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IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

Tropomyosin has been identified as the major cross-reactive shellfish allergen, but recent studies showed the presence of other clinically relevant allergens. This study aims at determining the allergic immune responses of mice sensitized with raw and boiled shrimp extracts in comparison to recombinant tropomyosin (rTM). Female Balb/c mice were intragastrically sensitized and challenged with raw, boiled shrimp or rTM. Systemic, cellular and humoral allergic responses were compared, while allergenicity of the extracts was also compared by skin prick test (SPT) and immunoblot on shrimp allergic subjects. We showed that rTM and shrimp extracts induced IgE- and Th2-mediated allergic responses in mice, distinguished by remarkable intestinal inflammation in small intestine across all regimens. Notably, boiled shrimp extract exhibited the highest sensitization rate (73.7% of mice developed positive TM-specific IgE response) when compared with raw extract (47.8%) and rTM (34.8%). Mice sensitized with boiled extract manifested the highest allergen-specific IgE and Th2 cytokine responses than the others. Immunoblot results indicated that tropomyosin remained the major allergen in extract-based sensitization and had stronger allergenicity in a heat-treated form comparing to untreated TM, which was in line with the SPT results that boiled extract induced larger wheal size in patients. Hemocyanin and glycogen phosphorylase were also identified as minor allergens associated with manifestation of shrimp allergy. This study shows that boiled extract enhanced sensitization and Th2 responses in agreement with the higher allergenicity of heat-treated TM. This study thus presents three shrimp allergy murine models suitable for mechanistic and intervention studies, and in vivo evidence implies higher effectiveness of boiled extract for the clinical diagnosis of shellfish allergy.

Chlamydia vaccine approaches aspire to induce Th1 cells for optimal protection, despite the fact that there is no direct evidence demonstrating Th1-mediated Chlamydia clearance from the female reproductive tract (FRT). We recently reported that T-bet-deficient mice can resolve primary Chlamydia infection normally, undermining the potentially protective role of Th1 cells in Chlamydia immunity. Here, we show that T-bet-deficient mice develop robust Th17 responses and that mice deficient in Th17 cells exhibit delayed bacterial clearance, demonstrating that Chlamydia-specific Th17 cells represent an underappreciated protective population. Additionally, Th2-deficient mice competently clear cervicovaginal infection. Furthermore, we show that sensing of IFN-γ by non-hematopoietic cells is essential for Chlamydia immunity, yet bacterial clearance in the FRT does not require IFN-γ secretion by CD4 T cells. Despite the fact that Th1 cells are not necessary for Chlamydia clearance, protective immunity to Chlamydia is still dependent on MHC class-II-restricted CD4 T cells and IL-12p40. Together, these data point to IL-12p40-dependent CD4 effector maturation as essential for Chlamydia immunity, and Th17 cells to a lesser extent, yet neither Th1 nor Th2 cell development is critical. Future Chlamydia vaccination efforts will be more effective if they focus on induction of this protective CD4 T cell population.

The activation of CD4+ T‐cells in a T cell receptor (TCR)‐dependent antigen‐specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T‐cells recognise their cognate antigen during activation, TCR‐mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses. During the process of differentiation, TCR signal strength acts as a quantitative component in combination with the qualitative effects imparted by cytokines to polarise distinct T‐helper lineages. Here, we investigated the role of interleukin 2 (IL‐2) signalling in determining the outcome of TCR‐dependent differentiation. IL‐2 production was initiated as an early response to TCR‐induced activation and was regulated by the strength of TCR signalling initially received. In the absence of IL‐2, TCR dependent differentiation was found to be abolished. However, proliferative responses and early markers of activation were maintained, including the upregulation of GATA3, Tbet and Foxp3 at 24 h post‐stimulation. Demonstrating that IL‐2 signalling has a key role in stabilising and amplifying lineage‐specific transcirption factor expression during differentiation. Further, activation of IL‐2‐deficient T‐cells in the presence of exogenous cytokines was sufficient to restore differentiation whilst maintaining transcriptional signatures imparted during initial TCR signalling. Combined, our data demonstrate that the integration of quantitative TCR‐dependent signalling and qualitative IL‐2 signalling is essential for determining the fate of CD4+ T‐cells during differentiation. [ABSTRACT FROM AUTHOR]

Inhibiting the expression of spindle appendix cooled coil protein 1 (SPDL1) can slow down disease progression and is related to poor prognosis in patients with esophageal cancer. However, the specific roles and molecular mechanisms of SPDL1 in esophageal squamous cell carcinoma (ESCC) have not been explored yet. The current study aimed to investigate the expression levels of SPDL1 in ESCC via transcriptome analysis using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Moreover, the biological roles, molecular mechanisms, and protein networks involved in SPDL1 were identified using machine learning and bioinformatics. The cell counting kit-8 assay, EdU staining, and transwell assay were used to investigate the effects of inhibiting SPDL1 expression on ESCC cell proliferation, migration, and invasion. Finally, the correlation between the SPDL1 expression and cancer immune infiltrating cells was evaluated by analyzing data from the TCGA database. Results showed that SPDL1 was overexpressed in the ESCC tissues. The SPDL1 expression was related to age in patients with ESCC. The SPDL1 co-expressed genes included those involved in cell division, cell cycle, DNA repair and replication, cell aging, and other processes. The high-risk scores of SPDL1-related long non-coding RNAs were significantly correlated with overall survival and cancer progression in patients with ESCC (P < 0.05). Inhibiting the SPDL1 expression was effective in suppressing the proliferation, migration, and invasion of ESCC TE-1 cells (P < 0.05). The overexpression of SPDL1 was positively correlated with the levels of Th2 and T-helper cells, and was negatively correlated with the levels of plasmacytoid dendritic cells and mast cells. In conclusion, SPDL1 was overexpressed in ESCC and was associated with immune cells. Further, inhibiting the SPDL1 expression could effectively slow down cancer cell growth and migration. SPDL1 is a promising biomarker for treating patients with ESCC. [ABSTRACT FROM AUTHOR]

