RESUMEN
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.
Asunto(s)
Autoinmunidad , Factor de Transcripción Ikaros , Células Th2 , Ubiquitina-Proteína Ligasas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoinmunidad/genética , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/genética , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/patología , Linaje , Proteínas Proto-Oncogénicas c-fyn/genética , Proteínas Proto-Oncogénicas c-fyn/inmunología , Células Th2/inmunología , Células Th2/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunologíaRESUMEN
Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.
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Asma , Interleucina-13 , Animales , Humanos , Ratones , Sistema de Transporte de Aminoácidos y+ , Asma/genética , Asma/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ovalbúmina/metabolismo , Ovalbúmina/uso terapéutico , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/uso terapéutico , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
In lung, thromboxane A2 (TXA2) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens. Herein, we found that TXA2 reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased approximately 2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with TXA2. Naive CD4+ T cell differentiation to Th9 cells and IL-9 production were inhibited dose-dependently by TXA2 in vitro. TP receptor-deficient mice had an approximately 2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared with wild-type mice. Naive CD4+ T cells from TP-deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared with CD4+ T cells from wild-type mice. TXA2 also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, proinflammatory effects, TXA2 also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma.
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Asma , Diferenciación Celular , Linfocitos T Reguladores , Células Th2 , Tromboxano A2 , Animales , Ratones , Células Th2/inmunología , Células Th2/patología , Tromboxano A2/metabolismo , Tromboxano A2/inmunología , Linfocitos T Reguladores/inmunología , Asma/inmunología , Asma/patología , Asma/tratamiento farmacológico , Asma/genética , Ratones Noqueados , Interleucina-9/inmunología , Interleucina-9/genética , Interleucina-9/metabolismo , Neumonía/inmunología , Neumonía/patología , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Pulmón/inmunología , Pulmón/patología , Ovalbúmina/inmunología , Femenino , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.
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Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Piel/patología , Células Th2/patología , Resultado del Tratamiento , Método Doble Ciego , Índice de Severidad de la Enfermedad , Receptores CCR4/uso terapéuticoRESUMEN
Bronchial asthma (BA) is a heterogeneous chronic inflammatory disease of the respiratory tract. Allergic (atopic) asthma is the most common (up to 80% of cases) phenotype developing through the Th2-dependent mechanisms involving cytokines: IL-4, IL-5, IL-9, and IL-13. The genes encoding Th2-cytokines have a mosaic structure (encode exons and introns). Therefore, several mature mRNA transcripts and protein isoforms can be derived from a single mRNA precursor through alternative splicing, and they may contribute to BA pathogenesis. Analysis of the published studies and databases revealed existence of the alternative mRNA transcripts for IL-4, IL-5, and IL-13. The alternative transcripts of IL-4 and IL-5 carry open reading frames and therefore can encode functional proteins. It was shown that not only alternative mRNA transcripts exist for IL-4, but alternative protein isoforms, as well. Natural protein isoform (IL-4δ2) lacking the part encoded by exon-2 was identified. Similarly, alternative mRNA transcript with deleted exon-2 (IL-5δ2) was also identified for IL-5. In this review, we summarize current knowledge about the identified alternative mRNA transcripts and protein isoforms of Th2-cytokinins, first of all IL-4 and IL-5. We have analyzed biological properties of the alternative variants of these cytokines, their possible role in the allergic asthma pathogenesis, and considered their diagnostic and therapeutic potential.
