Allergen-induced Eosinophil Cytolysis Is a Primary Mechanism for Granule Protein Release in Human Upper Airways

Abstract

Cytotoxic eosinophil granule proteins are considered important in the pathogenesis of allergic airway diseases such as rhinitis and asthma. To explore the cellular mechanisms behind eosinophil granule release in human allergic airways, 16 symptom-free patients with seasonal allergic rhinitis were challenged daily with allergen during 1 wk. Nasal lavage samples and biopsies, obtained before and 24 h after the last allergen exposure, were processed for immunohistochemical and electron microscopic analysis. The allergen challenges produced nasal symptoms, marked tissue eosinophilia, and an increase in lavage fluid levels of eosinophil cationic protein (ECP). The nasal mucosa areas with intense extracellular immunoreactivity for ECP were associated with abundant free eosinophil granules. Electron microscopy confirmed the free granules and revealed that all mucosal eosinophils were involved in granule release, either by cytolysis (33%) or piecemeal degranulation (PMD) (67%). Resting or apoptotic eosinophils were not observed. Cytolytic eosinophils had less signs of intracellular granule release (p < 0. 001) and a higher content of intact granules (p < 0.001) compared with viable eosinophils in the same tissue. This study demonstrates eosinophil cytolysis (ECL) as a distinct mechanism for granule mediator release in human allergic airway mucosa. The nature and extent of the ECL and its product (i.e., protein-laden extracellular granules) indicate that allergen-induced cytolysis is a primary and major mechanism for the release of eosinophil proteins in human allergic airway inflammation in vivo.

An etiological role for aeroallergens and eosinophils in experimental esophagitis

“…The accumulation of eosinophils, especially intraepithelial eosinophils, the detection of extracellular granules, and epithelial cell hyperplasia mimic the pathophysiological changes observed in individuals with various forms of eosinophilic esophagitis (6). Of note, the detection of protein-laden free eosinophil granules is a common pathological observation in human eosinophilic inflammation (33). It is likely that sensitization occurs by pulmonary exposure, since oral or intragastric allergen exposure alone fails to elicit eosinophilia.…”

“…Interestingly, some of these granules had a preserved core structure, suggesting that they were released as intact granules. These ultrastructural features, mainly eosinophil cytolysis and the release of free proteinladen eosinophil granules, are the most common finding associated with eosinophilic mucosal inflammation in human disorders (32,33).…”

Eosinophil degranulation status in allergic rhinitis: observations before and during seasonal allergen exposure

“…Preliminary results already suggest that eosinophils, occurring in the target tissue during active seasonal allergic rhinitis, may exhibit more pronounced degranulation than in many other common diseases characterised by tissue eosinophilia, e.g. inflammatory bowel disease and asthma [8,9]. However, as yet, little is known about the dynamics of eosinophil degranulation in allergic rhinitis, especially when the disease progresses from a nonsymptomatic baseline situation into an active symptomatic condition.…”

“…Another goal was to establish the baseline degranulation status in nonsymptomatic patients. Thus, a transmission electron microscopic (TEM) detailed analysis was employed to assess the level of eosinophil degranulation in allergic rhinitis before and during seasonal allergen exposure [9,10]. Also, the occurrence of eosinophil cationic protein (ECP) in nasal tissues and lavage fluids was determined.…”

Non-allergic activation of eosinophils after strenuous endurance exercise

“…43 ECP plays an important role in the pathogenesis of URT allergic inflammation 11 and asthma, where it is released in response to allergen-immunoglobulin E (IgE) crosslinking. 14 Recently, it was reported that a dietary deficiency of antioxidant vitamins may play a role in increasing the severity of asthma. 24 Bowler amd Crapo 6 suggested that augmentation of existing antioxidant defences with catalytic antioxidants might be useful in attenuating respiratory disorders through counteracting the effects of inflammatory cells such as airway eosinophils.…”