In recent years, as more and more lung-cancer patients have been treated with immunotherapeutic agents, their survival has been prolonged compared to before. It is well known that BTK (Bruton's tyrosine kinase) is predominantly found in cells of the hematopoietic system. However, there is a distinct lack of literature on BTK expression in lung adenocarcinoma (LUAD) patients and its effect on the immune microenvironment. Consequently, the main goal of this investigation was to analyze how BTK expression in lung adenocarcinoma affects its progression, along with its prognostic significance, through the utilization of bioinformatics online resources and publicly available databases. Data on the sequencing results and clinical records of lung adenocarcinoma patients were gathered from The Cancer Genome Atlas (TCGA) database. Based on the expression level of BKT, TCGA categorized lung adenocarcinoma patients into BTK high-expression and low-expression groups. We investigated the effects of BKT on clinicopathologic, genomic, and immunologic characteristics of lung adenocarcinoma patients. We analyzed BTK mRNA expression in tumors and normal tissues using two key resources: Tumor Immuno Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). We analyzed the prognosis of the patients using GEPIA2 and validated the results using univariate and multivariate analyses. In addition, we assessed BTK protein expression by Human Protein Atlas (HPA). We sought to elucidate the clinical prognostic significance of BTK in The TCGA using the online tool GEPIA 2. Furthermore, to clarify the biologic roles and pathways linked to BTK, we conducted a genomic enrichment analysis of the information. To predict the proportion of various immune cell infiltrations in the immune microenvironment of lung adenocarcinoma patients diagnosed in the TCGA database, we performed an analysis using the TIMER online tool. Using TIMER and CIBERSORT, the correlation between genes co-expressed with BTK and the corresponding tumor-infiltrating immune cells was explored; finally, the relationship between BTK expression and immune infiltration and immune checkpoints in the TMB group and the high and low groups was analyzed by R language analysis using the TCGA database. The expression of BTK provides some hints about the prognosis of the patients. The high expression of BTK is involved in immune response regulation signaling pathways, leukocyte-mediated immunity, leukocyte intercellular adhesion, graft rejection, and complement. Analysis of the GEPIA 2 database showed that BTK was co-expressed with the genes FGD2, SASH3, NCKAP1L, CD53, ARHGAP30 and LPXN. Increased expression of the above-mentioned genes resulted in increased proportions of CD8 + T cells, memory CD4 + T cells, B cells, macrophages, and dendritic cells, and decreased proportions of Treg cells and TH2 cells. In addition, our study revealed a strong positive correlation between various key immune checkpoints (e.g., PDCD1, CD274, PDCD1LG2, CTLA4, HAVCR2, LAG3, TIGIT, and SIGLEC15) and BTK expression. In conclusion, increased BTK expression in lung adenocarcinoma is closely associated with prolonged survival of lung-cancer patients. Moreover, the genes classified under the BTK high-expression group exhibit significant enrichment in immune-related pathways, suggesting a potential impact on the tumor microenvironment. We investigated the potential of BTK as a tumor suppressor gene in predicting prolonged patient survival. In addition, we further investigated the possibility that BTK further affects the immunotherapeutic response of patients by influencing the microenvironment of tumor immune infiltration, but the relevant mechanisms remain to be further studied. [ABSTRACT FROM AUTHOR]

This article discusses the role of miR-10b-5p in alleviating the Th2 inflammatory response in allergic rhinitis. The study found that miR-10b-5p was downregulated in the nasal mucosa of mice with allergic rhinitis and that overexpression of miR-10b-5p decreased the levels of IgE and Th2 cytokines. The researchers identified the Src homology 2 domain-containing phosphatase 2 (SHP2) as a potential target of miR-10b-5p and demonstrated that miR-10b-5p reduced Th2 cell activation by downregulating SHP2. In a mouse model, miR-10b-5p and an SHP2 inhibitor alleviated allergic rhinitis symptoms and reduced Th2 inflammatory responses. These findings provide insights into the molecular mechanisms of allergic rhinitis and suggest potential treatment strategies. [Extracted from the article]

Aim: Pancreatic ductal adenocarcinoma (PAAD) is recognized as an exceptionally aggressive cancer that both highly lethal and unfavorable prognosis. The mitochondrial metabolism pathway is intimately involved in oncogenesis and tumor progression, however, much remains unknown in this area. In this study, the bioinformatic tools have been used to construct a prognostic model with mitochondrial metabolism-related genes (MMRGs) to evaluate the survival, immune status, mutation profile, and drug sensitivity of PAAD patients. Method: Univariate Cox regression and LASSO regression were used to screen the differentially expressed genes (DEGs), and multivariate Cox regression was used to develop the risk model. Kaplan–Meier estimator was employed to identify MMRGs signatures associated with overall survival (OS). ROC curves were utilized to evaluate the model's performance. Maftools, immunedeconv and CIBERSORT R packages were applied to analyze the gene mutation profiles and immune status. The corresponding sensitivity to pharmaceutical agents was assessed using oncoPredict R packages. Results: A prognostic model with five MMRGs was developed, which defined the patients as high-risk showed lower survival rates. There was good consistency among individuals categorized as high-risk, showing elevated rates of genetic alterations, particularly in the TP53 and KRAS genes. Furthermore, these patients exhibited increased levels of immunosuppression, characterized by an increased presence of macrophages, neutrophils, Th2 cells, and regulatory T cells. Additionally, high-risk patients showed increased sensitivity to Sabutoclax and Venetoclax. Conclusion: By utilizing a gene signature associated with mitochondrial metabolism, a prognostic model has been established which could be a highly efficient method for predicting the outcomes of PAAD patients. [ABSTRACT FROM AUTHOR]

Abstract\nPLAIN LANGUAGE SUMMARYSignal transducer and activator of transcription (STAT) 4 and STAT6 play a crucial role in immune cells by transducing signals from specific cytokine receptors, and inducing transcription of genes involved in cell-mediated and humoral immunity. These two different defense mechanisms against pathogens are regulated by two specific CD4+ T helper (Th) cells known as Th1 and Th2 cells. Many studies have shown that several diseases including cancer, inflammatory, autoimmune and allergic diseases are associated with a Th1/Th2 imbalance caused by increased or decreased expression/activity of STAT4 or STAT6 often due to genetic and epigenetic aberrances. An altered expression of STAT4 has been observed in different tumors and autoimmune diseases, while a dysregulation of STAT6 signaling pathway is frequently observed in allergic conditions, such as atopic dermatitis, allergic asthma, food allergy, and tumors such as Hodgkin and non-Hodgkin lymphomas. Recently, dysregulations of STAT4 and STAT6 expression have been observed in SARS-CoV2 and monkeypox infections, which are still public health emergencies in many countries. SARS-CoV-2 can induce an imbalance in Th1 and Th2 responses with a predominant activation of STAT6 in the cytosol and nuclei of pneumocytes that drives Th2 polarization and cytokine storm. In monkeypox infection the virus can promote an immune evasion by inducing a Th2 response that in turn inhibits the Th1 response essential for virus elimination. Furthermore, genetic variations of STAT4 that are associated with an increased risk of developing systemic lupus erythematosus seem to play a role in defense against SARS-CoV-2 infection.Signal transducer and activator of transcription (STAT) proteins are important and complex regulators of transcription that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. STAT proteins are phosphorylated/activated in the cytoplasm by Janus Kinases (JAKs) a family of nonreceptor tyrosine kinases associated to type I and type II cytokine receptors. There are seven STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. STAT4 is activated by IL-12 after binding with its specific receptor and induces the production in Th1 cells of IFN-γ, which allows these cells to be particularly effective in protecting against viruses and intracellular bacteria. STAT6 is activated by IL-4 and IL-13 and is required for the development of Th2 immune response and for the production of Th2 cytokines IL-4, IL-5, and IL-13 that contribute to humoral response with the synthesis of antigen specific antibodies in B cells. Although STAT4 plays an important role in many physiological functions, an altered expression of this transcription factor, often due to genetic and epigenetic aberrances, has been observed in different tumors and autoimmune diseases. Dysregulation of STAT6 signaling pathway, often caused by genetic mutations in the STAT6 gene, has been observed in several allergic conditions and tumors such as Hodgkin and non-Hodgkin lymphomas. [ABSTRACT FROM AUTHOR]