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Asma , Citocinas , Humanos , Citocinas/genética , Citocinas/metabolismo , Empalme Alternativo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-5/genética , Interleucina-5/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Asma/genética , Asma/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Shaoyao-Gancao Tang (SGT) is a traditional Chinese medicine formulation. It has been used to treat kinds of pain and to alleviate asthma in clinic. However, the mechanism of action is not known. AIM OF THE STUDY: To investigate the anti-asthma effect of SGT involving modulation of the T-helper type 1 (Th1) Th1/Th2 ratio in the gut-lung axis and alteration of the gut microbiota (GM) in rats with ovalbumin (OVA)-induced asthma. MATERIALS AND METHODS: The main constituents of SGT were analyzed by high-performance liquid chromatography (HPLC). A model of asthma was established in rats by OVA-induced allergen challenge. Rats suffering from asthma (RSAs) were treated with SGT (2.5, 5.0 and 10.0 g/kg), dexamethasone (1 mg/kg) or physiologic saline for 4 weeks. The level of immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF) and serum was determined by enzyme-linked immunosorbent assay. Histology of lung and colon tissues was investigated using staining (hematoxylin and eosin and periodic acid-Schiff). The Th1/Th2 ratio and levels of cytokines (interferon (IFN)-γ and interleukin (IL)-4) in the lung and colon were detected by immunohistochemistry. The GM in fresh feces was analyzed by 16 S rRNA gene sequencing. RESULTS: Twelve main constituents (gallic acid, albiflorin, paeoniflorin, liquiritin apioside, liquiritin, benzoic acid, isoliquiritin apioside, isoliquiritin, liquiritigenin, glycyrrhizic acid, isoliquiritigenin and glycyrrhetinic acid) of SGT were simultaneously determined by HPLC. SGT treatment (5.0 and 10.0 g/kg) was found to reduce the IgE level (a vital marker of hyper-responsiveness) in BALF and serum, improve typical morphological changes (inflammatory-cell infiltration and goblet cell metaplasia) in the lung and colon, alleviate airway remodeling (including bronchiostenosis and basement membrane-thickening) in the lung, significantly decrease the IL-4 level and increase the IFN-γ level in the lung and colon, which led to restoration of the IFN-γ/IL-4 ratio. The dysbiosis and dysfunction of GM in RSAs were modulated by SGT. The abundance of bacteria of the genera Ethanoligenens and Harryflintia was increased in RSAs and was decreased upon SGT treatment. The abundance of Family_XIII_AD3011_group was decreased in RSAs and increased upon SGT treatment. Moreover, SGT therapy increased the abundance of bacteria of the genera Ruminococcaceae_UCG-005 and Candidatus_Sacchrimonas, and decreased that of Ruminococcus_2 and Alistipes. CONCLUSIONS: SGT ameliorated rats with OVA-induced asthma via regulation of the Th1/Th2 ratio in the lung and gut, and modulated the GM.
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Asma , Microbioma Gastrointestinal , Ratas , Animales , Ratones , Ovalbúmina/farmacología , Interleucina-4 , Asma/inducido químicamente , Asma/tratamiento farmacológico , Asma/patología , Pulmón , Líquido del Lavado Bronquioalveolar , Citocinas/farmacología , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Células Th2/patologíaRESUMEN
OBJECTIVE: We aimed to investigate the differences of transcriptome profile between 2 groups of high-grade serous ovarian cancer (HGSOC) patients with distinct outcomes and identify potential biomarkers for recurrence. METHODS: RNA sequencing was performed in 2 groups of HGSOC patients with similar demographic characteristics but exhibiting distinct progression-free survival (PFS). Transcriptome data of poor response (PR; PFS ≤6 months) and good response (GR; PFS ≥12 months) group were compared. We employed xCell to evaluate the abundance of 63 cells in tumor microenvironment. The predictive value of recurrence-related tumor infiltration cells was validated in cohort data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) dataset. The weighted correlation network analysis was performed to identify the genes related to cell infiltration. RESULTS: PR patients exhibited a distinct tumor infiltration immune cells-related transcriptional profile compared to GR patients, such as lower signatures of leukocyte differentiation, activation and chemotaxis. The fraction of T-helper 2 (Th2) cells infiltration was significantly higher in PR group than in GR group. High infiltration of Th2 was significantly associated with unfavorable prognosis in the GEO cohort (area under the curve=0.84 at 6 months recurrence) and TCGA cohort (p=0.008). Genes enriched to extracellular matrix organization and integrin binding were relevant to Th2 infiltration. CONCLUSION: Patients with HGSOC having shorter PFS exhibited a distinct gene signature that related to tumor-infiltrating immune cells. The level of Th2 infiltration could facilitate patient recurrence risk stratification and may be a promising biomarker for prognosis prediction and immune-related treatment.
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Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/patología , Células Th2/metabolismo , Células Th2/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Microambiente TumoralRESUMEN
Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4Rα), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4Rα signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1creIL-4Rα-/lox, iLCKcreIL-4Rα-/lox, LCKcreIL-4Rα-/lox, CD4creIL-4Rα-/lox, Foxp3creIL-4Rα-/lox and IL-4Rα-/lox littermate controls. IL-4Rα-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4Rα-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of γδT cells during acute AD. Our results suggest that IL-4Rα responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.
