RESUMO
Introduction: The therapeutic efficacy for airway allergies needs to be improved. Th2 polarization is a primary pathological feature of airway allergies. We constructed chimeric antigen-LgDNA (Lactobacillus rhamnosus DNA) nanoparticles (CAP-NPs). The effects of CAP-NPs on reconciling airway Th2 polarization were tested. Methods: In this study, disulfide bond-linked antigen-major histocompatibility complex II (MHC II)-LgDNA nanoparticles (NPs) were constructed and designated CAP-NPs. An airway Th2 polarization mouse model was established to test the effects of CAP-NPs on suppressing the Th2 response. Results: The CAP-NP components of ovalbumin (OVA), major histocompatibility complex II (MHC II), and LgDNA were confirmed in a series of laboratory tests. The CAP-NPs remained stable at pH7.2 for at least 96 h. In in vitro experiments, CAP-NPs bound to the surface of OVA-specific CD4+ T cells, which resulted in apoptosis of the antigen-specific CD4+ T cells. Removal of any of the three components from the NPs abolished the induction of apoptosis of antigen specific CD4+ T cells. CAP-NPs increased the expression of lysine-specific demethylase 5A (KDM5A) in CD4+ T cells. Histone H3K9 and the gene promoter of caspase 8 were demethylated by KDM5A, which led to transcription and expression of the caspase 8 gene. Administration of CAP-NPs significantly alleviated experimental airway Th2 polarization through activating the caspase 8-apoptosis signaling pathway. Discussion: In this paper, we constructed CAP-NPs that could induce antigen-specific CD4+ T cell apoptosis. Administration of CAP-NPs efficiently alleviated experimental airway Th2 polarization.
Assuntos
Apoptose , Nanopartículas , Ovalbumina , Células Th2 , Animais , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Nanopartículas/química , Camundongos , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Caspase 8/metabolismo , Caspase 8/genética , Feminino , DNA/química , DNA/administração & dosagem , Antígenos/administração & dosagem , Antígenos/química , Linfócitos T CD4-Positivos/efeitos dos fármacosRESUMO
BACKGROUND: Improvement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy. METHODS: A cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy. RESULTS: The Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4+ T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4+ T cells in the airways, and mitigated airway Th2 polarization. CONCLUSIONS: We constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4+ T cell apoptosis, and reconcile airway Th2 polarization.
Assuntos
Eosinófilos , Células Th2 , Animais , Células Th2/imunologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Antígenos/imunologia , Ovalbumina/imunologia , Hipersensibilidade/imunologia , Feminino , Hipersensibilidade Respiratória/imunologia , Linfócitos T CD4-Positivos/imunologia , Lacticaseibacillus rhamnosus/imunologiaRESUMO
Introduction: After mild COVID-19 that does not require hospitalization, some individuals develop persistent symptoms that may worsen over time, producing a multisystemic condition termed Post-COVID condition (PCC). Among other disorders, PCC is characterized by persistent changes in the immune system that may not be solved several months after COVID-19 diagnosis. Methods: People with PCC were recruited to determine the distribution and functionality of CD4+ T helper (Th) subsets in comparison with individuals with mild, severe, and critical presentations of acute COVID-19 to evaluate their contribution as risk or protective factors for PCC. Results: People with PCC showed low levels of Th1 cells, similar to individuals with severe and critical COVID-19, although these cells presented a higher capacity to express IFNγ in response to stimulation. Th2/Th1 correlation was negative in individuals with acute forms of COVID-19, but there was no significant Th2/Th1 correlation in people with PCC. Th2 cells from people with PCC presented high capacity to express IL-4 and IL-13, which are related to low ventilation and death associated with COVID-19. Levels of proinflammatory Th9 and Th17 subsets were significantly higher in people with PCC in comparison with acute COVID-19, being Th1/Th9 correlation negative in these individuals, which probably contributed to a more pro-inflammatory than antiviral scenario. Th17 cells from approximately 50% of individuals with PCC had no capacity to express IL-17A and IL-22, similar to individuals with critical COVID-19, which would prevent clearing extracellular pathogens. Th2/Th17 correlation was positive in people with PCC, which in the absence of negative Th1/Th2 correlation could also contribute to the proinflammatory state. Finally, Th22 cells from most individuals with PCC had no capacity to express IL-13 or IL-22, which could increase tendency to reinfections due to impaired epithelial regeneration. Discussion: People with PCC showed skewed polarization of CD4+ Th subsets with altered functionality that was more similar to individuals with severe and critical presentations of acute COVID-19 than to people who fully recovered from mild disease. New strategies aimed at reprogramming the immune response and redirecting CD4+ Th cell polarization may be necessary to reduce the proinflammatory environment characteristic of PCC.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Idoso , Adulto , Células Th1/imunologia , Células Th2/imunologia , Linfócitos T CD4-Positivos/imunologia , Síndrome de COVID-19 Pós-Aguda , Citocinas/metabolismo , Citocinas/imunologia , Células Th17/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
