RESUMO
BACKGROUND: Subcutaneous immunotherapy (SCIT) can induce systemic reactions (SRs) in certain patients, but the underlying mechanisms remain to be fully elucidated. METHODS: AR patients who were undergoing standardized HDM SCIT (Alutard, ALK) between 2018 and 2022 were screened. Those who experienced two consecutive SRs were included in the study group. A control group was established, matched 1:1 by gender, age, and disease duration with the study group, who did not experience SRs during SCIT. Clinical and immunological parameters were recorded and analyzed both before SCIT and after 1 year of treatment. RESULTS: A total of 161 patients were included, with 79 (49.07%) in the study group. The study group had a higher proportion of AR combined asthma (26.8% vs. 51.8%, p < 0.001) and higher levels of sIgE to HDM and HDM components (all p < .001). Serum IL-4 and IL-13 levels in the study group were higher than those in the control group (p < .05). The study group received a lower maintenance dosage of HDM extracts injections than control group due to SRs (50000SQ vs. 100000SQ, p < .05). After 1 year of SCIT, the VAS score, the lung function parameters of asthmatic patients over 14 years old significantly improved in both groups (all p < .05). After a 7-day exposure to 20 µg/mL HDM extracts, the percentages of Th1, Th17, Tfh10, and Th17.1 in PBMCs decreased, while the Tfh13 cells significantly increased in the study group (p < .05). CONCLUSION: The type 2 inflammatory response is augmented in HDM-induced AR patients who experienced SRs during SCIT. Despite this, SCIT remains effective in these patients when administered with low-dosage allergen extracts.
Assuntos
Dessensibilização Imunológica , Pyroglyphidae , Rinite Alérgica , Humanos , Masculino , Feminino , Dessensibilização Imunológica/métodos , Criança , Rinite Alérgica/imunologia , Rinite Alérgica/terapia , Pyroglyphidae/imunologia , Injeções Subcutâneas , Animais , Adolescente , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/administração & dosagem , Asma/imunologia , Asma/terapia , Imunoglobulina E/sangue , Alérgenos/imunologia , Alérgenos/administração & dosagem , Células Th2/imunologiaRESUMO
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.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Neoplasias Pancreáticas , Esfingomielinas , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1/metabolismo , Esfingomielinas/metabolismo , Citocinas/metabolismo , Linhagem Celular Tumoral , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Células Th17/imunologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Nanopartículas/química , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacosRESUMO
Introduction: Asthma, a chronic respiratory disease closely associated with inflammation, presents ongoing treatment challenges. IALLIPF (le-Ala-Leu-Leu-Ile-Pro-Phe) is one of millet prolamins peptides (MPP) which shows anti-oxidant bioactivity by reducing the production of reactive oxygen species (ROS). Tryptophan (Trp, W) is an amino acid that has been demonstrated to possess anti-inflammatory effects. We introduce a novel cathepsin B-activatable bioactive peptides nanocarrier, PEG-IALLIPF-GFLG-W (MPP-Trp), designed for immunotherapy of asthma. Methods: MPP-Trp is synthesized, purified, and its characteristics are investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) are examined to evaluate anti-inflammatory effects of IALLIPF, Trp and MPP-Trp. The immunomodulatory effects of IALLIPF, Trp and MPP-Trp on Th1/Th2 cell populations and cytokines are investigated by flow cytometry, qRT-PCR and ELISA assays. We explore the therapeutic effect of MPP-Trp in the mouse model of asthma by the analysis of lung histology and ELISA. It is necessary to study the biocompatibility of MPP-Trp by CCK8 assay and histopathologic analysis using hematoxylin and eosin (HE) staining. Results: In asthmatic peripheral blood mononuclear cells (PBMCs), IALLIPF, Trp and MPP-Trp are able to significantly alleviate inflammation by inhibiting the yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), especially MPP-Trp. MPP-Trp significantly upregulates Th1 cell levels while notably reducing Th2 cell levels. Furthermore, MPP-Trp effectively elevates the expression and production of interferon-gamma (IFN-γ), an essential cytokine from Th1 cells. Additionally, MPP-Trp markedly diminishes the mRNA expression and levels of key asthma pathogenesis cytokines, such as interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-5 (IL-5), in asthma PBMCs. MPP-Trp ameliorates pulmonary pathological alterations and significantly inhibits OVA-induced inflammation in mice with asthma. It has little influence on the cell viability in Asthma-PBMCs treated with various concentrations or durations of MPP-Trp. No pathological changes, including in the heart, liver, spleen, lung, and kidney tissues, are observed in non-sensitized and non-challenged mice treated with MPP-Trp (20 mg/kg). Discussion: Our research demonstrates that MPP-Trp has immunomodulatory effects on Th1/Th2 cell populations, essential in managing asthma. It considerably alleviates OVA-induced asthma by shifting the immune response towards a Th1-dominant profile, thereby reducing Th2-driven inflammation. Therefore, this novel bioactive peptide nanocarrier, MPP-Trp, holds promise as a candidate for asthma immunotherapy.