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Linfocitos B , Dermatitis Atópica , Subunidad alfa del Receptor de Interleucina-4 , Células Th2 , Animales , Ratones , Alérgenos/efectos adversos , Linfocitos B/metabolismo , Linfocitos B/patología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Inmunoglobulina E/sangre , Inmunoglobulina E/química , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de Interleucina-4/metabolismo , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
Asthma is characterized by increased airway hyperresponsiveness, reversible airflow limitation, and remodeling due to allergic airway inflammation. Asthma has been proposed to be classified into various phenotypes by cluster analyses integrating clinical information and laboratory data. Recently, asthma has been classified into two major endotypes, Type 2-high and Type 2-low asthma, and various subtypes based on the underlying molecular mechanisms. In Type 2-high asthma, Th2 cells, together with group 2 innate lymphoid cells (ILC2s), produce type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13, which play crucial roles in causing airway inflammation. The roles of ILC2s in asthma pathogenesis have been analyzed primarily in murine models, demonstrating their importance not only in IL-33- or papain-induced innate asthma models but also in house dust mite (HDM)- or ovalbumin (OVA)-induced acquired asthma models evoked in an antigen-specific manner. Recently, evidence regarding the roles of ILC2s in human asthma is also accumulating. This minireview summarizes the roles of ILC2s in asthma, emphasizing human studies.
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Asma , Inmunidad Innata , Humanos , Ratones , Animales , Linfocitos , Asma/patología , Pulmón/patología , Citocinas , Inflamación/patología , Modelos Animales de Enfermedad , Células Th2/patologíaRESUMEN
BACKGROUND: Cell division cycle 42 (CDC42) modulates the pathogenesis of allergic rhinitis (AR) through regulating immunity, allergic response, and T-helper (Th)1/Th2 imbalance. This study aimed to evaluate the potential of CDC42 to reflect disease risk, symptom scores, and Th1/Th2 axis of AR and the correlation of its vertical change with symptom amelioration after treatment. METHODS: CDC42, Th1 cells, and Th2 cells in the peripheral blood mononuclear cells (PBMCs) and interferon-γ and interleukin-4 in the serum were determined in 200 AR patients. Simultaneously, PBMC CDC42 was detected in 50 non-atopic obstructive snoring patients [as disease controls (DCs)] and 50 healthy controls (HCs). RESULTS: CDC42 was increased in AR patients compared with DCs and HCs (both p < 0.001) but showed no difference between DCs and HCs (p = 0.054). In AR patients, CDC42 was positively linked to rhinorrhea, itching, sneezing, and total nasal symptom scores (TNSS) (all p < 0.05), but not congestion score (p = 0.052). Meanwhile, CDC42 showed positive correlations with Th2 cells (p < 0.001) and interleukin-4 (p = 0.005), a negative correlation with Th1/Th2 axis (p = 0.001), but no correlation with Th1 cells (p = 0.095) or interferon-γ (p = 0.174). Notably, CDC42 at week 4 after treatment (W4) was reduced compared with that at enrollment (W0) (p < 0.001) and positively correlated with TNSS at W4 (p < 0.001); from W0 to W4, CDC42 change also positively correlated with TNSS change (p = 0.004). CONCLUSION: CDC42 is elevated and positively correlates with symptom scores and Th2 cells, whose short-term reduction reflects symptom alleviation in AR patients.
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Interleucina-4 , Rinitis Alérgica , Ciclo Celular , Citocinas/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Leucocitos Mononucleares/metabolismo , Rinitis Alérgica/epidemiología , Células Th2/metabolismo , Células Th2/patología , Proteína de Unión al GTP cdc42RESUMEN
Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4+ T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6-GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4+ T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases.