Summary The etiology of allergy is closely linked to type 2 inflammatory responses ultimately leading to the production of allergen‐specific immunoglobulin E (IgE), a key driver of many allergic conditions. At a high level, initial allergen exposure disrupts epithelial integrity, triggering local inflammation via alarmins including IL‐25, IL‐33, and TSLP, which activate type 2 innate lymphoid cells as well as other immune cells to secrete type 2 cytokines IL‐4, IL‐5 and IL‐13, promoting Th2 cell development and eosinophil recruitment. Th2 cell dependent B cell activation promotes the production of allergen‐specific IgE, which stably binds to basophils and mast cells. Rapid degranulation of these cells upon allergen re‐exposure leads to allergic symptoms. Recent advances in our understanding of the molecular and cellular mechanisms underlying allergic pathophysiology have significantly shaped the development of therapeutic intervention strategies. In this review, we highlight key therapeutic targets within the allergic cascade with a particular focus on past, current and future treatment approaches using monoclonal antibodies. Specific targeting of alarmins, type 2 cytokines and IgE has shown varying degrees of clinical benefit in different allergic indications including asthma, chronic spontaneous urticaria, atopic dermatitis, chronic rhinosinusitis with nasal polyps, food allergies and eosinophilic esophagitis. While multiple therapeutic antibodies have been approved for clinical use, scientists are still working on ways to improve on current treatment approaches. Here, we provide context to understand therapeutic targeting strategies and their limitations, discussing both knowledge gaps and promising future directions to enhancing clinical efficacy in allergic disease management. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionThe COVID-19 pandemic has caused significant morbidity and mortality globally. The role of plasma-derived extracellular vesicles (EVs) in pediatric COVID-19 patients remains unclear.We isolated EVs from healthy controls (n = 13) and pediatric COVID-19 patients (n = 104) with varying severity during acute and convalescent phases using serial ultracentrifugation. EV effects on healthy PBMCs, naïve CD4+ T cells, and monocytes were assessed through in vitro assays, flow cytometry, and ELISA.Our findings indicate that COVID-19 severity correlates with diverse immune responses. Severe acute cases exhibited increased cytokine levels, decreased IFNγ levels, and lower CD4+ T cell and monocyte counts, suggesting immunosuppression. EVs from severe acute patients stimulated healthy cells to express higher PDL1, increased Th2 and Treg cells, reduced IFNγ secretion, and altered Th1/Th17 ratios. Patient-derived EVs significantly reduced proinflammatory cytokine production by monocytes (p < .001 for mild, p = .0025 for severe cases) and decreased CD4+ T cell (p = .043) and monocyte (p = .033) populations in stimulated healthy PBMCs.This study reveals the complex relationship between immunological responses and EV-mediated effects, emphasizing the impact of COVID-19 severity. We highlight the potential role of plasma-derived EVs in early-stage immunosuppression in severe COVID-19 patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by autoimmune destruction of the myelin sheath, leading to irreversible and progressive functional deficits in patients. Pre-clinical studies involving the use of neural stem cells (NSCs) have already demonstrated their potential in neuronal regeneration and remyelination. However, the exclusive application of cell therapy has not proved sufficient to achieve satisfactory therapeutic levels. Recognizing these limitations, there is a need to combine cell therapy with other adjuvant protocols. In this context, extracellular vesicles (EVs) can contribute to intercellular communication, stimulating the production of proteins and lipids associated with remyelination and providing trophic support to axons. This study aimed to evaluate the therapeutic efficacy of the combination of NSCs and EVs derived from oligodendrocyte precursor cells (OPCs) in an animal model of multiple sclerosis. OPCs were differentiated from NSCs and had their identity confirmed by gene expression analysis and immunocytochemistry. Exosomes were isolated by differential ultracentrifugation and characterized by Western, transmission electron microscopy and nanoparticle tracking analysis. Experimental therapy of C57BL/6 mice induced with experimental autoimmune encephalomyelitis (EAE) were grouped in control, treated with NSCs, treated with OPC-derived EVs and treated with a combination of both. The treatments were evaluated clinically using scores and body weight, microscopically using immunohistochemistry and immunological profile by flow cytometry. The animals showed significant clinical improvement and weight gain with the treatments. However, only the treatments involving EVs led to immune modulation, changing the profile from Th1 to Th2 lymphocytes. Fifteen days after treatment revealed a reduction in reactive microgliosis and astrogliosis in the groups treated with EVs. However, there was no reduction in demyelination. The results indicate the potential therapeutic use of OPC-derived EVs to attenuate inflammation and promote recovery in EAE, especially when combined with cell therapy. [ABSTRACT FROM AUTHOR]

Aims: In addition to reducing the respiratory function, crystalline silica (SiO2) disturbs the immune response by affecting immune cells during the progression of silicosis. Regulatory T cell (Treg) differentiation may play a key role in the abnormal polarization of T helper cell (Th)1 and Th2 cells in the development of silicosis-induced fibrosis. Alpha-lipoic acid (ALA) has immunomodulatory effects by promoting Tregs differentiation. Thus, ALA may have a therapeutic potential for treating autoimmune disorders in patients with silicosis. However, little is known regarding whether ALA regulates the immune system during silicosis development. Results: We found that the expression levels of collagen increased, and the antioxidant capacity was lower in the Lias−/−+SiO2 group than in the Lias+/++SiO2 group. The proportion of Tregs decreased in the peripheral blood and spleen tissue in mice exposed to SiO2. The proportion of Tregs in the Lias−/−+SiO2 group was significantly lower than that in the Lias+/++SiO2 group. Supplementary exogenous ALA attenuates the accumulation of inflammatory cells and extracellular matrix in lung tissues. ALA promotes the immunological balance between Th17 and Treg responses during the development of silicosis-induced fibrosis. Innovation and Conclusion: Our findings confirmed that low expression of lipoic acid synthase aggravates SiO2-induced silicosis, and that supplementary exogenous ALA has therapeutic potential by improving Tregs in silicosis fibrosis. [ABSTRACT FROM AUTHOR]

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production—particularly IL-4/13—are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects. [ABSTRACT FROM AUTHOR]

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells. [ABSTRACT FROM AUTHOR]