Assuntos
Asma , Catepsina B , Citocinas , Imunoterapia , Animais , Asma/tratamento farmacológico , Asma/imunologia , Camundongos , Citocinas/metabolismo , Imunoterapia/métodos , Catepsina B/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas/química , Óxido Nítrico , Portadores de Fármacos/química , Feminino , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Células Th2/imunologia , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Humanos , Triptofano/química , Triptofano/farmacologia , Triptofano/administração & dosagem , Células Th1/imunologia , Células Th1/efeitos dos fármacosRESUMO
BACKGROUND: The Gran Chaco ecoregion is a well-known hotspot of several neglected tropical diseases (NTDs) including Chagas disease, soil-transmitted helminthiasis and multiparasitic infections. Interspecific interactions between parasite species can modify host susceptibility, pathogenesis and transmissibility through immunomodulation. Our objective was to test the association between human co-infection with intestinal parasites and host parasitaemia, infectiousness to the vector and immunological profiles in Trypanosoma cruzi-seropositive individuals residing in an endemic region of the Argentine Chaco. METHODS: We conducted a cross-sectional serological survey for T. cruzi infection along with an intestinal parasite survey in two adjacent rural villages. Each participant was tested for T. cruzi and Strongyloides stercoralis infection by serodiagnosis, and by coprological tests for intestinal parasite detection. Trypanosoma cruzi bloodstream parasite load was determined by quantitative PCR (qPCR), host infectiousness by artificial xenodiagnosis and serum human cytokine levels by flow cytometry. RESULTS: The seroprevalence for T. cruzi was 16.1% and for S. stercoralis 11.5% (n = 87). We found 25.3% of patients with Enterobius vermicularis. The most frequent protozoan parasites were Blastocystis spp. (39.1%), Giardia lamblia (6.9%) and Cryptosporidium spp. (3.4%). Multiparasitism occurred in 36.8% of the examined patients. Co-infection ranged from 6.9% to 8.1% for T. cruzi-seropositive humans simultaneously infected with at least one protozoan or helminth species, respectively. The relative odds of being positive by qPCR or xenodiagnosis (i.e. infectious) of 28 T. cruzi-seropositive patients was eight times higher in people co-infected with at least one helminth species than in patients with no such co-infection. Trypanosoma cruzi parasite load and host infectiousness were positively associated with helminth co-infection in a multiple regression analysis. Interferon-gamma (IFN-γ) response, measured in relation to interleukin (IL)-4 among humans infected with T. cruzi only, was 1.5-fold higher than for T. cruzi-seropositive patients co-infected with helminths. The median concentration of IL-4 was significantly higher in T. cruzi-seropositive patients with a positive qPCR test than in qPCR-negative patients. CONCLUSIONS: Our results show a high level of multiparasitism and suggest that co-infection with intestinal helminths increased T. cruzi parasitaemia and upregulated the Th2-type response in the study patients.