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Proteínas Quinasas Activadas por AMP , Células Th2 , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Inflamación/patología , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones , Ratones Noqueados , Sirtuina 1/genética , Células Th2/patologíaRESUMEN
BACKGROUND: Asthma is a major public health problem worldwide. Emerging data from epidemiological studies show that allergies and allergic diseases may be linked to anxiety, depression and cognitive decline. However, little is known about the effect of asthma, an allergic lung inflammation, on cognitive decline/behavioral changes. Therefore, we investigated the hypothesis that allergic lung inflammation causes inflammation in the brain and leads to neurobehavioral changes in mice. METHODS: Wild-type C57BL/6J female mice were sensitized with nasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. A series of neurocognitive tests for anxiety and/or depression were performed before and after the intranasal HDM administration. After the behavior tests, tissues were harvested to measure inflammation in the lungs and the brains. RESULTS: HDM-treated mice exhibited significantly increased immobility times during tail suspension tests and significantly decreased sucrose preference compared with PBS controls, suggesting a more depressed and anhedonia phenotype. Spatial memory impairment was also observed in HDM-treated mice when assessed by the Y-maze novel arm tests. Development of lung inflammation after 6 weeks of HDM administration was confirmed by histology, bronchoalveolar lavage (BAL) cell count and lung cytokine measurements. Serum pro-inflammatory cytokines and Th2-related cytokines levels were elevated in HDM-sensitized mice. In the brain, the chemokine fractalkine was increased in the HDM group. The c-Fos protein, a marker for neuronal activity, Glial Fibrillary Acidic Protein (GFAP) and chymase, a serine protease from mast cells, were increased in the brains from mice in HDM group. Chymase expression in the brain was negatively correlated with the results of sucrose preference rate in individual mice. CONCLUSIONS: 6 weeks of intranasal HDM administration in mice to mimic the chronic status of lung inflammation in asthma, caused significant inflammatory histological changes in the lungs, and several behavioral changes consistent with depression and altered spatial memory. Chymase and c-Fos proteins were increased in the brain from HDM-treated mice, suggesting links between lung inflammation and brain mast cell activation, which could be responsible for depression-like behavior.
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Asma , Hipersensibilidad , Neumonía , Animales , Asma/metabolismo , Asma/patología , Líquido del Lavado Bronquioalveolar , Quimasas/metabolismo , Quimasas/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inflamación/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Neumonía/metabolismo , Neumonía/patología , Pyroglyphidae/metabolismo , Sacarosa , Células Th2/patologíaRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and the immune inflammatory response is thought to play an important role in pathogenesis. However, the immunophenotype of patients with COPD is unknown. Herein, we evaluated the immunophenotype of patients with acute exacerbation of COPD (AECOPD). METHODS: A cross-sectional study was conducted in West China Hospital from September 2018 to October 2019. The proportion of CD4 + T lymphocyte subtypes (Th1, Th2, Th17 and Treg) and levels of serum cytokines in the peripheral blood of patients with AECOPD, stable COPD (SCOPD), healthy smokers (HSs)and healthy controls (HCs) were evaluated. RESULTS: A total of 15 HCs, 19 HSs, 42 patients with SCOPD, and 55 patients with AECOPD were included. Compared to patients with SCOPD, Th1 cells, Th17 cells, Treg cell ratio, Th1/Th2 cell ratio, and the levels of C-reactive protein, interleukin (IL)-6, and IL-10 were significantly increased in patients with AECOPD (P < 0.001), while the proportion of Th2 cells was significantly reduced (P < 0.01). The proportion of Th17 cells was positively correlated with COPD Assessment Test score (r = 0.266, P = 0.009), modified Medical Research Council dyspnea score (r = 0.858, P < 0.0001), and Th1 cell ratio (r = 0.403, P < 0.0001) and negatively correlated with forced vital capacity (r = - 0.367, P = 0.009) and proportion of Th2 cells (r = - 0.655, P < 0.0001). CONCLUSIONS: The immunophenotype of patients with AECOPD shows abnormal activation of Th1, Th17, and Treg cells. There is a correlation between the proportion of Th17 cells and the severity of COPD; therefore, this may represent a novel index for the evaluation of COPD severity. TRIAL REGISTRATION: China Clinical Trials Registry, ChiCTR1800018452, registered 19 September 2018, https://www.chictr.org.cn/index.aspx .
