The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020.

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also reflect on patient data from clinical trials that feature anti-eosinophil therapeutics.

Sputum autoantibodies in patients with severe eosinophilic asthma.

BACKGROUND: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. OBJECTIVES: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. METHODS: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. RESULTS: We report a "polyclonal" autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell-attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid-unresponsive nature of these eosinophilic patients. CONCLUSION: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.

A Survival Case of Fulminant Right-Side Dominant Eosinophilic Myocarditis.

A 59-year-old Japanese woman was admitted to a nearby hospital with dyspnea and general malaise. Transthoracic echocardiography revealed right ventricular (RV) dilatation with severely reduced systolic function and leftward shift of the intraventricular septum. She was initially diagnosed with acute right heart failure, and fell into cardiogenic shock requiring an intra-aortic balloon pump and inotropic agents. An endomyocardial biopsy (EMB) demonstrated extensive interstitial edema, infiltration of inflammatory cells including numerous eosinophils, and myocytolysis with eosinophil degranulation. She was histologically diagnosed with eosinophilic myocarditis. Steroid pulse therapy was initiated, and her hemodynamic status improved along with dramatic recovery of the RV function. EMB 6 days after the initiation of steroid pulse therapy showed the disappearance of infiltration and degranulation of eosinophils, although lymphocytic infiltration still remained. Positron emission tomography-computed tomography (PET/CT) 23 days after steroid pulse therapy showed an increased 18F-FDG uptake in the intraventricular septum and left ventricle, suggesting persistent myocardial inflammation. She was then treated with a maintenance dose of prednisolone. She became free of symptoms and follow-up echocardiography showed normal cardiac function 3 months after the initiation of corticosteroid treatment. In addition, EMB and PET/CT showed no inflammation. This is the first case report of fulminant and right-sided dominant eosinophilic myocarditis successfully treated with corticosteroid.

Hypereosinophilia-associated acute intradialytic hypotension: a report of three cases and literature review.

Occasionally, patients undergoing dialysis develop acute severe hypotension that requires interruption of dialysis within minutes of initiating every dialysis session. Although the underlying causes of recurrent intradialytic hypotension are evaluated extensively, including dialysis-associated allergic reactions or other possible causes, the definitive cause is sometimes missed. Dialysis is a life-sustaining procedure; therefore, prompt identification and management of the underlying cause of dialysis intolerance are crucial. Herein, we report three cases of patients undergoing dialysis who presented with hypereosinophilia-associated acute intradialytic hypotension. All three patients developed acute severe hypotension within minutes after the start of every dialysis session. The prescriptions for dialysis were changed, but episodes of intradialytic hypotension persisted. Pretreatment with methylprednisolone given intravenously before the dialysis session was also ineffective. All patients had hypereosinophilia (> 1500/µL) of different etiology. Eosinophil-lowering therapy with 0.5 mg/kg of prednisolone given orally daily was initiated, and all of them could restart dialysis without any hypotensive episodes within a few days. Our case report and literature review indicated that hypereosinophilia, regardless of its etiology, could result in severe acute hypotension shortly after the start of dialysis session. The oral administration of prednisolone daily was highly effective on hypereosinophilia-associated intradialytic hypotension, while pretreatment with intravenous corticosteroid therapy just before dialysis had no effect. Hypereosinophilia-associated acute intradialytic hypotension is an under-recognized condition; therefore, clinicians need to be aware of this clinical entity and initiate effective treatment strategies. We also provide a brief summary of previously published cases.

Bronchiectasis in severe asthma is associated with eosinophilic airway inflammation and activation.

Background: Bronchiectasis is a common comorbidity in severe asthma; causative pathogenic mechanisms are not fully understood but may differ from other causes of bronchiectasis. The role of eosinophilic airway inflammation, a classic feature of asthma predominantly driven by IL-5 and IL-13, in bronchiectasis is unclear, but association with disruption of the airway epithelium through eosinophil degranulation and increased mucus production is plausible. Objective: We sought to describe the prevalence of bronchiectasis in an unselected population of patients with severe asthma, and the association with the airway eosinophilic inflammation and activation. Methods: All patients with severe asthma according to European Respiratory Society/American Thoracic Society criteria (high-dose inhaled corticosteroids/oral corticosteroids), attending 4 respiratory clinics over a 1-year period, were included. All patients underwent high-resolution computed tomography and induced sputum was collected and analyzed for a cell differential count, free eosinophilic granules, and airway messenger RNA expression of T2 inflammatory pathways. Results: Bronchiectasis was present in 31% (34 of 108) of patients with severe asthma, and half (52%) of these patients had airway eosinophilia whereas only 16% of patients without bronchiectasis had airway eosinophilia. Patients with bronchiectasis had a significantly higher sputum eosinophil count (5.3 vs 0.8; P = .001) as well as more extensive eosinophil degranulation, compared with those without bronchiectasis (13% vs 2%; P = .05), suggesting a higher degree of eosinophil activation. Pairwise analyses identified significantly higher messenger RNA expression of Charcot-Leyden crystal galectin in patients with bronchiectasis (P = .02). Conclusions: Bronchiectasis in severe asthma was associated with eosinophilic airway inflammation and eosinophilic degranulation as well as messenger RNA expression of Charcot-Leyden crystal galectin.

Schistosomiasis Mansoni-Recruited Eosinophils: An Overview in the Granuloma Context.