Assuntos
Doença de Chagas , Coinfecção , Helmintíase , Enteropatias Parasitárias , Trypanosoma cruzi , Humanos , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/isolamento & purificação , Coinfecção/parasitologia , Coinfecção/epidemiologia , Coinfecção/imunologia , Doença de Chagas/epidemiologia , Doença de Chagas/complicações , Doença de Chagas/parasitologia , Doença de Chagas/sangue , Doença de Chagas/imunologia , Animais , Adulto , Estudos Transversais , Masculino , Feminino , Enteropatias Parasitárias/epidemiologia , Enteropatias Parasitárias/parasitologia , Enteropatias Parasitárias/complicações , Enteropatias Parasitárias/imunologia , Pessoa de Meia-Idade , Helmintíase/complicações , Helmintíase/parasitologia , Helmintíase/epidemiologia , Helmintíase/imunologia , Adulto Jovem , Adolescente , Argentina/epidemiologia , Estudos Soroepidemiológicos , Strongyloides stercoralis/imunologia , Strongyloides stercoralis/isolamento & purificação , Parasitemia/parasitologia , Parasitemia/epidemiologia , Células Th2/imunologia , Criança , Estrongiloidíase/epidemiologia , Estrongiloidíase/parasitologia , Estrongiloidíase/complicações , Estrongiloidíase/imunologia , Estrongiloidíase/sangue , Idoso , Citocinas/sangue , Anticorpos Antiprotozoários/sangueRESUMO
Tropomyosin (TM) is the main allergen in shrimp (Litopenaeus vannamei). In this study, the effects of allergenicity and structure of TM by glycosylation (GOS-TM), phosphate treatment (SP-TM), and glycosylation combined with phosphate treatment (GOS-SP-TM) were investigated. Compared to GOS-TM and SP-TM, the IgG/IgE binding capacity of GOS-SP-TM was significantly decreased with 63.9 ± 2.0 and 49.7 ± 2.7%, respectively. Meanwhile, the α-helix content reduced, surface hydrophobicity increased, and 10 specific amino acids (K30, K38, S39, K48, K66, K74, K128, K161, S210, and K251) were modified by glycosylation on six IgE linear epitopes of GOS-SP-TM. In the BALB/c mice allergy model, GOS-SP-TM could significantly reduce the levels of specific IgE, IgG1, and CD4+IL-4+, while the levels of IgG2a, CD4+CD25+Foxp3+, and CD4+IFN-γ+ were increased, which equilibrated Th1 and Th2 cells, thus alleviating allergic symptoms. These results indicated that glycosylation combined with phosphate treatment can provide a new insight into developing hypoallergenic shrimp food.
Assuntos
Alérgenos , Imunoglobulina E , Penaeidae , Fosfatos , Tropomiosina , Animais , Feminino , Humanos , Camundongos , Alérgenos/imunologia , Alérgenos/química , Proteínas de Artrópodes/imunologia , Proteínas de Artrópodes/química , Hipersensibilidade Alimentar/imunologia , Glicosilação , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/química , Camundongos Endogâmicos BALB C , Penaeidae/imunologia , Penaeidae/química , Fosfatos/química , Frutos do Mar/análise , Hipersensibilidade a Frutos do Mar/imunologia , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Tropomiosina/imunologia , Tropomiosina/químicaRESUMO
Objective To investigate the effects of astragaloside IV(AS-IV) on the balance of T helper type 1 (Th1) and Th2 cells in mice with IgA nephropathy (IgAN) and its possible mechanism. Methods The IgAN model of BALB/c mice was established. Successfully modeled mice were randomly divided into four groups: model, AS-IV low dose, AS-IV medium dose and AS-IV high dose groups, with 10 mice in each group. Another 10 mice served as the control group. Mice in the low, medium and high dose groups were administered 12.5, 25 and 50 mg/kg AS-IV suspension (prepared in normal saline) by gavage, while the control and model groups were given an equivalent volume of normal saline. The 24-hour urinary protein (24 h UPr) content and urine red blood cell count were measured in each group. The levels of blood urea nitrogen (BUN), serum creatinine (Scr) and albumin (ALB) were determined. Serum interferon γ (IFN-γ), interleukin 4 (IL-4) and IL-10 levels were detected by ELISA. The ratio of Th1/Th2 cells in peripheral blood of mice was detected using flow cytometry. Histopathological changes in the kidney of mice were observed by HE staining. RT-PCR and Western blot were used to detect the mRNA and protein expressions of T cell immunoglobulin and mucin domain gene 1 (TIM-1), Toll-like receptor 4 (TLR4) in mouse kidney tissue. Results Compared with the model group, in weeks 12 and 15, the urine red blood cell count, 24 h UPr, BUN, Scr, levels of IL-4 and IL-10, the proportion of Th2 cells, as well as the mRNA and protein expression levels of TIM-1 and TLR4 were significantly decreased in the low, medium and high dose groups of AS-IV, and the levels of ALB, IFN-γ, the proportion of Th1 cells and Th1/Th2 cell ratio were increased, with the high-dose group showing the best effects. Conclusion AS-IV can inhibit TIM-1 signaling pathway, increase the Th1/Th2 cell ratio, inhibit the inflammatory reaction, and alleviate the renal injury in IgAN mice.
