Structural Basis for the GM-CSF- and IL-3-Mediated Stimulation of Eosinophil Production and Function in Humans
Gerald J. Gleich, A. Barry Kay in Eosinophils in Allergy and Inflammation, 2019
Human eosinophils are specialized cells believed to play a central role in the control of parasitic infections and allergic reactions. Two important factors that regulate the production and function of eosinophils are the hemopoietic growth factors GM-CSF and IL-3. We have studied the basis for the stimulatory effects of GM-CSF and IL-3 on eosinophils by examining which regions of these molecules are involved in binding and in stimulating eosinophil production or their functional activation. In addition, we have examined the effect of mutations in GM-CSF and IL-3 on their ability to recognize the common β chain or the specific α chains of their receptors, seeking clues as to the contribution of each receptor chain in receptor activation and signaling in eosinophils. The results show that a glutamic acid in the first helix of GM-CSF is crucial for optimal stimulation of eosinophil production and function. Binding studies revealed that this residue selectively interacts with the β chain of the GM-CSF receptor, thus implicating this chain in signaling. Furthermore, given that the β chain of the GM-CSF receptor is also part of the IL-3 and IL-5 receptors, and that a glutamic acid exists in an analogous position in IL-3 and IL-5, these results predict that similar dissociation of binding will be observed in the other two eosinophil activators, IL-3 and IL-5. Mutagenesis of IL-3 revealed two residues involved in function, substitution of which led to an IL-3 analog with increased capacity to stimulate eosinophil production and function. Binding experiments indicate that these residues are involved in binding to the α chain of the IL-3 receptor. Taken together, these results identify crucial yet distinct regions in GM-CSF and IL-3 involved in eosinophil stimulation and point to both the α and β chains of their receptors as important for receptor activation and signaling in eosinophils. The identification of these two regions offers, in addition, the possibility of constructing new mutants with more defined functional specificity and with the potential to behave as selective agonists or antagonists of eosinophil function.
Pulmonary Immunology
Lourdes R. Laraya-Cuasay, Walter T. Hughes in Interstitial Lung Diseases in Children, 2019
In normal persons, less than 1% of bronchoalveolar lavage fluid cells are eosinophils. However, in certain disorders including eosinophilic pneumonia and idiopathic pulmonary fibrosis their numbers dramatically increase in pulmonary alveoli. The bone-marrow derived eosinophil is present in the circulation in small numbers, e.g., for each eosinophil in the blood approximately 500 eosinophils are present in loose connective tissues. (Also a bone marrow reserve of eosinophils exists.)Morphologically, the presence of large granules — up to 20 in each cell — characterizes this cell. In addition, the mature eosinophil contains a small granule. Eosinophilic granules contain major basic protein, eosinophilic cationic protein, and other enzymes including arylsulfatase, phospholipases, acid phosphatase, β-glucoronidase, ribonuclease, and cathepsin. Eosinophils have several functions including a role in immunity to parasites. It has been shown in vitro that major basic protein is highly lethal for schistosomula of schistosoma mansoni. Another role for the eosinophil is to act as a “damper” on the process of inflammation by inactivating inflammatory products derived from the neutrophil. Eosinophils are also capable of phagocytosis, although less efficiently than the neutrophil. Finally, the major basic protein of the eosinophil can produce tissue damage in a clinical and experimental setting. This process is similar to the neutrophil which causes tissue damage in a variety of lung disorders.
