Origins and functions of eosinophils in two non-mucosal tissues.

Eosinophils are a type of granulocyte named after the presence of their eosin-stained granules. Traditionally, eosinophils have been best known to play prominent roles in anti-parasitic responses and mediating allergic reactions. Knowledge of their behaviour has expanded with time, and they are now recognized to play integral parts in the homeostasis of gastrointestinal, respiratory, skeletal muscle, adipose, and connective tissue systems. As such, they are implicated in a myriad of pathologies, and have been the target of several medical therapies. This review focuses on the lifespan of eosinophils, from their origins in the bone marrow, to their tissue-resident role. In particular, we wish to highlight the functions of eosinophils in non-mucosal tissues with skeletal muscle and the adipose tissues as examples, and to discuss the current understanding of their participation in diseased states in these tissues.

Immune Cell-Mediated Autoimmune Responses in Severe Asthma.

Severe asthma (SA) has heterogeneous inflammatory phenotypes characterized by persistent airway inflammation (eosinophilic and/or neutrophilic inflammation) and remodeling. Various immune cells (eosinophils, neutrophils, and macrophages) become more activated and release inflammatory mediators and extracellular traps, damaging the protective barrier of airway epithelial cells and further activating other immune and structural cells. These cells play a role in autoimmune responses in asthmatic airways, where the adaptive immune system generates autoantibodies, inducing immunoglobulin G-dependent airway inflammation. Recent studies have suggested that adult asthmatics had high titers of autoantibodies associated with asthma severity, although pathogenic factors or diagnostic criteria are not well-defined. This challenge is further compounded by asthmatics with the autoimmune responses showing therapy insensitivity or failure to current pharmacological and biological treatment. This review updates emerging mechanisms of autoimmune responses in asthmatic airways and provides insights into their roles, proposing potential biomarkers and therapeutic targets for SA.

Eosinophilic Asthma: Pathophysiology and Therapeutic Horizons.

Asthma is a prevalent chronic non-communicable disease, affecting approximately 300 million people worldwide. It is characterized by significant airway inflammation, hyperresponsiveness, obstruction, and remodeling. Eosinophilic asthma, a subtype of asthma, involves the accumulation of eosinophils in the airways. These eosinophils release mediators and cytokines, contributing to severe airway inflammation and tissue damage. Emerging evidence suggests that targeting eosinophils could reduce airway remodeling and slow the progression of asthma. To achieve this, it is essential to understand the immunopathology of asthma, identify specific eosinophil-associated biomarkers, and categorize patients more accurately based on the clinical characteristics (phenotypes) and underlying pathobiological mechanisms (endotypes). This review delves into the role of eosinophils in exacerbating severe asthma, exploring various phenotypes and endotypes, as well as biomarkers. It also examines the current and emerging biological agents that target eosinophils in eosinophilic asthma. By focusing on these aspects, both researchers and clinicians can advance the development of targeted therapies to combat eosinophilic pathology in severe asthma.

Role of peripheral and tissue eosinophils and eosinophil cationic protein in pediatric inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease (IBD), eosinophilic gastrointestinal disease (EGID), and functional abdominal pain disorder (FAPD) present with nonspecific gastrointestinal (GI) symptoms clinically and also have some similarities in pathogeneses associated with eosinophils. Therefore, we aimed to evaluate the role of eosinophils in IBD compared to EGID and FAPD by investigating eosinophils in peripheral blood and GI tissue and eosinophil cationic protein (ECP). METHODS: Pediatric patients with chronic GI symptoms who underwent endoscopic biopsies were enrolled. Complete blood cell counts, inflammatory markers, immunoglobulin E (IgE), serum ECP levels, and endoscopic and histopathologic findings were retrospectively reviewed. RESULTS: A total of 387 patients were included: 179 with EGID, 107 with IBDs, and 82 with FAPD. Peripheral absolute eosinophil count (AEC), total IgE, and serum ECP were significantly higher in both IBD and EGID than in FAPD (all p < 0.05). Statistically significant differences were noted among the three groups in tissue eosinophil counts in each segment of GI tract except for the esophagus (p < 0.05). Significant differences were observed in tissue eosinophil counts in the ascending, sigmoid colon, and rectum between EGID and IBD (p < 0.05). Peripheral and tissue eosinophils in the stomach and duodenum revealed positive correlation in both EGID and IBD (both p < 0.001). CONCLUSION: Elevated eosinophil-related markers, as well as increased tissue eosinophilic infiltration in the affected areas of the GI tract in both IBD and EGID compared to FAPD, suggest that eosinophils might play a common important role in the pathogeneses of both diseases.

