Food allergies and eosinophilic gastrointestinal diseases
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
The heritability of the predisposition to allergic disease suggests a genetic basis, but susceptibility genes for food allergy are as yet largely unidentified. Common (atopy) and unique (food allergy) genetic risk factors may contribute to allergic responses to food. Genome-wide association studies have identified intriguing candidates that may provide new insight into disease pathogenesis, particularly for EoE. The first genome-wide association study for EoE showed that eotaxin-3, a prominent eosinophil-recruiting chemokine, was the most upregulated gene in the esophageal epithelia of children with EoE. Further work has identified an epithelial cluster of EoE-associated genes, including filaggrin, an epidermal barrier protective protein. Loss-of-function variants in filaggrin are associated with atopic dermatitis in some patients. This finding is particularly relevant to EoE, since the esophagus (like the skin) is lined by squamous epithelium. If epithelial barrier function is impaired, as may occur with loss of filaggrin function, luminal allergens could enter the lamina propria and initiate an allergic response. Finally, variants in the epithelial cell alarmin TSLP have been implicated in susceptibility to EoE. The disease model that emerges involves a series of genes related to epithelial barrier defects, eosinophil chemotaxis, and predisposition to a TH2 phenotype (Figure 35.6).
Pathophysiology of asthma
Louis-Philippe Boulet in Applied Respiratory Pathophysiology, 2017
Eosinophils are considered key cells in asthma. Airway eosinophilia is mainly driven by IL-5, which promotes the production of eosinophils in the bone marrow and contributes to the recruitment of eosinophils through the influence of chemokines such as eotaxins 1, 2, and 3 (CCL11, CCL24, and CCL26, respectively); regulated upon activation, normal T cell expressed and secreted (RANTES); macrophage inflammatory protein (MIP)-1α; and arachidonic acid metabolites including cysteinyl leukotrienes and 5-keto eicosatetraenoic acid [36]. This type of cell increases in the bronchial mucosa after an allergic response. Its pro-inflammatory effects result in the liberation of cytokines, such as IL-3, IL-4, IL-5, and IL-13, various basic proteins, chemokines, growth factors, enzymes, and lipid mediators.
Pathophysiology of Atopic Dermatitis and Atopiform Dermatitis
Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld in Atopic Dermatitis and Eczematous Disorders, 2014
A number of eosinophil-attracting cytokines are responsible for the trafficking of these cells to sites of cutaneous inflammation. These include IL-5, IL-8, RANTES, eotaxin, eotaxin-2, eotaxin-3, monocyte chemoattractant protein (MCP)-3, MCP-4 and TNF-α (Lampinen et al. 2004). Th2, mast, and epithelial cells are important sources of many of these mediators, and it is now recognized that eosinophils themselves produce many cytokines and play an important role in immunoregulation. Recently, the pluripotential cytokine macrophage migration inhibitory factor (MIF), which is expressed at higher levels in the skin and blood of patients with AD, has been proposed as a major factor causing eosinophil accumulation in the skin (Yoshihisa et al. 2010).
What place will tezepelumab hold in the treatment paradigm in chronic rhinosinusitis?
Published in Expert Review of Clinical Immunology, 2023
Valentin Favier, Jérémy Charriot, Louis Crampette, Arnaud Bourdin, Engi Ahmed
T2-polyps have been shown to be mainly composed of monotonous p63-expressing basal cells associated to a loss of the other classical epithelial subtypes notably secretory and ciliated cells [5]. Single cell RNA sequencing of NP highlighted an impairment in the differentiation ability of basal cells that accumulate at this early ontogenic state (‘basal cell hyperplasia’). Basal cells in eosinophilic CRSwNP showed the highest expression of proinflammatory genes, especially those linked to type 2 inflammation, including the nitric oxide synthase (NOS2), that may be linked to high exhaled nitric oxide (FeNO) levels, TSLP, IL-4/13-induced genes, chemokines such as eotaxin-3, CLC (Charcot-Leyden crystal), and protease inhibitors such as cystatins. Eotaxin 3 is a potent chemoattractant for eosinophils through the binding to the cell surface chemokine receptor CCR3.
Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study
Published in OncoImmunology, 2021
Wencheng Zhang, Cihui Yan, Tian Zhang, Xi Chen, Jie Dong, Jingjing Zhao, Dong Han, Jun Wang, Gang Zhao, Fuliang Cao, Dejun Zhou, Hongjing Jiang, Peng Tang, Lujun Zhao, Zhiyong Yuan, Quanren Wang, Ping Wang, Qingsong Pang
We found both high level of IL-27 and high level of IL-15 in peripheral blood were associated with better survival. The cytokine IL-15 has a key role in promoting survival, proliferation and activation of natural killer and T cells.46,47 IL-27 had double ways in antitumor efficacy.48 Both IL-15 and IL-27 contribute to maintain homeostasis of memory T cells.49,50 As far, their association with survival in checkpoint blockade with or without conventional anti-tumor therapies was little known. Eotaxin-3 was the most highly induced gene in eosinophilic esophagitis patients compared with its expression level in healthy individuals.51 Eotaxin-3 had two receptors CCR3 and CX3CR1. Eotaxin-3 expressed by hepatocellular carcinoma cells could recruit CX3CR1+ MDSCs to the tumor tissue.52 IL-22 is exclusively produced by immune cells. Increased numbers of intratumoral and peripheral IL-22 secreting cells have been reported in lung, gastric, colorectal, pancreatic and hepatocellular carcinomas and enhanced tumor progression.53 Neither Eotaxin-3 nor IL-22 was reported in esophageal cancer. Our findings in peripheral blood illustrate the important role of systemic immune response in antitumour treatment and provide convenient biomarkers for patient selection. Lastly, for patients with CCND1/FGF19/FGF4 amplification, combining targeted therapy might improve treatment efficiency, and deserves further study.
Drug treatment strategies for eosinophilic esophagitis in adults
Published in Expert Opinion on Pharmacotherapy, 2022
A pivotal role has been recognized to IL-13 in EoE, as this Th2 cytokine promotes epithelial dysfunction with increased permeability, fibrous remodeling and production of the eosinophil chemoattractant eotaxin-3[23]. After the insufficient effectivenss provided by dectrekumab (the first anti-IL-13 mAb tested in EoE) Cendakimab is now being investigated in this disease: Some effectiveness compared to placebo were demonstrated in a phase 2 RCT [120] which tested two weekly subcutaneous (SC) injectable doses: 50% of patients treated with either active drug dose had <15 peak eos/hpf after a 16-week therapy. EREFS score was reduced over placebo in patients treated with cendakimab, despite almost no patients achieved esophageal normalization. However, clinical benefit was not superior to that obtained with placebo. Currently, a phase 3 RCTs is being conducted with cendakimab at 360 mg dose compared to placebo in adult and adolescent patients with active EoE (NCT04753697), with no results from this trial available to date.