Assuntos
Glomerulonefrite por IGA , Receptor Celular 1 do Vírus da Hepatite A , Camundongos Endogâmicos BALB C , Saponinas , Transdução de Sinais , Células Th1 , Células Th2 , Triterpenos , Animais , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/genética , Triterpenos/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/imunologia , Saponinas/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Camundongos , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Interleucina-4/genética , Interleucina-4/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interferon gama/metabolismo , Interferon gama/genética , Masculino , FemininoRESUMO
Objective: The Chinese medicine Jianpi-Huayu decoction (, JPHY) can alleviate cancer-related fatigue in patients with liver cancer. However, its mechanism remains unclear. In this study, we used BALB/c mice with liver cancer model to investigate whether JPHY alleviates cancer-related fatigue by regulating Th1/Th2 immune balance; and the possible association with the IL-27/STAT1 signaling pathway. Methods: We established a mouse model of liver cancer fatigue. Mice were gavaged with physiological saline, low, medium, or high concentrations of JPHY respectively; and intraperitoneal injection of fludarabine (STAT1 pathway inhibitor) with JPHY for 21 days. We recorded the general condition of the mice, and assessed fatigue using scoring criteria and Exhausted Swimming Test. We calculated the spleen and thymus indices, performed H&E staining and immunohistochemical analysis on liver tumor tissues to observe the tumor proliferation marker ki67. We quantified the secretion levels of IFN-γ and IL-2 produced by Th1 cells in serum and splenic lymphocytes, as well as the secretion of IL-4, IL-10 by Th2 cells, and IL-27 in the signaling pathway through ELISA analysis. We evaluated the expression levels of p-STAT1 and STAT1 in spleen tissues using Western blot analysis. Results: JPHY exhibits a therapeutic effect on hepatocellular carcinoma-induced splenomegaly in murine models by upregulating the pro-inflammatory cytokines IFN-γ and IL-2 and downregulating the anti-inflammatory cytokines IL-4 and IL-10. Moreover, JPHY suppresses ki67 expression, reduces tumor-related inflammation infiltration, and ameliorates cancer-associated fatigue. Additionally, the expression of phosphorylated protein p-STAT1 is down-regulated. Conclusion: JPHY may improve the Th1/Th2 immune balance through its anti-inflammatory effects and promotion of IL-27-induced STAT1 phosphorylation, thereby alleviating fatigue in mice with liver cancer.
Assuntos
Medicamentos de Ervas Chinesas , Fadiga , Neoplasias Hepáticas , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT1 , Transdução de Sinais , Células Th1 , Células Th2 , Animais , Fator de Transcrição STAT1/metabolismo , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Fadiga/tratamento farmacológico , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Modelos Animais de Doenças , Equilíbrio Th1-Th2/efeitos dos fármacos , Masculino , Interleucinas/metabolismo , Interleucina-27RESUMO
Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.