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Enfermedad Pulmonar Obstructiva Crónica , Estudios Transversales , Humanos , Interleucina-6 , Células TH1 , Células Th17 , Células Th2/patologíaRESUMEN
To identify the effect of long noncoding RNA (lncRNA) FR215775 in regulating CD4+ T cells on murine models of allergic rhinitis (AR), the expression of lncRNA FR215775 in primary Th2 cells was detected through qRT-PCR. After knocking down the expression of lncRNA FR215775 via Sh-FR215775-Ads, Cell Counting Kit-8, cytometric bead array, and fluorescence-activated cell sorting were performed to determine its functions in vitro. Moreover, lncRNA FR215775-silencing or nonsilencing cells were injected intravenously into AR mice. Then, hematoxylin and eosin, Alcian blue-periodic acid Schiff, and toluidine blue staining were performed, and the levels of IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, IFN-γ, and TNF in the AR mice were also determined. We found that the expression of lncRNA FR215775 was specifically higher in the murine primary Th2 cells. After the knockdown of lncRNA FR215775, the proliferation of CD4+ T cells was inhibited, and the expressions of IL-4 and IL-5 in the cell culture supernatant were significantly decreased (P < 0.001), along with the percentage of Th2 cells (P < 0.05). The lncRNA FR215775-silencing AR group showed less serious allergic symptoms and a low level of ovalbumin-specific immunoglobulin E (P < 0.01). Meanwhile, the eosinophilia inflammation, goblet cell hyperplasia, and mast cell inflammation in the nasal mucosa all decreased, which indicated attenuated allergic inflammation in the lncRNA FR215775-silencing AR group. In addition, the Th2-related cytokines IL-4 and IL-5 were downregulated in the serum and nasal lavage fluid of this group (P < 0.01). In conclusion, lncRNA FR215775 may play a vital role in the function and differentiation of Th2 cells, which may encourage allergic inflammation. These results may provide significant insights into AR pathogenesis and offer new treatment targets for alleviating AR.
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ARN Largo no Codificante , Rinitis Alérgica , Células Th2 , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/patología , Interleucina-4/genética , Interleucina-4/farmacología , Interleucina-5/genética , Interleucina-5/inmunología , Ratones , Ratones Endogámicos BALB C , Mucosa Nasal/patología , Ovalbúmina , ARN Largo no Codificante/genética , ARN Largo no Codificante/inmunología , Rinitis Alérgica/genética , Rinitis Alérgica/inmunología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
OBJECTIVE: This study aimed to screen anaplasia-related genes that influence the progression of retinoblastoma (RB) and to identify immune cells associated with the poor prognosis. METHODS: Differentially expressed genes (DEGs) between retina and RB samples were acquired from gene expression omnibus (GEO) database. Candidate hub genes were screened by taking intersections among the co-expressed genes, the hub nodes, and DEGs of the validation set. The hub genes were identified by receiver operating characteristic (ROC) and quantitative real-time PCR (qPCR). Immune infiltration levels of RB tissues were estimated using single-sample gene set enrichment analysis (ssGSEA). The functions of RB cells were detected by CCK8, EDU and flow cytometry assays. RESULTS: 665 DEGs involved in the genesis and progression of RB were acquired from GEO database. 29 candidate hub genes were screened by examining 43 co-expressed genes and 63 hub nodes. 9 hub genes (CHEK1, EXO1, FANCI, GTSE1, MELK, MKI67, NCAPH, PRC1, and UBE2T) strongly related to the anaplastic grades were validated by ROC curve analysis (AUC >0.8). Based on the ssGSEA scores, the immune infiltration levels of Th2 cells were positively associated with anaplastic grade. qPCR assay showed that 9 hub genes were upregulated in RB cells, and UBE2T expressed remarkably high. CCK 8, EDU, and flow cytometry assays revealed that UBE2T silencing inhibited the proliferation of RB cells and incited apoptosis. CONCLUSIONS: The increased infiltration of Th2 cells and upregulated expression of 9 hub genes predict a poor prognosis of RB. UBE2T can be a therapeutic target for RB treatment.
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Neoplasias de la Retina , Retinoblastoma , Enzimas Ubiquitina-Conjugadoras , Biomarcadores , Proteínas de Ciclo Celular/genética , Biología Computacional , Redes Reguladoras de Genes , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Nucleares/genética , Pronóstico , Proteínas Serina-Treonina Quinasas , Retinoblastoma/genética , Células Th2/patología , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
The health and economic burden of colitis is increasing globally. Understanding the role of host genetics and metagenomics is essential to establish the molecular basis of colitis pathogenesis. In the present study, we have used a common composite dose of DSS to compare the differential disease severity response in C57BL/6 (Th1 biased) and BALB/c (Th2 biased) mice with zero mortality rates. We employed multi-omics approaches and developed a newer vector analysis approach to understand the molecular basis of the disease pathogenesis. In the current report, comparative transcriptomics, metabonomics, and metagenomics analyses revealed that the Th1 background of C57BL/6 induced intense inflammatory responses throughout the treatment period. On the contrary, the Th2 background of BALB/c resisted severe inflammatory responses by modulating the host's inflammatory, metabolic, and gut microbial profile. The multi-omics approach also helped us discover some unique metabolic and microbial markers associated with the disease severity. These biomarkers could be used in diagnostics.