BACKGROUND: This study aimed to explore the changes in Th cells and cytokines in the peripheral blood of patients with multiple myeloma before and after treatment and at the time of the bacterial infection. METHODS: In total, 23 newly diagnosed MM patients admitted to the Hospital and 23 healthy individuals were selected as the study group and the control group, respectively. Flow cytometry was used to detect the Th1 and Th2 lymphocytes and cytokines, such as IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, INF-γ, IL-17A, IL-1b, TNF-α, TNF-ß, and IL-12P70, in the peripheral blood of the patients at initial diagnosis, before and after treatment, and at the time of the bacterial infection. RESULTS: The Th1% and Th1/Th2 ratio at the time of the initial diagnosis were lower in the MM patients than in the control group, whereas the Th2% at initial diagnosis was higher in the MM patients than in the control group. The levels of IL-6, IL-8, IL-10, and IL-17A at initial diagnosis were higher in the MM patients than in the control group. After 4 cycles of treatment, the Th2% in the patients was lower than before the treatment and the Th1/Th2 ratio in the patients was higher than before the treatment. The Th1% and the levels of IL-6, IL-8, IL-10, and INF-γ increased, while the level of IL-12P70 decreased, when MM patients got a bacterial infection. The abovementioned differences were statistically significant (p < 0.05). CONCLUSIONS: The Th1/Th2 deviation affects the immune function of the MM patients. There were significant changes in the Th1 and Th2 lymphocytes and cytokines in newly diagnosed MM patients after the treatment. The changes in the Th lymphocytes and cytokines may be an indicator of bacterial infection.
Assuntos
Citocinas , Mieloma Múltiplo , Células Th1 , Células Th2 , Humanos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Citocinas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th2/imunologia , Idoso , Equilíbrio Th1-Th2 , Adulto , Estudos de Casos e Controles , Infecções Bacterianas/sangue , Infecções Bacterianas/imunologia , Infecções Bacterianas/diagnósticoAssuntos
Vacinas contra COVID-19 , COVID-19 , Células Th1 , Células Th2 , Síndrome Uveomeningoencefálica , Humanos , Vacina BNT162/efeitos adversos , COVID-19/prevenção & controle , COVID-19/imunologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Células Th1/imunologia , Células Th2/imunologia , Síndrome Uveomeningoencefálica/imunologia , Síndrome Uveomeningoencefálica/induzido quimicamente , Síndrome Uveomeningoencefálica/diagnóstico , Vacinação/efeitos adversosRESUMO
Epithelial-derived IL-33 (Interleukin-33), as a member of alarm signals, is a chemical substance produced under harmful stimuli that can promote innate immunity and activate adaptive immune responses. Type 2 inflammation refers to inflammation primarily mediated by Type 2 helper T cells (Th2), Type 2 innate lymphoid cells (ILC2), and related cytokines. Type 2 inflammation manifests in various forms in the lungs, with diseases such as asthma and chronic obstructive pulmonary disease chronic obstructive pulmonary disease (COPD) closely associated with Type 2 inflammation. Recent research suggests that IL-33 has a promoting effect on Type 2 inflammation in the lungs and can be regarded as an alarm signal for Type 2 inflammation. This article provides an overview of the mechanisms and related targets of IL-33 in the development of lung diseases caused by Type 2 inflammation, and summarizes the associated treatment methods. Analyzing lung diseases from a new perspective through the alarm of Type 2 inflammation helps to gain a deeper understanding of the pathogenesis of these related lung diseases. This, in turn, facilitates a better understanding of the latest treatment methods and potential therapeutic targets for diseases, with the expectation that targeting lL-33 can propose new strategies for disease prevention.
Assuntos
Interleucina-33 , Humanos , Interleucina-33/metabolismo , Interleucina-33/imunologia , Animais , Inflamação/imunologia , Imunidade Inata , Células Th2/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Asma/imunologiaRESUMO
Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.