Assuntos
Asma , Ferroptose , Pulmão , Metabolômica , Animais , Asma/induzido quimicamente , Camundongos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Ferroptose/efeitos dos fármacos , Dibutilftalato/toxicidade , Células Th2/imunologia , Estresse Oxidativo , Poluentes Ambientais/toxicidade , Microplásticos/toxicidade , Eosinófilos/efeitos dos fármacos , Plásticos/toxicidadeRESUMO
Dorstenia psilurus is a widely used plant spice in traditional African medicine to treat pain-related conditions. However, the anti-inflammatory mechanisms underlying this activity and the main active ingredients of D. psilurus have not yet been fully characterized. This study aimed to isolate and identify the main active anti-inflammatory constituents of the D. psilurus extract and to investigate the underlying anti-inflammatory mechanisms in murine macrophages. Chromatographic techniques and spectroscopic data were used for compound isolation and structure elucidation. The Griess reagent method and the ferrous oxidation-xylenol orange assay were used to evaluate the inhibition of NO production and 15-lipoxygenase activity, respectively. Cyclooxygenase activity was assessed using the fluorometric COX activity assay kit, and Th1/Th2 cytokine measurement was performed using a flow cytometer. The results indicated that the extract and fractions of D. psilurus inhibit NO production and proliferation of RAW 264.7 macrophage cells. Bioguided fractionation led to the identification of psoralen, a furocoumarin, as the main bioactive anti-inflammatory compound. Psoralen inhibited NO production and 15-lipoxygenase activity and reduced pro-inflammatory Th1 cytokines (IFN-γ, TNF-α, and IL-2) while increasing the secretion of anti-inflammatory cytokines (IL-4, IL-6, and IL-10) in activated RAW 264.7 macrophage cells. The encouraging results obtained in this study suggest that psoralen-based multiple modulation strategies could be a useful approach to address the treatment of inflammatory diseases.
Assuntos
Citocinas , Ficusina , Lipopolissacarídeos , Macrófagos , Raízes de Plantas , Animais , Camundongos , Células RAW 264.7 , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Raízes de Plantas/química , Lipopolissacarídeos/farmacologia , Ficusina/farmacologia , Ficusina/química , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/metabolismo , Células Th2/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Óxido Nítrico/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
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.
Assuntos
Asma , Asma/imunologia , Humanos , Animais , Citocinas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Células Th2/imunologia , Eosinófilos/imunologia , Neutrófilos/imunologia , Subpopulações de Linfócitos T/imunologiaRESUMO
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.
Assuntos
Asma , Fator 2 Relacionado a NF-E2 , Células Th2 , Animais , Feminino , Humanos , Camundongos , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinofilia/imunologia , Eosinofilia/metabolismo , Glicólise , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação Oxidativa , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
In lab settings, inbred mouse strains like BALB/c, C57BL/6J, and C57BL/6N are commonly used. Research in immunology and infectious diseases indicates that their Th1 and Th2 immune responses differ. However, the specific differences in the immune response to the vaccination still require investigation. In this study, ovalbumin (OVA) was used as an antigen and CpG-enriched recombinant plasmid (pUC18-CpG) as an adjuvant for immunisation. The level of serum-specific antibody IgG was detected by indirect ELISA. At 35dpi, serum cytokine levels were measured using MILLIPLEX®. T lymphocyte clusters from mouse spleen were examined using flow cytometry to investigate the immunological effects of the CPG-OVA vaccine on three different types of mice. The results showed that pUC18-CpG as an adjuvant could successfully enhance the immune response. BALB/c had the highest level of IgG antibody. In the OVA-only group, the CD4+/CD8+ ratio of the three types of mice was generally increased, and the BALB/c group had the highest ratio. After inoculation with CpG-OVA, the CD4+/CD8+ ratio of the three types of mice was lower than that of the OVA-only group, and C57BL/6J was the lowest. Compared with the CpG-OVA group of the three kinds of mice, the levels of Th2 cytokines IL-6 and IL-10 in BALB/c were increased compared with C57BL/6J and C57BL/6N. After OVA, the six cytokines secreted in C57BL/6J were higher than those in the C57BL/6N OVA group. Therefore, C57 is a better model for examining the function of the vaccine in cellular immunity, whereas BALB/c mice are more prone to humoral immunity. In addition to highlighting the CpG plasmid's ability to successfully activate the immune response of Th1 and Th2, as well as the expression of IgG in vivo and promote T cell immune typing, this study provides valuable insights into immunology and the selection of mouse models for infectious diseases, providing a valuable resource for designing more effective vaccines in the future.