Takayasu arteritis (TAK) is a granulomatous vasculitis that affects large arteries. T cells are important in TAK pathophysiology as these cells orchestrate granulomatous infiltration in arteries. This study aims to evaluate effector CD4+ T cells in the peripheral blood and the aortic wall of TAK patients and to analyze associations with disease activity and therapy. We performed a longitudinal study including 30 TAK patients and 30 controls. CD3+ T cells, CD3+CD4− T cells, CD4+ T cells, and Th1, Th2, and Th17 cells were evaluated in peripheral blood by flow cytometry, and the expression of CD4, CD8, Tbet, GATA-3, and RORγT was analyzed in the aorta of six patients by immunohistochemistry. TAK patients presented lower CD3+ T cells and CD4+ T cells (P = 0.031 and P = 0.039, respectively) than controls. Patients with active disease and those in remission had higher proportions of Th17 cells than controls (P = 0.016 and P = 0.004, respectively). Therapy for TAK did not result in significant differences concerning CD4+ effector T-cell subpopulations. Disease duration correlated with the number and percentage of Th2 cells (rho = −0.610 and rho = −0.463, respectively) and with Th17 cells (rho = −0.365 and rho = −0.568). In the aorta, the expression of CD8 was higher than CD4, whereas GATA-3, Tbet, and RORγT were expressed in this order of frequency. In conclusion, TAK patients present an increased Th17 response in the peripheral blood regardless of disease activity, whereas in the aortic tissue CD8 cells and the Th2 response were predominant. Patients with Takayasu arteritis present reduced CD4 + T cells and a predominance of Th17 cells compared to controls in the peripheral blood. Disease duration was correlated with Th2 and Th17 cells. In the aorta, CD8 prevailed over CD4, whereas GATA-3, Tbat, and ROR-gamma T were expressed in this order of frequency. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches. Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H4 receptor impacts TH2 cells and contributes to AD pathophysiology. Methods: Total CD4+ T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real‐time PCR and ELISA. Results: H4 receptor mRNA expression was upregulated concentration dependent upon IL‐4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL‐5 and IL‐13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H4 receptor‐selective‐agonist when compared to the untreated control. Conclusion: We show for the first time an H4 receptor dependent upregulation of the pro‐inflammatory cytokines IL‐5 and IL‐13 in human TH2 cells by histamine. This suggests that the blockade of the H4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies. [ABSTRACT FROM AUTHOR]

This article emphasizes the significance of colostrum, the initial milk produced by mothers after childbirth, in safeguarding infants against helminth infections. The study conducted on mice revealed that depriving them of colostrum resulted in reduced expansion of innate lymphoid type 2 cells (ILC2) and CD4+ T cells in the small intestine, making them more susceptible to helminth infection. Additionally, colostrum was found to influence the composition of gut microbiota and the secretion of alarmins, which are crucial for ILC2 proliferation and activation. The findings underscore the critical role of colostrum in guiding the development of the gut immune system and protecting against infections. The article also draws attention to the global issue of inadequate colostrum feeding and its impact on the health of newborns. [Extracted from the article]

This article discusses a study on the cytokines present in the sputum of severe asthma patients who have not responded to anti-inflammatory therapy. The study found that patients with persistently high levels of fractional exhaled nitric oxide (FeNO) after treatment had significantly higher levels of IL-13, a cytokine associated with Th2 inflammation. The study suggests that IL-13 may be a key factor in the regulation of FeNO levels in these patients. The findings have implications for the treatment of severe asthma and the need for further research in this area. [Extracted from the article]

Goto‐Kakizaki (GK) rats develop a well‐defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T‐regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata‐3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti‐inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM. [ABSTRACT FROM AUTHOR]

Background Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. Objectives To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. Methods Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. Results The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3 + Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. Conclusions Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus. [ABSTRACT FROM AUTHOR]

Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL‐10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL‐10 in macrophages of BALF was associated with the levels of asthma‐related parameters. The immune‐suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL‐10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL‐10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG. [ABSTRACT FROM AUTHOR]

BACKGROUND: Food allergy has become a global public health problem. This study aimed to explore the possible anti‐allergic effect of vitamin C (VC). A rat basophilic leukemia (RBL)‐2H3 cell degranulation model was used to assess the effect of VC on degranulation in vitro, and an ovalbumin (OVA)‐induced BALB/c mouse allergy model was used to assess the anti‐allergy effect of VC in vivo. RESULTS: In vitro, VC significantly attenuated the release of β‐hexosaminidase, tryptase and histamine, and also reduced cytokine production (interleukins 4 and 6, tumor necrosis factor α) significantly (P < 0.05), with the inhibitory effect demonstrating a positive correlation with VC dose. In vivo, compared with the OVA group, the levels of serum immunoglobulins E and G1 of the VC low‐dose (VCL) group (50 mg kg−1) and high‐dose (VCH) group (200 mg·kg−1) were significantly reduced (P < 0.05). Furthermore, the plasma histamine level was also significantly decreased (P < 0.05). Moreover, TH2 cell polarization in mice of the VCL and VCH groups was significantly inhibited (P < 0.05), promoting the TH1/TH2 cell polarization balance. Additionally, VC treatment enhanced the expression of CD80 (P < 0.05) in spleen and small intestine tissues, while significantly inhibiting the expression of CD86 (P < 0.05); notably, high‐dose VC treatment was more effective. CONCLUSION: VC exerted an anti‐allergic effect through inhibiting degranulation and regulating TH1/TH2 cell polarization balance. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model. [ABSTRACT FROM AUTHOR]

Different delivery methods can cause variations in the composition and structure of intestinal microbiota in neonates. However, the impact of the microecological environment on host immune function requires further investigation. In this study, 75 healthy neonates were divided into two groups: vaginal delivery group (n = 36) and cesarean section group (n = 39). Fecal and peripheral blood samples were collected from the 7th to the 10th day. 16S rRNA sequencing technique was performed to investigate the gut microbiota on fecal samples. Levels of immunoglobulins and Th1 and Th2 cells in the peripheral blood of neonates were measured. The abundance of Escherichia, Bifidobacterium, and Bacteroides in neonates in the cesarean section group was significantly lower than that in the vaginal delivery group. Metabolic pathway analysis showed three significantly up-regulated metabolic pathways in the intestinal microbiota of neonates in the cesarean section group. The levels of serum IgG and IL-12p70 in the cesarean section group were lower than those in the vaginal delivery group, and the proportion of IFN-γ/IL-4 was significantly lower in the cesarean section group compared to the vaginal delivery group. The mode of delivery has potential impact on the intestinal microbiota and immune functions of neonates, potentially leading to an imbalance of Th1/Th2 cells in neonates delivered by cesarean section. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Approximately 70% of individuals allergic to birch pollen (Bet v 1.01 [Bet]) develop a secondary food allergy (e.g., hazelnut: Cor a 1.04 [Cor]), due to allergen cross‐reactivity. However, standard immunotherapy for type I allergies often does not improve the food allergy sufficiently. We analyzed the allergen‐specific and cross‐reactive suppressive capacity of primary human regulatory T cells (Treg) induced by autologous IL‐10‐modulated dendritic cells (IL‐10 DC) in vitro and in vivo.CD4+ T cells of patients with birch pollen and associated hazelnut allergies were differentiated into Bet‐specific or non‐specific induced Treg (iTreg). After Bet‐ or Cor‐specific restimulation the phenotype, proliferation, and suppressive capacity of iTreg subsets were analyzed. iTreg function was further investigated in humanized mouse models of airway and intestinal allergy, generated by engraftment of peripheral blood mononuclear cells from allergic donors into immunodeficient animals.After IL‐10 DC priming and allergen‐specific restimulation (Bet or Cor), non‐specific control iTreg remained anergic, whereas Bet‐specific iTreg proliferated extensively and exhibited a regulatory phenotype (enhanced expression of CTLA‐4, PD‐1, TNFR2, IL‐10). Accordingly, activated Bet‐specific iTreg displayed a high capacity to suppress Bet‐ and Cor‐induced responder Th2 cell responses in vitro, indicating induction of both allergen‐specific (birch) and cross‐reactive tolerance (hazelnut). In vivo, the beneficial effect of Bet‐specific iTreg was verified in humanized mouse models of allergic airway and intestinal inflammation, resulting in reduced allergen‐induced clinical symptoms, and immune responses.Human IL‐10 DC‐induced iTreg facilitate allergen‐specific and cross‐reactive tolerance. Therefore, they are potential candidates for regulatory cell therapy in allergic and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease, and its development is the result of a combination of factors, including genetic factors, environmental factors, immune dysfunction and other factors. Its specific mechanism has not yet been fully investigated. With the improvement of disease models, research on the pathogenesis of asthma has made great progress. Immunological disorders play an important role in asthma. Previously, we thought that asthma was mainly caused by an imbalance between Th1 and Th2 immune responses, but this theory cannot fully explain the pathogenesis of asthma. Recent studies have shown that T-cell subsets such as Th1 cells, Th2 cells, Th17 cells, Tregs and their cytokines contribute to asthma through different mechanisms. For the purpose of the present study, asthma was classified into distinct phenotypes based on airway inflammatory cells, such as eosinophilic asthma, characterized by predominant eosinophil aggregates, and neutrophilic asthma, characterized by predominant neutrophil aggregates. This paper will examine the immune mechanisms underlying different types of asthma, and will utilize data from animal models and clinical studies targeting specific immune pathways to inform more precise treatments for this condition. [ABSTRACT FROM AUTHOR]