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Colitis , Células TH1 , Animales , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Metagenómica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células TH1/patología , Células Th2/patologíaRESUMEN
Graves' disease (GD) is a kind of autoimmune diseases. The development of GD is closely related to the imbalance of Th1/Th2 generated by the differentiation of CD4+ T cells. This study was sought to clarify the role of lncRNA RUNX1-IT1 and explore the mechanism of its function. The expressions of RUNX1-IT1 and Neural cell adhesion molecule (NrCAM) in the peripheral blood of GD patients were detected by qRT-PCR and Western blot. We performed RNA pull down, RIP, and ChIP experiments to verify the correlation between p53 and RUNX1-IT1, p53 and NrCAM. The levels of Th1 cells differentiation markers were detected by Flow cytometry assay and ELISA. The expressions of lncRNA RUNX1-IT1 and NrCAM were most significantly up-regulated in CD4+ T cells of GD patients, and NrCAM expression was significantly positively correlated with RUNX1-IT1 expression. Furthermore, p53 was a potential transcription factor of NrCAM, which could interact with NrCAM. NrCAM level was up-regulated after the overexpression of p53 in CD4+ T cells, while knockdown of RUNX1-IT1 reversed this effect. Down-regulation of NrCAM and RUNX1-IT1 could decrease the mRNA and protein levels of transcriptional regulator T-bet and CXC chemokine ligand 10 (CXCL10) in CD4+ T cells. Our results suggested that RUNX1-IT1 regulated the expressions of the important Th1 factor T-bet, CXCL10, and interferon γ (IFN-γ) by regulating NrCAM transcription, thus participating in the occurrence and development of specific autoimmune disease GD.
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Moléculas de Adhesión Celular , Enfermedad de Graves , ARN Largo no Codificante , Células TH1 , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Quimiocinas CXC/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Enfermedad de Graves/metabolismo , Enfermedad de Graves/patología , Humanos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Células TH1/inmunología , Células TH1/patología , Células Th2/inmunología , Células Th2/patología , Transcripción Genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Hemin, a substrate of heme oxygenase (HO)-1, induces HO-1 expression on a variety of cells to exert anti-oxidant and anti-inflammatory roles. However, the role of HO-1 in allergic diseases for dendritic cells (DCs) is not fully understood. Here, we report that HO-1 modulates asthmatic airway inflammation by hemin-treated DC-released extracellular vesicles (DCEVs). Following induction of bone marrow-derived DCs by hemin and then by house dust mite (HDM) in vitro, mouse CD4+ naïve T cells were cocultured with DCEVs to determine T helper (h) cell differentiation. C57BL/6 mice were sensitized by different stimuli-induced DCEVs and challenged with HDM to analyze the changes of inflammatory cells and cytokines in the lung and bronchoalveolar lavage fluid. The results showed that hemin-treated DCEVs (hemin-DCEVs) express phosphatidylserine (PS), CD81, heat shock protein 70, and HO-1, which facilitates regulatory T (Treg) cells differentiation in vitro and in vivo. In HDM-induced asthmatic mouse model, hemin-DCEVs inhalation reduced eosinophils infiltration and mucus secretion in the airway, decreased the levels of IL-4, IL-5, and IL-13 in the lung and the number of Th2 cells in mediastinal lymph nodes (MLNs), and increased the number of Treg cells in MLNs. Thus, our study demonstrated, for the first time, that EVs from HO-1-overexpressing DCs alleviate allergic airway inflammation of eosinophilic asthma by potentiating Treg cells differentiation and limiting proinflammatory cytokine secretion, which expands our understanding of HO-1 function, opening the door for HO-1 inducer-like hemin as a novel therapeutic strategy for asthma or other allergic diseases.
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Asma , Vesículas Extracelulares , Hipersensibilidad , Animales , Asma/metabolismo , Células Dendríticas/metabolismo , Vesículas Extracelulares/metabolismo , Hemina/metabolismo , Hemina/farmacología , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Pyroglyphidae , Células Th2/patologíaRESUMEN
Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-ß) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.