral vectors (3 × 106 TU/mL). Naïve CD-4+ T cells were isolated from the spleen and used to explore the effects of RSAD2 on Th2 cell differentiation. RSAD2 expression was higher in the asthma group than in the control group. RSAD2 knockdown alleviated inflammatory cell infiltration and reduced the number of goblet cells. Low RSAD2 expression decreased the levels of IgE, IL-25, IL-33, and TSLP, and it reduced the number of inflammatory cells in the bronchoalveolar lavage fluid. RSAD2 silencing suppressed Th2-related cytokine levels (such as IL-4, IL-5, and IL-13) and increased Th1-related cytokine levels (such as IFN-γ). Additionally, RSAD2 knockdown inhibited the phosphorylation of JAK1, JAK3, and STAT6, and downregulated GATA-3 expression. RSAD2 overexpression increased inflammatory cell infiltration and mucus secretion in the lung tissues of mice pretreated with D-TRP. D-TRP pretreatment reduced OVA-specific IgE content and IL-4 and IL-5 levels, and it increased the IFN-γ levels; however, RSAD2 overexpression reversed these effects. In conclusion, RSAD2 knockdown can mitigate OVA-induced asthma by regulating the Th2 immune response via JAK/STAT6 pathway inhibition.