Introduction: Maternal obesity poses risks for both mother and offspring during pregnancy, with underlying mechanisms remaining largely unexplored. Obesity is associated with microbial gut dysbiosis and low-grade inflammation, and also the diet has a major impact on these parameters. This study aimed to investigate how maternal obesity and diet contribute to changes in immune responses, exploring potential associations with gut microbiota dysbiosis and adverse pregnancy outcomes in mice. Methods: Before mating, C57BL/6 mice were assigned to either a high-fat-diet (HFD) or low-fat-diet (LFD) to obtain obese (n=17) and lean (n=10) mice. To distinguish between the effects of obesity and diet, 7 obese mice were switched from the HFD to the LFD from day 7 until day 18 of pregnancy (“switch group”), which was the endpoint of the study. T helper (Th) cell subsets were studied in the spleen, mesenteric lymph nodes (MLN) and Peyer’s patches (PP), while monocyte subsets and activation status were determined in maternal blood (flow cytometry). Feces were collected before and during pregnancy (day 7,14,18) for microbiota analysis (16S rRNA sequencing). Pregnancy outcome included determination of fetal and placental weight. Results: Obesity increased splenic Th1 and regulatory T cells, MLN Th1 and PP Th17 cells and enhanced IFN-g and IL-17A production by splenic Th cells upon ex vivo stimulation. Switching diet decreased splenic and PP Th2 cells and classical monocytes, increased intermediate monocytes and activation of intermediate/ nonclassical monocytes. Obesity and diet independently induced changes in the gut microbiota. Various bacterial genera were increased or decreased by obesity or the diet switch. These changes correlated with the immunological changes. Fetal weight was lower in the obese than the lean group, while placental weight was lower in the switch than the obese group. Discussion: This study demonstrates that obesity and diet independently impact peripheral and intestinal immune responses at the end of pregnancy. Simultaneously, both factors affect specific bacterial gut genera and lead to reduced fetal or placental weight. Our data suggest that switching diet during pregnancy to improve maternal health is not advisable and it supports pre/ probiotic treatment of maternal obesity-induced gut dysbiosis to improve maternal immune responses and pregnancy outcome. [ABSTRACT FROM AUTHOR]

Introduction: Allergic rhinitis (AR) is an upper airway inflammatory disease of the nasal mucosa. Conventional treatments such as symptomatic pharmacotherapy and allergen-specific immunotherapy have considerable limitations and drawbacks. As an emerging therapy with regenerative potential and immunomodulatory effect, mesenchymal stem cell-derived exosomes (MSC-Exos) have recently been trialed for the treatment of various inflammatory and autoimmune diseases. Methods: In order to achieve sustained and protected release of MSC-Exos for intranasal administration, we fabricated Poly(lactic-co-glycolic acid) (PLGA) micro and nanoparticles-encapsulated MSC-Exos (PLGA-Exos) using mechanical double emulsion for local treatment of AR. Preclinical in vivo imaging, ELISA, qPCR, flow cytometry, immunohistochemical staining, and multiomics sequencing were used for phenotypic and mechanistic evaluation of the therapeutic effect of PLGA-Exos in vitro and in vivo. Results: The results showed that our PLGA platform could efficiently encapsulate and release the exosomes in a sustained manner. At protein level, PLGA-Exos treatment upregulated IL-2, IL-10 and IFN-γ, and downregulated IL-4, IL-17 and antigen-specific IgE in ovalbumin (OVA)-induced AR mice. At cellular level, exosomes treatment reduced Th2 cells, increased Tregs, and reestablished Th1/Th2 balance. At tissue level, PLGA-Exos significantly attenuated the infiltration of immune cells (e.g., eosinophils and goblet cells) in nasal mucosa. Finally, multiomics analysis discovered several signaling cascades, e.g., peroxisome proliferator-activated receptor (PPAR) pathway and glycolysis pathway, that might mechanistically support the immunomodulatory effect of PLGA-Exos. Discussion: For the first time, we present a biomaterial-facilitated local delivery system for stem cell-derived exosomes as a novel and promising strategy for AR treatment. [ABSTRACT FROM AUTHOR]