Assuntos
Administração Intranasal , Anticorpos Monoclonais , Asma , Líquido da Lavagem Broncoalveolar , Citocinas , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Ovalbumina , Proteína Tumoral 1 Controlada por Tradução , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/induzido quimicamente , Ovalbumina/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Citocinas/metabolismo , Camundongos , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologia , Células Th2/imunologia , Células Th2/efeitos dos fármacosRESUMO
Fecal microbiota transplantation (FMT) is currently a promising therapy for inflammatory bowel disease (IBD). However, clinical studies have shown that there is an obvious individual difference in the efficacy of FMT. Therefore, it is a pressing issue to identify the factors that influence the efficacy of FMT and find ways to screen the most suitable patients for this therapy. In this work, we targeted the stimulator of interferon genes (STING), a DNA-sensing protein that regulates host-defense. By comparing the differential efficacy of FMT in mice with different expression level of STING, it is revealed that FMT therapy provides treatment for DSS-induced colitis in a STING-dependent manner. Mechanistically, FMT exerts a regulatory effect on the differentiation of intestinal Th17 cells and macrophages, splenic Th1 and Th2 cells, as well as Th1 cells of the mesenteric lymph nodes via STING, down-regulating the colonic M1/M2 and splenic Th1/Th2 cell ratios, thereby improving the imbalanced immune homeostasis in the inflamed intestine. Meanwhile, based on the 16SrDNA sequencing of mice fecal samples, STING was found to facilitate the donor strain colonization in recipients' gut, mainly Lactobacillales, thereby reshaping the gut microbiota disturbed by colitis. Consequently, we proposed that STING, as a key target of FMT therapy, is potentially a biomarker for screening the most suitable individuals for FMT to optimize treatment regimens and enhance clinical benefit.
Assuntos
Colite , Sulfato de Dextrana , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Animais , Humanos , Camundongos , Colite/terapia , Colite/induzido quimicamente , Colite/imunologia , Colo/microbiologia , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Macrófagos/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Allergic rhinitis (AR) is a chronic, non-infectious inflammatory condition of the nasal mucosa mediated by IgE. There is a need for the development of novel medications to treat this ailment. Isoorientin is a naturally occurring flavonoid that possesses antioxidant, anti--inflammatory, and various other advantageous characteristics. However, its potential effects on AR remain unclear. This study evaluates the therapeutic effects of isoorientin on ovalbumin (OVA)-induced allergic rhinitis (AR) in mice and explores the underlying mechanism. Our study revealed that isoorientin administration effectively decreased the frequency of nose rubbing and sneezing in AR mice. The groups treated with isoorientin showed a significant decrease in serum levels of IgE and histamine, with reductions of 40% and 30%, respectively. Isoorientin ameliorated inflammation of the nasal mucosa and restored the Th1/Th2 balance. In addition, isoorientin inhibited the activation of the NF-κB pathway in nasal tissues. In summary, Isoorientin alleviates OVA-stimulated AR in mice by restoring Th1/Th2 balance and blocking the NF-κB pathway. Thus, isoorientin exhibits promise as a natural therapeutic agent for allergic rhinitis.
Assuntos
Modelos Animais de Doenças , Imunoglobulina E , Luteolina , Camundongos Endogâmicos BALB C , NF-kappa B , Mucosa Nasal , Ovalbumina , Rinite Alérgica , Equilíbrio Th1-Th2 , Animais , Luteolina/farmacologia , Ovalbumina/imunologia , Camundongos , Rinite Alérgica/imunologia , Rinite Alérgica/tratamento farmacológico , Equilíbrio Th1-Th2/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/efeitos dos fármacos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , NF-kappa B/metabolismo , Células Th2/imunologia , Feminino , Humanos , Alérgenos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Histamina/metabolismo , Histamina/sangueRESUMO
OBJECTIVE: Chlamydia pneumoniae (C. pneumoniae) is a gram-negative intracellular bacterium that causes respiratory infections in humans. C. pneumoniae is responsible for cell activation and production of cytokines that may contribute to inflammatory responses in asthma. Cell-mediated immune responses are important for protective immunity; however, these responses may be impaired in asthma. In this study, we examined cytokine responses (IL-21, IL-12, IL-13) responsible for T helper (Th)1 versus Th2 responses in C. pneumoniae-stimulated PBMC from subjects with or without asthma. These cytokines could be potential biomarkers in the evaluation of past C. pneumoniae infection. METHODS: Peripheral blood mononuclear cells (PBMC) (1×106/mL) from stable adult asthmatic (N=6) and non-asthmatic subjects (N=6) were infected +/- C. pneumoniae TW-183 at a multiplicity of infection (MOI)=0.1, using dose responses (1:10, 1:100), and cultured 48 hrs. Cytokine responses (Interleukin (IL)-21, IL-12, IL-13) were measured in supernatants (ELISA). RESULTS: Cytokine responses (mean differences: unstimulated-stimulated cells) were significant for IL-12 (1:10, 1:100) (P=0.0005, 0.0005) but not for IL-21 or IL-13 (Wilcoxon signed-rank test). Cytokine levels were higher in asthmatic subjects for IL-13 (mean differences: non-asthma-asthma) (unstimulated, 1:10, 1:100) (-210±167, -140±113, -89±59, respectively) (P=0.05, 0.05, 0.05, respectively) compared with non-asthma. However, IL-21 and IL-12 responses were similar in both groups. When subjects were stratified according to C. pneumoniae IgG antibody status, no significant differences in cytokine responses were observed. CONCLUSION: Differential cytokine patterns in subjects with or without asthma may suggest a mechanism for the development of persistent infection with C. pneumoniae.