Major basic protein is a useful marker to distinguish eosinophilic esophagitis from IBD-associated eosinophilia in children.

OBJECTIVES: The incidence of eosinophilic esophagitis (EoE) is 3-5 times greater in patients with inflammatory bowel disease (IBD) compared with the general population. This study aimed to differentiate true EoE from esophageal eosinophilia in IBD patients by evaluating expression of major basic protein (MBP) and interleukin-13 (IL-13) in esophageal biopsies. METHODS: This retrospective study included subjects who had an esophagogastroduodenoscopy with esophageal biopsies for IBD work up or suspicion for EoE. Patients were classified into 5 groups: EoE with ≥15 eosinophils per high power field (eos/hpf), EoE-IBD with ≥15 eos/hpf, IBD eosinophilia with 1-14 eos/hpf, IBD and control groups. Biopsies were stained with MBP and IL-13 antibodies and the results (% staining/total tissue area), demographic, and clinical findings were compared among the groups. RESULTS: The median for MBP staining levels in EoE-IBD was 3.8 (interquartile range 1.3-23), significantly lower than in EoE at 52.8 (8.3-113.2), but higher than in IBD eosinophilia at 0.2 (0-0.9; p < 0.001) and negligible in the IBD and control groups. IL-13 expression in EoE was significantly higher only compared with IBD and controls not with EoE-IBD or IBD eosinophilia. MBP predicted EoE with 100% sensitivity and 99% specificity while IL-13 had 83% sensitivity and 90% specificity using cutoff point from the cohort without EoE-IBD patients. Based on MBP cutoff point that distinguished EoE from non EoE, 56% in EoE-IBD were MBP-positive whereas 100% in EoE group (p < 0.05). CONCLUSIONS: MBP may be an excellent marker in distinguishing true EoE from eosinophilia caused by IBD. Our data implied that MBP together with endoscopic and histologic changes can assist EoE diagnosis in IBD patients.

Addressing diagnostic dilemmas in eosinophilic esophagitis using esophageal epithelial eosinophil-derived neurotoxin.

OBJECTIVES: Eosinophil-derived neurotoxin (EDN) is a viable marker of eosinophilic esophagitis (EoE) disease activity. We studied the utility of measuring EDN from esophageal epithelial brushings for diagnosing EoE, focusing on two scenarios: (1) cases of exclusive distal eosinophilia and (2) cases of discrepancy between endoscopy and histology. METHODS: Records of patients who underwent esophagogastroduodenoscopy (EGD) with EDN measured via esophageal brushings at Arnold Palmer Hospital for Children in Orlando, Florida from January 2014 to October 2018 were retrospectively reviewed. Demographics, clinical, endoscopic, and histologic data were collected. RESULTS: We reviewed 231 patient records (66.7% male, mean age 10.3 years, range 1-22 years). EDN values correlated with endoscopic reference score (EREFS) and peak eosinophil count (PEC) (Spearman's rho = 0.756 (p < 0.001) and 0.824 (p < 0.001) respectively). Average PEC, EREFS, and EDN concentrations were higher in patients with active EoE than in controls or patients with EoE in remission (inactive). When grouping patients based on esophageal eosinophilia distribution, EDN mirrored PEC, and EREFS. Patients with exclusive distal eosinophilia had lower EDN concentrations than those with eosinophilia in >1 level of the esophagus (23.8 ± 46.1 mcg/mL vs. 171.3 ± 205.8 mcg/mL respectively, p < 0.001). EDN values were more consistent with EREFS in cases of discrepancies between endoscopic findings and pathology (p < 0.001). CONCLUSION: EDN measured in esophageal brushing samples reflects disease activity objectively and accurately. It also offers significant value in cases of exclusive distal esophageal eosinophilia and when discrepancies exist between endoscopy and histology.

A Mouse Model for Eosinophilic Esophagitis (EoE).