Lymphedema occurs as a result of lymphatic vessel damage or obstruction, leading to the lymphatic fluid stasis, which triggers inflammation, tissue fibrosis, and adipose tissue deposition with adipocyte hypertrophy. The treatment of lymphedema is divided into conservative and surgical approaches. Among surgical treatments, methods like lymphaticovenular anastomosis and vascularized lymph node transfer are gaining attention as they focus on restoring lymphatic flow, constituting a physiologic treatment approach. Lymphatic endothelial cells form the structure of lymphatic vessels. These cells possess button-like junctions that facilitate the influx of fluid and leukocytes. Approximately 10% of interstitial fluid is connected to venous return through lymphatic capillaries. Damage to lymphatic vessels leads to lymphatic fluid stasis, resulting in the clinical condition of lymphedema through three mechanisms: Inflammation involving CD4+ T cells as the principal contributing factor, along with the effects of immune cells on the VEGF-C/VEGFR axis, consequently resulting in abnormal lymphangiogenesis; adipocyte hypertrophy and adipose tissue deposition regulated by the interaction of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ; and tissue fibrosis initiated by the overactivity of Th2 cells, leading to the secretion of profibrotic cytokines such as IL-4, IL-13, and the growth factor TGF-β1. Surgical treatments aimed at reconstructing the lymphatic system help facilitate lymphatic fluid drainage, but their effectiveness in treating already damaged lymphatic vessels is limited. Therefore, reviewing the pathophysiology and molecular mechanisms of lymphedema is crucial to complement surgical treatments and explore novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Parasite diseases are recognized as major concerns in the fugu aquaculture industry in China. While understanding the genetic mechanisms of immune response is a crucial step which can facilitate disease control and selective breeding. In this study, transcriptome analysis was performed to identify key genes and understand the underlying mechanisms associated with Cryptocaryon irritans resistance. Finally, our study provided insights into the immunosuppression in fugu under C. irritans infection. The tiger pufferfish (Takifugu rubripes), also known as fugu, has recently suffered from severe C. irritans infections under aquaculture environment, yet the underlying immune mechanisms against the parasite remain poorly understood. In this study, we conducted a comprehensive transcriptome analysis of the gill tissue from infected and uninfected fish using PacBio long-read (one pooled sample each for seriously infected and healthy individuals, respectively) and Illumina short-read (three pools for mildly infected, seriously infected, and healthy individuals, respectively) RNA sequencing technologies. After aligning sequence data to fugu's reference genome, 47,307 and 34,413 known full-length transcripts were identified and profiled in healthy and infected fish, respectively. Similarly, we identified and profiled 1126 and 803 novel genes that were obtained from healthy and infected fish, respectively. Interestingly, we found a decrease in the number of alternative splicing (AS) events and long non-coding RNAs (lncRNAs) after infection with C. irritans, suggesting that they may be involved in the regulation of the immune response in fugu. There were 687 and 1535 differentially expressed genes (DEGs) in moderately and heavily infected fish, respectively, compared to uninfected fish. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that immune-related DEGs in the two comparison groups were mainly enriched in cytokine-cytokine receptor interactions, ECM-receptor interactions, T-cell receptor signaling pathways, Th1 and Th2 cell differentiation, and Th17 cell differentiation pathways. Further analysis revealed that a large number of immune-related genes were downregulated in infected fish relative to uninfected ones, such as CCR7, IL7R, TNFRSF21, CD4, COL2A1, FOXP3B, and ITGA8. Our study suggests that C. irritans is potentially a highly efficient parasite that may disrupt the defense mechanisms of fugu against it. In addition, in combination of short-read RNA sequencing and previous genome-wide association analyses, we identified five key genes (NDUFB6, PRELID1, SMOX, SLC25A4, and DENND1B) that might be closely associated with C. irritans resistance. This study not only provides valuable resources of novel genic transcripts for further research, but also provides new insights into the immune mechanisms underlying C. irritans infection response in farmed fugu. [ABSTRACT FROM AUTHOR]

Objective: Cuproptosis is a novel cell death dependent on mitochondrial respiration and regulated by copper. This study aimed to investigate the cuproptosis‐related gene DLAT potential value in gastric cancer (GC). Methods: Bioinformatics was used to analyze DLAT expression. DLAT expression in GC cell lines was detected using qRT‐PCR. Cell proliferation ability was assessed using CCK8 and cell cycle assay. Cell migration and invasion were assessed using wound healing and transwell assay. A prognostic assessment was performed through survival and Cox regression analysis. DLAT protein expression was analyzed through HPA immunohistochemistry. Biological functions and processes were analyzed through GO and KEGG enrichment analysis and PPI. Correlation with immune cell infiltration and immune checkpoint genes was analyzed for DLAT. Results: DLAT expression was upregulated in GC tissues and cells and correlated with shorter survival for patients. Age, gender, histological typing, lymph node metastasis, and distant metastasis were identified as independent prognostic factors affecting OS in GC. DLAT protein was upregulated in GC. The biological functions and pathways enriched in DLAT were mainly linked to mitochondrial respiration and the TCA cycle. The expression of DLAT was found to be positively correlated with the infiltration of Th and Th2 immune cells and only positively correlated with the expression of the BTN2A1 immune checkpoint gene. Conclusion: DLAT has the potential to serve as a prognostic assessment factor in GC. The expression of DLAT was correlated with immune infiltration and tumor immune escape, providing a new target for immunotherapy of GC. [ABSTRACT FROM AUTHOR]

Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1− late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development. The transcription factor GATA3 is enhanced in innate lymphoid type 2 cells (ILC2). Here the authors characterize the super enhancer regions of GATA3 and show that these enhancers are required to drive GATA3 expression and stage specific ILC2 development. [ABSTRACT FROM AUTHOR]

Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα−/− mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy. Collectively, our findings suggest the involvement of Th2 cells in allergic asthma (AA) by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy. This summary graph shows allergen-induced IL-18 and IL-18Rα expressions in blood CD4, Th2, and Th17 cells of AA. Graphical Abstract [ABSTRACT FROM AUTHOR]

This mathematical model delves into the dynamics of the immune system during Chronic Myeloid Leukemia (CML) therapy with imatinib. The focus lies in elucidating the allergic reactions induced by imatinib, specifically its impact on T helper (Th) cells and Treg cells. The model integrates cellular interactions, drug pharmacokinetics, and immune responses to unveil the mechanisms underlying the dominance of Th2 over Th1 and Treg cells, leading to allergic manifestations. Through a system of coupled delay differential equations, the interplay between healthy and leukemic cells, the influence of imatinib on T cell dynamics, and the emergence of allergic reactions during CML therapy are explored. [ABSTRACT FROM AUTHOR]

Asthma is a widespread airway disorder where GATA3-dependent Type-2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma-associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926-970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma-associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP-qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral T cell subsets. We next generated mice lacking the mG900 region (mG900KO mice) were generated by the CRISPR-Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady-state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady-state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM-induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high-throughput sequencing (4C-seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a neurological disorder that causes disability and paralysis, especially among young adults. Although interactions of several factors, such as viral infections, autoimmunity, genetic and environmental factors, performance a role in the beginning and progression of the disease, the exact cause of MS is unknown to date. Different immune cells such as Th1 and Th17 play an impressive role in the immunopathogenesis of MS, while, regulatory cells such as Th2 and Treg diminish the severity of the illness. Sex hormones have a vital role in many autoimmune disorders, including multiple sclerosis. Testosterone, estrogen and progesterone have various roles in the progress of MS, which higher prevalence of disease in women and more severe in men reveals the importance of sex hormones' role in this disease. Vitamin D after chemical changes in the body, as an active hormone called calcitriol, plays an important role in regulating immune responses and improves MS by modulating the immune system. The optimum level of calcium in the body with vitamin D modulates immune responses and calcium as an essential ion in the body plays a key role in the treatment of autoimmune diseases. The interaction between vitamin D and sex hormones has protective and therapeutic effects against MS and functional synergy between estrogen and calcitriol occurs in disease recovery. Moreover, vitamin D and calcium interact with each other to regulate the immune system and shift them to anti-inflammatory responses. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease that can be broadly classified into type 2, which is primarily steroid-sensitive and eosinophilic, and non-type 2, which is primarily steroid-resistant and neutrophilic. While the mechanisms leading to the development of molecular-targeted therapies for type 2 asthma are being elucidated, much remains to be learned about non-type 2 asthma. To investigate the role of oxidative stress in refractory allergic airway inflammation, we compared asthma models generated by immunizing wild-type and nuclear factor erythroid-2-related factor 2 (Nrf2)-deficient mice with the house dust mite antigen. Both asthma models had similar levels of airway inflammation and hyperresponsiveness, but the Nrf2-deficient mice had increased oxidative stress and exacerbated neutrophilic airway inflammation compared with the wild-type mice. Type 2 cytokines and the expression of GATA3, a transcription factor that is important for Th2 cell differentiation, had decreased in Nrf2-deficient mice compared with the wild-type mice, whereas helper T (Th) 17 cytokines and the expression of RORγt, which is important for Th17 cell differentiation, had increased. Furthermore, the neutrophilic airway inflammation caused by Nrf2 deficiency was ameliorated by interleukin (IL)-17 neutralization. We have concluded that the disruption of the Nrf2-mediated antioxidant defense system contributed to the induction of Th17 differentiation and exacerbated allergic neutrophilic airway inflammation. [ABSTRACT FROM AUTHOR]