Assuntos
Asma , Chlamydophila pneumoniae , Interleucina-12 , Interleucina-13 , Interleucinas , Leucócitos Mononucleares , Humanos , Asma/imunologia , Asma/microbiologia , Chlamydophila pneumoniae/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Interleucina-12/metabolismo , Adulto , Masculino , Feminino , Interleucinas/metabolismo , Interleucina-13/metabolismo , Pessoa de Meia-Idade , Citocinas/metabolismo , Células Th2/imunologiaRESUMO
Materials and Methods: Using flow cytometry, we identified and quantified Group 2 innate lymphocytes, T helper 2 cells, follicular helper T cells, and T helper 17 cells in peripheral blood samples from 49 individuals with asthma. We then conducted cross-sectional analyses to assess relationships between levels of these immune cells and lung function parameters, including the percentage predicted forced expiratory volume in 1 s (%FEV1). We also examined correlations between the proportions of immune cells and type 2 biomarkers. Results: Proportions of CXCR5+ follicular helper T cells in human peripheral blood, as opposed to Group 2 innate lymphoid cells (ILC2) or T helper 2 cells, were significantly higher in cases with %FEV1 < 80% compared to those with %FEV1 ≥ 80%. Further, these proportions correlated negatively with %FEV1 and positively with blood eosinophil counts. Conclusions: The proportion of circulating follicular helper T cells, but not T helper 2 cells or Group 2 innate lymphoid cells, may reflect the presence of airway obstruction caused by persistent type 2 inflammation.
Assuntos
Asma , Receptores CXCR5 , Células T Auxiliares Foliculares , Humanos , Asma/imunologia , Asma/sangue , Feminino , Masculino , Receptores CXCR5/metabolismo , Pessoa de Meia-Idade , Adulto , Células T Auxiliares Foliculares/imunologia , Estudos Transversais , Obstrução das Vias Respiratórias/imunologia , Obstrução das Vias Respiratórias/sangue , Biomarcadores , Linfócitos T Auxiliares-Indutores/imunologia , Imunidade Inata , Idoso , Eosinófilos/imunologia , Citometria de Fluxo , Contagem de Linfócitos , Células Th2/imunologia , Testes de Função RespiratóriaRESUMO
The critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2-mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen.
Assuntos
Doença Celíaca , Proteínas Alimentares , Modelos Animais de Doenças , Hipersensibilidade Alimentar , Tolerância Imunológica , Animais , Humanos , Camundongos , Hipersensibilidade Alimentar/imunologia , Doença Celíaca/imunologia , Doença Celíaca/etiologia , Doença Celíaca/metabolismo , Proteínas Alimentares/imunologia , Proteínas Alimentares/metabolismo , Células Th2/imunologia , Autoimunidade , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismoRESUMO
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation.
Assuntos
Esofagite Eosinofílica , Células Th2 , Humanos , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/patologia , Células Th2/imunologia , Células Th2/metabolismo , Inflamação/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Dermatite Atópica/patologiaRESUMO
Schistosomiasis, a parasitic disease caused by Schistosoma spp., affects more than 250 million people worldwide. S. mansoni in particular affects the gastrointestinal tract and, through its eggs, induces a Th2 immune response leading to granuloma formation. The relationship between egg load and immune response is poorly understood. We investigated whether the quantity of parasitic eggs influences the immune response in S. mansoni-infected hamsters. The hepatic and intestinal egg load was assessed, and cytokine expression as well as the expression of three major egg-derived proteins were analyzed in monosex- and bisex-infected animals by qRT-PCR. Statistical correlations between egg load or egg-derived factors Ipse/alpha-1, kappa-5, and omega-1, and the immune response were analyzed in liver and colon tissue. Surprisingly, no correlation of the Th1 cytokines with the hepatic egg load was observed, while the Th2 cytokines Il4, Il5, and Il13 showed an inverse correlation in the liver but not in the colon. A longer embryogenesis of the parasitic eggs in the liver could explain this correlation. This conclusion is supported by the lack of any correlation with immune response in the colon, as the intestinal passage of the eggs is limited to a few days.