Assuntos
Adjuvantes Imunológicos , Citocinas , Imunidade Celular , Imunidade Humoral , Imunoglobulina G , Animais , Feminino , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Citocinas/metabolismo , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/sangue , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Ovalbumina , Células Th2/imunologiaRESUMO
The airway epithelium plays a pivotal role in regulating mucosal immunity and inflammation. Epithelial barrier function, homeostasis of luminal fluid, and mucociliary clearance are major components of mucosal defense mechanisms. The epithelial sodium channel (ENaC) is one of the key players in controlling airway fluid volume and composition, and characteristic cytokines cause ENaC and barrier dysfunctions following pulmonary infections or allergic reactions. Given the limited understanding of the requisite duration and magnitude of cytokines to affect ENaC and barrier function, available treatment options for restoring normal ENaC activity are limited. Previous studies have demonstrated that distinct amino acids can modulate epithelial ion channel activities and barrier function in intestines and airways. Here, we have investigated the time- and concentration-dependent effect of representative cytokines for Th1- (IFN-γ and TNF-α), Th2- (IL-4 and IL-13), and Treg-mediated (TGF-ß1) immune responses on ENaC activity and barrier function in human bronchial epithelial cells. When cells were exposed to Th1 and Treg cytokines, ENaC activity decreased gradually while barrier function remained largely unaffected. In contrast, Th2 cytokines had an immediate and profound inhibitory effect on ENaC activity that was subsequently followed by epithelial barrier disruption. These functional changes were associated with decreased membrane protein expression of α-, ß-, and γ-ENaC, and decreased mRNA levels of ß- and γ-ENaC. A proprietary blend of amino acids was developed based on their ability to prevent Th2 cytokine-induced ENaC dysfunction. Exposure to the select amino acids reversed the inhibitory effect of IL-13 on ENaC activity by increasing mRNA levels of ß- and γ-ENaC, and protein expression of γ-ENaC. This study indicates the beneficial effect of select amino acids on ENaC activity in an in vitro setting of Th2-mediated inflammation suggesting these amino acids as a novel therapeutic approach for correcting this condition.
Assuntos
Aminoácidos , Brônquios , Citocinas , Células Epiteliais , Canais Epiteliais de Sódio , Canais Epiteliais de Sódio/metabolismo , Canais Epiteliais de Sódio/genética , Humanos , Brônquios/citologia , Brônquios/metabolismo , Brônquios/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Citocinas/metabolismo , Aminoácidos/farmacologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Linhagem Celular , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Interleucina-13/metabolismoRESUMO
Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
Assuntos
Imunidade Adaptativa , Fator de Transcrição GATA3 , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Camundongos , Imunidade Adaptativa/imunologia , Linfócitos/imunologia , Imunidade Inata/imunologia , Camundongos Knockout , Células Th2/imunologia , FemininoRESUMO
ß-Lactoglobulin (ßLG) is a major allergen in bovine milk protein. This study was designed to investigate changes in ßLG structure, digestibility, and allergenicity induced by covalent binding modification with different contents of (-)-epigallocatechin 3-gallate (EGCG). The reaction of EGCG conjugation with ßLG reached saturation at a molar ratio of 1:60 ßLG:EGCG. Conjugation with EGCG altered the ßLG structure, decreased IgE-binding capacity, and increased digestibility in a dose-dependent manner. In vivo studies showed that covalent conjugation with EGCG can reduce ßLG-induced allergic symptoms with reducing levels of IgE, histamine, and mast cell protease-1 (mMCP-1) and the percentage of sensitized mast cells. Allergenicity was reduced more effectively in saturated ßLG-EGCG conjugates compared to semisaturated conjugates. Observed changes in IFN-γ, IL-4, IL-5, IL-10, and TGF-ß levels suggested that ßLG-EGCG conjugates were able to promote Th1/Th2 immune balance. These findings further our understanding of the relationship between the degree of polyphenol conjugation and the allergenicity of food allergens.
