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The role of inducible costimulatory molecular ligand (ICOSL) in children with neutrophilic asthma.

ABSTRACT: Background:It has been shown that certain severe and refractory asthma cases are caused by neutrophil and not eosinophil infiltration. Inducible costimulatory molecular ligand (ICOSL) expression is closely associated with tumor and autoimmune diseases, yet a limited amount of data has been published regarding the significance of ICOSL in children with neutrophilic asthma. The present study aimed to explore the clinical significance of abnormal expression of ICOSL in peripheral blood and bronchoalveolar lavage fluid (BALF) samples of children with neutrophilic asthma. Methods:Selected children from the Children's Hospital of Soochow University who met the diagnostic criteria of asthma and excluded patients with a pathogen-positive etiology. Children who were admitted to the hospital for foreign body inhalation in the same period acted as the control group. Children with more than 50% of neutrophils in BALF samples were assigned to the neutrophilic asthma group (NA group), and the remaining subjects composed the asthma group (A group). The expression levels of ICOSL, IL-4, IL-17, IFN-?, neutrophil elastase (NE), and matrix metalloproteinase-9 (MMP-9) were detected in plasma and BALF samples by enzyme-linked immunosorbent assays, in order to analyze the differences in the levels of cytokines and clinical characteristics between children with neutrophilic asthma and non-neutrophilic asthma. Moreover, the potential mechanism of ICOSL in neutrophilic asthma was explored. Results:32 children were enrolled: 12 children in the NA group and 20 children in the A group. The mean hospitalization time of the NA group was longer than that of the A group (P<0.05). The concentration levels of ICOSL, IL-17, NE, and MMP-9 in plasma and BALF samples in the NA group were higher than those in the A group, while the levels of IFN-? exhibited opposite. A significant correlation was found between ICOSL and IL-17 levels in plasma (r=0.753, P=0.012) and BALF (r=0.774, P=0.009) samples in the NA group. Conclusions:Children with neutrophilic asthma were more severely affected, experiencing a considerably more difficult clinical treatment and longer hospitalization time. ICOSL may regulate the secretion of IL-17 by Th17 and increase the levels of NE and MMP-9, which are involved in the development of immune inflammation in neutrophils.

SUBMITTER: Dong H

PROVIDER: S-EPMC7475312 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The role of inducible costimulatory molecular ligand (ICOSL) in children with neutrophilic asthma.

Dong Heting H Wang Ting T Wang Meijuan M Yan Yongdong Y Zhang Xinxing X Gu Wenjing W Ji Wei W Huang Li L Chen Zhengrong Z

Translational pediatrics 20200801 4

<h4>Background</h4>It has been shown that certain severe and refractory asthma cases are caused by neutrophil and not eosinophil infiltration. Inducible costimulatory molecular ligand (ICOSL) expression is closely associated with tumor and autoimmune diseases, yet a limited amount of data has been published regarding the significance of ICOSL in children with neutrophilic asthma. The present study aimed to explore the clinical significance of abnormal expression of ICOSL in peripheral blood and ...[more]

PMID: 32953544

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Project description:BackgroundProgrammed death-ligand 1 (PD-L1) is an important immune checkpoint inhibitor. Recent studies suggest that the PD-L1-mediated pathway may be a promising target in allergic asthma. However, the mechanism by which PD-L1 represses neutrophilic asthma (NA) remains unclear. In this study, we examined correlations between the expression of PD-L1 and the production of T helper cell type 1 (Th1), T helper cell type 2 (Th2), and T helper cell type 17 (Th17) cells in pediatric patients with NA and a mouse model.MethodsThe clinical samples of 26 children with asthma and 15 children with a bronchial foreign body were collected over a period of 12 months by the Children's Hospital of Soochow University. An experimental mouse model of asthma was established to study NA. An enzyme-linked immunoassay (ELISA) was used to assess soluble PD-L1 (sPD-L1) and cytokines [e.g., interleukin (IL)-4, IL-6, interferon gamma (IFN-γ), IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF)] in bronchoalveolar lavage fluid (BALF).ResultsNA patients had significantly higher levels of sPD-L1, IL-6, IL-17, and GM-CSF in their BALF than non-NA and control patients (P<0.05). In a murine model of asthma, the positive rate and fluorescence intensity of PD-L1 in the NA group and the immunoglobulin G (IgG)-treated NA group were higher than in the PD-L1 antibody (Ab)-treated NA group and the phosphate-buffered saline (PBS) control group (P<0.05). In the plasma and the BALF of the NA group and the IgG-treatment NA group, the levels of IL-17, IL-4, tumor necrosis factor alpha (TNF-α), and granulocyte colony-stimulating were higher than those in the PBS control group (P<0.05). The histopathological examination of lung tissues from all mice groups showed that a large number of inflammatory cells were found around the airway in the NA group and the IgG-treatment group.ConclusionsPD-L1 may contribute to the Th17/IL-17 immune response, which is associated with neutrophilic inflammation and asthma. A PD-L1 blockade reduces pulmonary neutrophils and mucus production.

Project description:PurposeWe assess the efficacy of two next-generation biologic therapies in treating experimental autoimmune uveitis.MethodsVariable binding domains from shark immunoglobulin novel antigen receptors (VNARs) were fused with a mouse IgG2a constant domain (Fc) to generate VNAR-Fc molecules with binding specificity to tumor necrosis factor alpha (TNFα) or inducible T-cell costimulatory ligand (ICOSL). Treatment with VNAR-Fc fusion proteins was compared to treatment with dexamethasone or vehicle in the Lewis rat model of experimental autoimmune uveitis (EAU). Inflammation control was determined by comparing OCT clinical and histologic scores, and aqueous humor protein concentration. The concentration of 27 inflammatory cytokines in the aqueous humor was measured using a multiplex enzyme-linked immunosorbent assay platform.ResultsAdministration of S17-Fc significantly decreased clinical, histologic, and aqueous protein levels when compared to vehicle treatment. Inflammation scores and aqueous protein levels in A5-Fc-treated animals were decreased compared to vehicle treatment, but not significantly. The concentration of vascular endothelial growth factor (VEGF), regulated on activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1α), interleukin (IL)-1β, LPS-induced CXC chemokine (LIX), monocyte chemoattractant protein-1 (MCP-1), and interferon (IFN)-γ were significantly decreased in the eyes of animals treated with dexamethasone. VNAR treatment demonstrated a trend towards decreased cytokine concentrations, but only VEGF and RANTES were significantly decreased by S17-Fc.ConclusionsTreatment with the anti-TNFα VNAR S17-Fc ameliorates EAU as effectively as treatment with corticosteroids.Translational relevanceVNAR-Fc molecules are a next-generation therapeutic biologic that overcome the limitations of classical biologic monoclonal antibodies, such as complex structure, large size, and limited tissue penetration. This is a novel drug modality that could result in the development of new therapy options for patients with noninfectious uveitis.

Dataset Information

The role of inducible costimulatory molecular ligand (ICOSL) in children with neutrophilic asthma.

Publications

The role of inducible costimulatory molecular ligand (ICOSL) in children with neutrophilic asthma.

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