Assuntos
Citocinas , Fígado , Schistosoma mansoni , Esquistossomose mansoni , Células Th2 , Animais , Schistosoma mansoni/imunologia , Fígado/parasitologia , Fígado/metabolismo , Citocinas/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/metabolismo , Cricetinae , Contagem de Ovos de Parasitas , Feminino , Mesocricetus , Colo/imunologia , Colo/metabolismo , Colo/parasitologia , Masculino , Proteínas de Helminto/metabolismo , Proteínas de Helminto/imunologia , Proteínas do OvoRESUMO
BACKGROUND: Asthma is a common immune disease with high morbidity in children. Type 2 inflammation is the center of asthma development, and mainly mediated by a subset of CD4 + T cells, T helper 2 (Th2) cells. Excess Th2 differentiation was generally associated with asthmatic attack. Casitas B-lineage lymphoma (c-CBL) was reported to involved in T cell development and databank showed its decreased expression in CD4 + T cells from peripheral blood of asthmatic children. This study aims to investigate the role of c-CBL in childhood asthma and Th2 differentiation, and explore the underlying mechanism. METHODS: We collected peripheral blood samples from clinical childhood asthma cases and healthy controls, and determined c-CBL expression in CD4 + T cells. Asthma was induced in neonatal mice by ovalbumin (OVA) intraperitoneal injection and aerosol inhalation, and c-CBL expression in CD4 + T cells from peripheral blood and spleen was measured. Gain-of-function experiments was performed to confirm the effects of c-CBL on Th2 differentiation in vitro. Finally, c-CBL was delivered into asthmatic mice via lentivirus infection to verify its effects on experimental asthma. RESULTS: c-CBL was lowly expressed in CD4 + T cells from asthmatic children than those of healthy controls. Similarly, it was downregulated in CD4 + T cells from peripheral blood and spleen of asthma mice. Overexpression of c-CBL restrained lung pathological injury and type 2 inflammation in experimental asthmatic mice. Gain-of-function experiments demonstrated that c-CBL inhibited Th2 differentiation of CD4 + T cells from healthy children, and mediated the ubiquitination of lymphocyte cell-specific protein-tyrosine kinase (LCK). LCK acted as a kinase to phosphorylate and activate c-JUN, which was predicted to bind promoter sequence of CD28 by bioinformatic analysis. Dual-luciferase reporter assay verified that c-JUN and ETS1 synergically enhanced transcription of CD28, and this transcription activation was aggravated by LCK overexpression. CONCLUSION: c-CBL alleviated asthma and suppressed Th2 differentiation by facilitating LCK ubiquitination, interrupting c-JUN activation and CD28 expression in vivo and in vitro. c-CBL/LCK/c-JUN/ETS1/CD28 axis was partially involved in childhood asthma, and may provide novel insights for clinical treatment for asthma.
Assuntos
Asma , Antígenos CD28 , Diferenciação Celular , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-cbl , Células Th2 , Asma/metabolismo , Asma/imunologia , Asma/genética , Animais , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Humanos , Células Th2/metabolismo , Células Th2/imunologia , Camundongos , Criança , Masculino , Feminino , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Antígenos CD28/metabolismo , Antígenos CD28/genética , Modelos Animais de Doenças , Transdução de Sinais , Pré-EscolarRESUMO
BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.