Objective: Epicardial adipose tissue (EAT) is a visceral fat that has been associated with coronary artery disease and atrial fibrillation. Previous work has revealed that EAT exhibits beige features. Methods: First, a new pan‐genomic microarray analysis was performed on previously collected paired human EAT and thoracic subcutaneous AT (thSAT) from the EPICAR study (n = 31) to decipher a specific immune signature and its link with browning genes. Then, adaptive (T and B cells) and innate lymphoid cell (ILC1, ILC2, and ILC3) immunophenotyping assay panels, including CD127, CD117, and prostaglandin D2 receptor 2, were performed on prospectively collected paired human multiorgan donors (n = 18; INTERFACE study). Results: In the EPICAR study, a positive correlation between the T helper cell subtype Th2 immune pathway and browning genes was found in EAT versus thSAT (r = 0.82; p < 0.0001). In the INTERFACE study, this correlation was also observed (r = 0.31; p = 0.017), and a preponderance of CD4+T cells, CD8+T cells, and a few B cells was observed in all ATs (p < 0.0001). An increase in ILCs was observed in visceral AT (VAT) (i.e., EAT + VAT; 30 ± 5 ILCs per gram of AT) compared with subcutaneous counterparts (i.e., thSAT + abdominal SAT; 8 ± 2 ILCs per gram of AT; p = 0.001), with ILC1 being the most frequent (ILC1 > ILC3 > ILC2). Numbers of ILCs per gram of AT correlated with several Th2 or browning genes (IL‐13, TNF receptor superfamily member 9 [TNFRSF9], and alkaline phosphatase, biomineralization associated [ALPL]). Interestingly, a specific increase in EAT‐ILC2 compared with other ATs was observed, including a significant proportion expressing CD69 and/or CD25 activation markers (97.9% ± 1.2%; p < 0.0001). Finally, more natural killer cells were observed in EAT + VAT than in thSAT + abdominal SAT (p = 0.01). Exclusion of patients with coronary artery disease in the EPICAR and INTERFACE studies did not modify the main findings. Gene expression phenotyping confirmed specific upregulation of Th2 pathway and browning genes (IL‐33 and uncoupling protein 1 [UCP‐1]) in EAT. Conclusions: This is the first study, to our knowledge, to provide a comparison between innate and adaptive lymphoid cells in human EAT. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. [ABSTRACT FROM AUTHOR]

Background: Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. The relevance of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, has been investigated in several inflammatory diseases, including allergic asthma. However, its potential role in AIT still needs to be addressed. Methods: Amurinemodel of AIT in ovalbumin-induced allergic airway inflammation was performed in AhR-deficient (AhR-/-) and wild-type mice. Furthermore, AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7Hbenzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome. Results: Although AhR-/- mice suffer stronger allergic responses than wild-type mice, experimental AIT is comparably effective in both. Nevertheless, combining AIT with the administration of 10-Cl-BBQ improved therapeutic effects by an AhRdependent mechanism, resulting in decreased cell counts in the bronchoalveolar fluid, decreased pulmonary Th2 and Th17 cell levels, and lower sIgE levels. Conclusion: This study demonstrates that the success of AIT is not dependent on the AhR. However, targeting the AhR during AIT can help to dampen inflammation and improve tolerogenic vaccination. Therefore, AhR ligands might represent promising candidates as immunomodulators to enhance the efficacy of AIT. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1- phenotype is restricted to the synovial lining layer. In contrast, the THY1+ phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis (S. epidermidis). Objective: To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp). Methods: To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry. Results: We identified Esp as the dominant candidate allergen of S. epidermidis. Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients’ T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33. Conclusion: The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp. Graphical abstract [ABSTRACT FROM AUTHOR]

Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity. Type 2 innate lymphoid cells are instrumental to the early phases of pulmonary allergic inflammation, but the negative regulation that leads to their inhibition in the resolution phase is less known. Here authors show that SLAM-family receptors control Il-13 production and NF-κB activation in the mediastinal lymph nodes but not in the lung, eventually setting a limit to lung inflammation. [ABSTRACT FROM AUTHOR]

Introduction: We investigated the function of type 2 innate lymphoid cells (ILC2s) and IL-33 in pulmonary tuberculosis (PTB). Methodology: Peripheral blood samples were collected from PTB patients and healthy controls. The cytometric bead array was used to detect plasma IL-33, TGF-β, IL-4, IL-5, IL-6, IL-10, IL-13, and soluble ST2 (sST2). ILC2s, Th2, and Treg cells were detected with flow cytometry. Quantitative real-time PCR was used to measure mRNA levels. ILC2s were co-cultured with peripheral blood mononuclear cells and then intervened with IL-33 or anti-ST2 antibody + IL-33 in vitro. IL-4, IL-6, IL-5, IL-10, IL-13, and TGF-β levels were measured by enzyme-linked immunosorbent assay. Results: Compared with healthy controls, the levels of IL-33, sST2, TGF-β, IL-10, and IL-6 in the plasma of PTB patients were significantly higher. No significant difference was found in the plasma IL-4, IL-5, and IL-13 levels. Patients with PTB had significantly increased ILC2s proportion and mRNA levels of RAR-related orphan receptor α and GATA binding protein 3. After 48 h of IL-33 stimulation in vitro, Treg cell proportion significantly increased and the IL-10 level was significantly elevated. Treatment with anti-ST2 abolished these effects. No significant difference was found in cytokines of IL-4, IL-6, IL-5, IL-13, and TGF-β, or Th2 cells before and after IL-33 treatment. ILC2s proportion in peripheral blood was increased and plasma IL-33 was upregulated in PTB patients. Conclusions: IL-33 may promote the growth of ILC2s and the production of Treg-related cell cytokines, but not Th2-related cell cytokines, to participate in immune response to PTB. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis is an allergen-induced immune response secondary to the binding of immunoglobulin-E (IgE) to sensitized mast cells. Approximately 40% of North Americans and 20% of the world's population are impacted by some form of allergy and it continues to increase in prevalence, especially among children. Specified IgE antibodies can be found in almost all cases of exposure to seasonal or perennial allergens. Activation and degranulation of mast cells lead to increased tear levels of histamine, tryptase, leukotrienes, cytokines, and prostaglandins. The release of these factors initiates the recruitment of inflammatory cells in the conjunctival mucosa, which causes the late-phase reaction. Signs and symptoms of ocular allergies include itching, tearing, chemosis, and hyperemia, which can lead to decreased productivity and poor quality of life. Many treatment options are available to improve symptoms, including, mast cell stabilizers, antihistamines, dual-acting agents, steroids, nonsteroidal anti-inflammatory drugs (NSAIDS), and other off-label treatment modalities. This review article provides an overview of different types of allergic conjunctivitis, its pathology and immunology, and recommended methods of treatment. [ABSTRACT FROM AUTHOR]