Bone Marrow
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The upper normal limit for the number of eosinophils in the blood is 0.35–05 × 10/L. Hypereosinophilia is defined as peripheral blood eosinophil counts >1.5 × 10/L (>1500/μL). Increased numbers of eosinophils in the BM (Figure 2.21) are often seen in both reactive and neoplastic processes. The differential diagnosis includes reactive eosinophilia in parasitic infections (strongyloidiasis, hookworm infection, filariasis, scabies, isosporiasis), bacterial infections (chronic tuberculosis, resolving scarlet fever), HIV, allergic disorders (asthma, atopic dermatitis), drug hypersensitivity, Loeffler’s syndrome, skin diseases (such as angiolymphoid hyperplasia), granulomatous disorders (sarcoidosis), neoplasms (leukemia, lymphoma, adenocarcinoma), abnormal T cells with aberrant phenotype (may or may not be clonal), vasculitis, collagen vascular disorders, inflammatory bowel disease, hypoadrenalism, interleukin (IL)-2 therapy, radiation exposure, cholesterol embolization, and Kimura’s disease. Chronic eosinophilic leukemia (CEL) is an MPN characterized by clonal proliferation of eosinophil precursors leading to persistent eosinophilia in the blood, BM, and peripheral tissues [2,23–26]. CEL, not otherwise specified (CEL, NOS), excludes patients with a Philadelphia chromosome (BCR–ABL fusion) or rearrangement of PDGFRA, PDGFRB, or FGFR1. The eosinophil count is >1.5 × 10/L in the blood and the blasts are
Emphysematous Phenotype is Characterized by Low Blood Eosinophils: A Cross-Sectional Study
Published in COPD: Journal of Chronic Obstructive Pulmonary Disease, 2017
Andriana I. Papaioannou, Konstantinos Kostikas, Anastasia Papaporfyriou, Leonidas Angelakis, Evgenia Papathanasiou, Georgios Hillas, Argyro Mazioti, Petros Bakakos, Nikolaos Koulouris, Spyros Papiris, Stelios Loukides
Sputum and blood eosinophils are proposed as candidate biomarkers for the identification of chronic obstructive pulmonary disease (COPD) patients at risk for exacerbation and treatment response. In this study, we evaluated the associations of eosinophils with the presence of emphysema in COPD patients. Induced sputum and blood eosinophil measurements were performed in consecutive COPD patients. Patients underwent lung function testing and high resolution computed tomography (HRCT) of the chest and the presence of emphysema was quantified. Patients with emphysematous lesions in ≥15% of the pulmonary parenchyma were considered having significant emphysema. Ninety-eight patients were included in the study. Patients with significant emphysema had lower blood eosinophil counts compared to patients without emphysema [median (IQR) 34.6 (0.0, 63.0) vs. 169.0 (110.0, 260.0) cells/µL, p < 0.001]; similar results were observed for the percentage (%) of blood eosinophils, but no difference was observed for sputum eosinophils. The differences were evident in frequent and non-frequent exacerbators and irrespective of the use of inhaled corticosteroids (ICS). Patients with significant emphysema in HRCT present lower levels of blood eosinophils and these differences were present irrespective of the frequent exacerbator history or the use of ICS. Blood eosinophils may not represent a clinically relevant biomarker in the presence of emphysema.
Role of eosinophils in protective immunity against secondary nematode infections
Published in Immunological Medicine, 2019
Infections with parasites, especially those involving nematodes that invade tissues, induce a strong Th2-type immune response, which increases immunoglobulin E and eosinophil levels in the blood and tissues. Eosinophils are not effective against all possible helminth infections, but are known to be effective against nematode larvae. In particular, when a host is re-infected by a species of nematode that it previously encountered, the activation of acquired immunity causes robust accumulation and activation of eosinophils that damages the nematode larvae. Eosinophil production and activation processes are mainly induced by interleukin (IL)-5, which is produced by Th2 cells and group 2 innate lymphoid cells, and eosinophils have been shown to generally participate in host defense, inflammation, and immunomodulation. Recently, several papers have reported host defense by non-antigen-specific immune activation, in which group 2 innate lymphoid cells and Th2 cells produce interleukin (IL)-5 and IL-13 in response to IL-33 stimulation. This immune activation is produced by migrating larvae of a species that differs from the species previously encountered. Eosinophils also play an important role in the eradication of migrating larvae. Thus, eosinophils contribute to host defense in both antigen-specific and non-antigen-specific manners.
Benralizumab: an updated treatment of eosinophilic asthma
Published in Expert Review of Respiratory Medicine, 2020
Breda Cushen, Andrew Menzies-Gow
Introduction: An estimated 5–10% of people with asthma have disease which remains uncontrolled despite maximal treatment with inhaled corticosteroids and long-acting beta-agonists. Benralizumab is currently licensed for use in patients with severe asthma who have an eosinophilic phenotype. Benralizumab depletes eosinophils by binding to the anti-IL5 receptor on the surface of eosinophils, mitigating the effect of IL-5 on eosinophil proliferation and survival, and induces natural killer cell-mediated eosinophil apoptosis. Areas covered: The authors review the mechanism of action and pharmacokinetic profile of Benralizumab and summarize the scientific data supporting its clinical efficacy and safety in severe asthma. Further, the authors highlight future studies of Benralizumab in asthma and other diseases. Expert opinion: Benralizumab lowers exacerbation rates, symptom burden, and oral glucocorticoid use, and improves lung function, in patients with severe eosinophilic asthma. Benralizumab is well tolerated and is an attractive choice for patients and physicians due to its eosinophil-depleting mechanism of action and less frequent dosing schedule. More data is needed to guide the selection of biologic therapy in severe asthma patients.