Eosinophils are remarkably recruited during schistosomiasis mansoni, one of the most common parasitic diseases worldwide. These cells actively migrate and accumulate at sites of granulomatous inflammation termed granulomas, the main pathological feature of this disease. Eosinophils colonize granulomas as a robust cell population and establish complex interactions with other immune cells and with the granuloma microenvironment. Eosinophils are the most abundant cells in granulomas induced by Schistosoma mansoni infection, but their functions during this disease remain unclear and even controversial. Here, we explore the current information on eosinophils as components of Schistosoma mansoni granulomas in both humans and natural and experimental models and their potential significance as central cells triggered by this infection.

Immunopathological and molecular basis of functional dyspepsia and current therapeutic approaches.

INTRODUCTION: Functional dyspepsia (FD) is widespread with 20% prevalence worldwide and a significant economic burden due to health care cost and constraints on daily activities of patients. Despite extensive investigation, the underlying causes of dyspepsia in a majority of patients remain unknown. Common complaints include abdominal discomfort, pain, burning, nausea, early satiety, and bloating. Motor dysfunction of the gut was long considered a major cause, but recent investigations suggest immune-based pathophysiological and molecular events in the duodenum are more probable contributing factors. Areas Covered: Inflammatory mediators and immune cells including duodenal eosinophils, intraepithelial lymphocytes, and T-cells have been implicated in the underlying cause of disease process, as have genetic factors. In this article, we critically reviewed findings, identified gaps in knowledge and suggested future directions for further investigation to identify targets and develop better therapeutic approaches. Expert commentary: Impaired gastric accommodation, slow gastric emptying, and increased visceral sensitivity have long been thought of as main causal factors of FD. However, more recent identification of eosinophilic degranulation and recruitment of T cells that induce mild duodenal inflammation are giving rise to new insights into immune-mediated pathophysiology. These insights offer promising avenues to explore for immune-mediated therapy in the future.

Identification of Piecemeal Degranulation and Vesicular Transport of MBP-1 in Liver-Infiltrating Mouse Eosinophils During Acute Experimental Schistosoma mansoni Infection.

Eosinophils have been long associated with helminthic infections, although their functions in these diseases remain unclear. During schistosomiasis caused by the trematode Schistosoma mansoni, eosinophils are specifically recruited and migrate to sites of granulomatous responses where they degranulate. However, little is known about the mechanisms of eosinophil secretion during this disease. Here, we investigated the degranulation patterns, including the cellular mechanisms of major basic protein-1 (MBP-1) release, from inflammatory eosinophils in a mouse model of S. mansoni infection (acute phase). Fragments of the liver, a major target organ of this disease, were processed for histologic analyses (whole slide imaging), conventional transmission electron microscopy (TEM), and immunonanogold EM using a pre-embedding approach for precise localization of major basic protein 1 (MBP-1), a typical cationic protein stored pre-synthesized in eosinophil secretory (specific) granules. A well-characterized granulomatous inflammatory response with a high number of infiltrating eosinophils surrounding S. mansoni eggs was observed in the livers of infected mice. Moreover, significant elevations in the levels of plasma Th2 cytokines (IL-4, IL-13, and IL-10) and serum enzymes (alanine aminotransferase and aspartate aminotransferase) reflecting altered liver function were detected in response to the infection. TEM quantitative analyses revealed that while 19.1% of eosinophils were intact, most of them showed distinct degranulation processes: cytolysis (13.0%), classical and/or compound exocytosis identified by granule fusions (1.5%), and mainly piecemeal degranulation (PMD) (66.4%), which is mediated by vesicular trafficking. Immunonanogold EM showed a consistent labeling for MBP-1 associated with secretory granules. Most MBP-1-positive granules had PMD features (79.0 ± 4.8%). MBP-1 was also present extracellularly and on vesicles distributed in the cytoplasm and attached to/surrounding the surface of emptying granules. Our data demonstrated that liver-infiltrating mouse eosinophils are able to degranulate through different secretory processes during acute experimental S. mansoni infections with PMD being the predominant mechanism of eosinophil secretion. This means that a selective secretion of MBP-1 is occurring. Moreover, our study demonstrates, for the first time, a vesicular trafficking of MBP-1 within mouse eosinophils elicited by a helminth infection. Vesicle-mediated secretion of MBP-1 may be relevant for the rapid release of small concentrations of MBP-1 under cell activation.

An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein.

BACKGROUND: A histologic hallmark of chronic rhinosinusitis (CRS) is an eosinophilic inflammation, present with and without nasal polyposis and independent of atopy. Eosinophils migrate through nasal tissue including the epithelium into the nasal airway mucus, where they form clusters and degranulate, releasing granule proteins including the toxic major basic protein (MBP). Specific biomarkers for CRS, which could be used as a diagnostic test for CRS with a high sensitivity and specificity, are presently lacking. Recently, an enzyme-linked immunosorbent assay (ELISA)-based test for MBP in nasal airway mucus received regulatory approval. METHODS: A new assay was specifically developed to detect released MBP in airway mucus. MBP levels in nasal mucus of 85 randomly selected CRS patients diagnosed by endoscopy, computed tomography (CT) scans and symptoms were compared to 13 healthy controls and 5 disease controls (allergic rhinitis). RESULTS: Overall, 92% (78/85) of CRS patients' mucus were positive for MBP (mean 7722 ng/mL) vs none of 13 healthy controls and none of 5 allergic rhinitis patients (<7.8 ng/mL; p < 0.000000000002). In this study, the MBP ELISA had a 92% sensitivity and 100% specificity for CRS. CONCLUSION: Free MBP in nasal mucus can be used as a biomarker to diagnose CRS. The MBP ELISA represents the first immunologically-based test to potentially distinguish CRS from the eosinophilic inflammation in allergic rhinitis.