Assuntos
Alérgenos , Catequina , Imunoglobulina E , Lactoglobulinas , Lactoglobulinas/química , Lactoglobulinas/imunologia , Catequina/análogos & derivados , Catequina/química , Catequina/imunologia , Animais , Alérgenos/imunologia , Alérgenos/química , Bovinos , Imunoglobulina E/imunologia , Humanos , Camundongos , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/prevenção & controle , Camundongos Endogâmicos BALB C , Feminino , Interferon gama/imunologia , Interferon gama/metabolismo , Quimases/química , Quimases/imunologia , Quimases/metabolismo , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Interleucina-5/imunologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Mastócitos/imunologia , Mastócitos/efeitos dos fármacosRESUMO
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.
Assuntos
Cesárea , Parto Obstétrico , Fezes , Microbioma Gastrointestinal , Células Th1 , Humanos , Recém-Nascido , Feminino , Fezes/microbiologia , Células Th1/imunologia , Masculino , Células Th2/imunologia , Gravidez , RNA Ribossômico 16S/genética , Imunoglobulina G/sangueRESUMO
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-ß, 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-ß levels were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with healthy controls, the levels of IL-33, sST2, TGF-ß, 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-ß, 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.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Linfócitos T Reguladores , Tuberculose Pulmonar , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Linfócitos T Reguladores/imunologia , Interleucina-33/sangue , Feminino , Masculino , Tuberculose Pulmonar/imunologia , Adulto , Pessoa de Meia-Idade , Citocinas/sangue , Células Th2/imunologia , Linfócitos/imunologia , Citometria de Fluxo , Adulto Jovem , Imunidade Inata , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Allergic asthma is a complex inflammatory disorder predominantly orchestrated by T helper 2 (Th2) lymphocytes. The anti-inflammatory protein Clara Cell 10-kDa (CC10), also known as secretoglobin family 1A member 1 (SCGB1A1), shows promise in modulating respiratory diseases. However, its precise role in asthma remains unclear. This study examines the potential of CC10 to suppress allergic asthma inflammation, specifically assessing its regulatory effects on Th2 cell responses and dendritic cells (DCs). Lower CC10 levels in asthma were observed and correlated with increased IgE and lymphocytes. Cc10-/- mice exhibited exacerbated allergic airway inflammation marked by increased inflammatory cell infiltration, Th2 cytokines, serum antigen-specific IgE levels, and airway hyperresponsiveness (AHR) in house dust mite (HDM)-induced models. Conversely, recombinant CC10 significantly attenuated these inflammatory responses. Intriguingly, CC10 did not directly inhibit Th cell activation but significantly downregulated the population of CD11b+CD103- DCs subsets in lungs of asthmatic mice and modulated the immune activation functions of DCs through NF-κB signaling pathway. The mixed lymphocyte response assay revealed that DCs mediated the suppressive effect of CC10 on Th2 cell responses. Collectively, CC10 profoundly mitigates Th2-type allergic inflammation in asthma by modulating lung DC phenotype and functions, highlighting its therapeutic potential for inflammatory airway conditions and other related immunological disorders.
Assuntos
Asma , Células Dendríticas , Pulmão , Células Th2 , Uteroglobina , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Asma/imunologia , Asma/patologia , Células Th2/imunologia , Células Th2/metabolismo , Uteroglobina/genética , Uteroglobina/metabolismo , Camundongos , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inflamação/patologia , Inflamação/imunologia , Inflamação/metabolismo , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Pyroglyphidae/imunologia , NF-kappa B/metabolismo , Citocinas/metabolismo , Feminino , Camundongos Endogâmicos BALB CRESUMO
The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxelâ +â cisplatinâ +â fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant ( P â <â 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group ( P â <â 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group ( P â <â 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Docetaxel , Fluoruracila , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Fluoruracila/administração & dosagem , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Interleucina-4 , Equilíbrio Th1-Th2/efeitos dos fármacos , Idoso , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Interferon gama , Células Th2/imunologia , Células Th2/efeitos dos fármacos , AdultoRESUMO
Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.