Assuntos
Hipertensão Pulmonar , Pulmão , Schistosoma mansoni , Animais , Camundongos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/parasitologia , Hipertensão Pulmonar/imunologia , Pulmão/parasitologia , Pulmão/imunologia , Pulmão/patologia , Schistosoma mansoni/imunologia , Cloridrato de Fingolimode/farmacologia , Feminino , Linfócitos T CD4-Positivos/imunologia , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/complicações , Esquistossomose mansoni/patologia , Modelos Animais de Doenças , Interleucina-4/metabolismo , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Esquistossomose/complicações , Esquistossomose/imunologia , Esquistossomose/parasitologiaRESUMO
Type 2 airway inflammation (T2AI), driven by type 2 innate lymphoid and CD4+ T helper 2 cells, leads to various diseases and conditions, such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma. Emerging evidence suggests the involvement of extracellular vesicles (EVs) in these diseases. In this review, we describe the immunological T2AI pathogenic mechanisms, outline EV characteristics, and highlight their applications in the diagnosis and treatment of T2AI. An extensive literature search was conducted using appropriate strategies to identify relevant articles from various online databases. EVs in various biological samples showed disease-specific characteristics for chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma, with some demonstrating therapeutic effects against these conditions. However, most studies have been limited to in vitro and animal models, highlighting the need for further clinical research on the diagnostic and therapeutic applications of EVs.
Assuntos
Vesículas Extracelulares , Células Th2 , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/imunologia , Humanos , Células Th2/imunologia , Células Th2/metabolismo , Animais , Asma/imunologia , Asma/metabolismo , Asma/terapia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Sinusite/imunologia , Sinusite/metabolismo , Sinusite/patologia , Sinusite/terapia , Rinite Alérgica/imunologia , Rinite Alérgica/metabolismo , Rinite Alérgica/terapia , Pólipos Nasais/imunologia , Pólipos Nasais/terapia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Rinite/imunologia , Rinite/terapia , Rinite/metabolismo , Rinite/patologiaRESUMO
Allergens and Th2 cytokines affect the homeostatic environment in the airways, leading to increased mucus production by goblet cells associated with altered adherens junctional complex (AJC) and tight junction (TJ) proteins responsible for maintaining epithelial barrier function. Circadian clock-dependent regulatory mechanisms such as inflammation and epithelial barrier function are gaining more attention due to their therapeutic potential against allergic inflammatory lung diseases. Currently, there are no studies to support whether REV-ERBα activation can attenuate Th2 cytokine-induced epithelial barrier dysfunction in human bronchial epithelial cells. We hypothesized that Th2 cytokine-induced epithelial barrier dysfunction may be protected by activating REV-ERBα. Treatment with Th2 cytokines or HDM significantly reduced the cell impedance, as confirmed by transepithelial electrical resistance (TEER). However, pre-treatment with SR10067 attenuated Th2 cytokine-induced barrier dysfunction, such as decreased permeability, improved TEER, localization of AJC and TJ proteins, and mRNA and protein levels of selected epithelial barrier and circadian clock targets. Overall, we showed for the first time that REV-ERBα activation regulates altered epithelial barrier function that may have direct implications for the treatment of asthma and other allergic diseases.
Assuntos
Brônquios , Citocinas , Células Epiteliais , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares , Células Th2 , Humanos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Citocinas/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Impedância Elétrica , Tiofenos/farmacologia , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismoRESUMO
As terahertz (THz) technology advances, the interaction between THz radiation and the living body, particularly its effects on the immune system, has attracted extensive attention but remains poorly understood. This study firstly elucidated that exposure to 3 THz-FEL radiation markedly suppressed contact hypersensitivity reactions in mice induced by DNFB, as evidenced by a reduction in ear thickness and a discernible recovery in the Th1/Th2 cell balance. 3 THz irradiation led to cellular stress in the irradiated skin locale, increasing the levels of IL-4 and IL-10 and modulating the activity and migration of dendritic cells and mast cells. Furthermore, THz irradiation precipitated a rapid alteration in the skin lipidome, altering several categories of bioactive lipids. These findings offer new insights into the immunomodulatory effects of THz radiation on living organisms and the potential underlying mechanisms, with implications for the development of therapeutic approaches in managing skin allergic diseases.
Assuntos
Interleucina-4 , Mastócitos , Pele , Radiação Terahertz , Animais , Camundongos , Mastócitos/efeitos da radiação , Mastócitos/imunologia , Pele/efeitos da radiação , Interleucina-4/metabolismo , Células Dendríticas/efeitos da radiação , Células Dendríticas/imunologia , Interleucina-10/metabolismo , Dermatite de Contato/imunologia , Dermatite de Contato/etiologia , Camundongos Endogâmicos BALB C , Dinitrofluorbenzeno , Feminino , Células Th2/efeitos da radiação , Células Th2/imunologia , Células Th1/efeitos da radiação , Células Th1/imunologiaRESUMO
Introduction: Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response. Methods: To understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs. Results: PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming. Conclusions: Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.