The ubiquitous soil-associated fungus Cryptococcus neoformans causes pneumonia that may progress to fatal meningitis. Recognition of fungal cell walls by C-type lectin receptors (CLRs) has been shown to trigger the host immune response. Caspase recruitment domain-containing protein 9 (Card9) is an intracellular adaptor that is downstream of several CLRs. Experimental studies have implicated Card9 in host resistance against C. neoformans; however, the mechanisms that are associated with susceptibility to progressive infection are not well defined. To further characterize the role of Card9 in cryptococcal infection, Card9em1Sq mutant mice that lack exon 2 of the Card9 gene on the Balb/c genetic background were created using CRISPR-Cas9 genome editing technology and intratracheally infected with C. neoformans 52D. Card9em1Sq mice had significantly higher lung and brain fungal burdens and shorter survival after C. neoformans 52D infection. Susceptibility of Card9em1Sq mice was associated with lower pulmonary cytokine and chemokine production, as well as reduced numbers of CD4+ lymphocytes, neutrophils, monocytes, and dendritic cells in the lungs. Histological analysis and intracellular cytokine staining of CD4+ T cells demonstrated a Th2 pattern of immunity in Card9em1Sq mice. These findings demonstrate that Card9 broadly regulates the host inflammatory and immune response to experimental pulmonary infection with a moderately virulent strain of C. neoformans. [ABSTRACT FROM AUTHOR]

Background: The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system. Objective: The present study aims to evaluate the effects of Toxocara cati (T. cati) somatic products on allergic airway inflammation. Methods: Between 2018 and 2020, T. cati adult worms were collected from stray cats in Mashhad, Iran (31 out of 186 cats), and their somatic extract was collected. Thirty BALB/c mice were equally divided into three groups, including the OVA group (sensitized and challenged with ovalbumin), the somatic administered group (received somatic extract along with ovalbumin sensitization), and the PBS group (sensitized and challenged with phosphate buffer saline). Bronchoalveolar lavage (BAL) fluid was collected to assess the number of cells, and lung homogenates were prepared for cytokine analysis. Histopathological analysis of the lungs was performed, and inflammatory cells and mucus were detected. Cytokine levels (IL‐4, IL‐5, IL‐10) were measured using enzyme‐linked immunosorbent assay (ELISA), and ovalbumin‐specific immunoglobulin E (IgE) levels were determined using a capture ELISA. Results: The somatic group significantly decreased regarding the lung pathological changes, including peribronchiolitis, perivasculitis, and eosinophil influx, compared to the group treated with ovalbumin alone. These changes were accompanied by a decrease in proinflammatory cytokines IL‐4 and IL‐5 and an increase in the anti‐inflammatory cytokine IL‐10, indicating a shift toward a more balanced immune response. The number of inflammatory cells in the BAL fluid was also significantly reduced in the somatic group, indicating a decrease in inflammation. Conclusion: These preclinical findings suggest that in experimental models, T. cati somatic extract exhibits promising potential as a therapeutic agent for mitigating allergic airway inflammation. Its observed effects on immune response modulation and reduction of inflammatory cell infiltration warrant further investigation in clinical studies to assess its efficacy and safety in human patients. Highlights: Allergic asthma is linked to Th2 cell responses, while corticosteroid side effects discourage patients.The hygiene hypothesis suggests helminth infections could reduce immune hypersensitivity.The administration of Toxocara cati somatic extract significantly decreased lung pathological changes associated with allergic airway inflammation, including peribronchiolitis, perivasculitis, and eosinophil influx.This reduction was accompanied by a shift in cytokine levels, with decreases in proinflammatory cytokines IL‐4 and IL‐5 and an increase in the anti‐inflammatory cytokine IL‐10, suggesting a rebalancing of the immune response.The somatic extract treatment significantly reduced inflammatory cell infiltration in the bronchoalveolar lavage fluid, indicating a decrease in overall inflammation within the airways. [ABSTRACT FROM AUTHOR]

Objectives: Sleep disturbance is common in autoimmune rheumatism diseases (ARD) and it plays an important role in activating disease and affects the quality of life. This study aims to evaluate the efficacy and acceptability of the novel electrical therapy on sleep disturbance in ARD patients and its effect on immunologic factors. Methods: A total of 51 ARD patients (26 treatment group and 25 control group) with sleep disturbance were enrolled in this study. Sleep parameters and immunological indicators (serum level of 12 cytokines and immune function) were collected. The novel electrical therapy was prescribed for 15–30 min 3–6 times a day. The Pittsburg Sleep Index (PSQI) was assessed before and after 3 months' treatment by Mi Energy equipment. Immune function and serum levels of cytokines of all participants at baseline and after treatment were tested with flow cytometry and flow immunofluorescence, respectively. Correlation analysis was used to analyze the relationship between sleep disturbance and immunologic factors. Multiple linear regression analysis was employed to investigate the risk of sleep disturbance in ARD. Results: The global score of PSQI (Baseline: 12.81 ± 4.07, After novel electrical therapy: 4.88 ± 2.76) was effectively improved after 3 months of adjuvant therapy by electrical therapy. We also found that serum levels of IL‐8 and IL‐1β statistically significantly decreased after novel electrical therapy. This adjuvant therapy can also significantly decrease the percentage of CD4 + CD8 + T cell, effector memory CD8 + T cell, Memory CD8 + T cell, Th17 cell, and plasma cell and significantly can increase the percentage of naïve CD8 + T cell, Th2 cell, and Tfh2 cell. Nevertheless, all serum level of 12 cytokines and the percentage of immune cells did not correlate with the PSQI global score except the Tc17 cell. Furthermore, age is an independent risk factor influencing PSQI scores (OR = 1.15, p < 0.05) in patients with autoimmune diseases through multiple linear regression analysis. Conclusions: Novel electrical therapy can effectively improve sleep disturbance in patients with ARD. It can also change the serum level of some cytokines (IL‐8 and IL‐1β) and percentage of immune cells (CD4 + CD8 + T cell, effector memory CD8 + T cell, Memory CD8 + T cell, Th17 cell, naïve CD8 + T cell, Th2 cell, Tfh2 cell, and plasma cell). [ABSTRACT FROM AUTHOR]