Eosinophilic esophagitis (EoE) is an emerging chronic T helper type 2 (Th2)-associated, allergic, and immune-mediated disease, characterized histologically by eosinophil-predominant mucosal inflammation and clinically by esophageal dysfunction. Over the past years, the prevalence of EoE has dramatically increased globally. Until recently, most studies of EoE focused on using human biopsies, which are also used for diagnostic purposes, or esophageal epithelial cell lines, which led to major advances in the understanding of EoE. Despite this, a robust mouse model that mimics human disease is still crucial for both understanding disease pathogenesis and as a preclinical model for testing future therapeutics. Herein, we describe a highly reproducible and robust model of EoE that can be performed using wild-type mice by ear sensitization with oxazolone (OXA) followed by intraesophageal challenges. Experimental EoE elicited by OXA mimics the main histopathological features of human EoE, including intraepithelial eosinophilia, epithelial and lamina propria thickening, basal cell hyperplasia, and fibrosis. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of EoE in mice using oxazolone Support Protocol 1: Preparing the mouse esophagus for histological analysis Support Protocol 2: Assessment of epithelial and lamina propria thickness using H&E staining Support Protocol 3: Assessment of eosinophilic infiltration using anti-MBP and basal cell proliferation using anti-Ki-67 staining Support Protocol 4: Flow cytometry of mouse esophageal samples Support Protocol 5: ELISA on protein lysates of esophageal samples.

A complex case of dysphagia with dual aetiology.

A woman in her early 60s was referred with dysphagia and chest pain to a tertiary referral centre specialising in oesophageal disorders. Cardiac symptom origin and sinister oesophageal pathology had been excluded at her local hospital in NHS Scotland. Under multidisciplinary team oversight, reinvestigation of mucosal pathology and oesophageal motility ultimately uncovered both Type III achalasia and eosinophilic oesophagitis. This case demonstrates the benefit of including provocative testing during high-resolution manometry to reproduce relevant dysphagia and the importance of stopping proton-pump inhibitors long enough to uncover excessive eosinophils which could otherwise be masked. Ultimately, tailored management for both conditions separately was required to achieve symptoms resolution.

Incontinentia pigmenti Stage 1 is not simply vesiculo-bullous but vesiculo-pustular.

Incontinentia pigmenti (IP) is a rare X-linked dominant, male-lethal disorder characterized by pathognomic skin lesions. As described in the literature the typical cutaneous changes follow the pattern of Blaschko's lines and develop in four stages that usually start at birth. Stage 1 is called vesicular, bullous or inflammatory. The vesicles are rapidly filled with eosinophils and thus turn into pustules. Thus, the term "pustular" is relevant to the first phase of IP, and the stage can be considered as "vesiculopustular/inflammatory" to be more precise than "vesicular" or "bullous."

Exploration of useful clinical laboratory values as diagnostic criteria for eosinophilic gastroenteritis.

BACKGROUND: Eosinophilic gastroenteritis (EGE) is a rare eosinophilic infiltrative disorder. In Japan, EGE is diagnosed using clinical symptoms as well as microscopic, haematologic and histopathological findings. In this study, we examined the usefulness of laboratory data in the diagnosis of EGE. METHODS: Patients who were diagnosed with EGE at Fujita Health University Bantane Hospital between April 2015 and December 2020 were enrolled in this study and their data was retrospectively analysed. We evaluated their medical history, laboratory data including leukocyte count, eosinophil count, immunoglobulin (Ig) E, thymus and activation-regulated chemokine (TARC), C-reactive protein (CRP), etc. and histopathological data were collected from the electronic medical records. RESULTS: One hundred twelve of 168 patients who were treated for EGE could be analysed. The peripheral eosinophil count was correlated with the duodenal or ascending colon eosinophil count; moreover, the blood lymphocyte count and the TARC were correlated with the transverse colon eosinophil count. Multivariate regression analysis showed correlations only in the oesophagus, stomach and duodenum. Specifically, correlations were noted between blood eosinophils and gastric eosinophils, blood eosinophils and duodenal eosinophils, blood lymphocytes and gastric eosinophils, blood IgE and oesophageal, gastric and duodenal eosinophils and CRP and oesophageal eosinophils. CONCLUSION: The extent of blood eosinophil count, lymphocyte count, IgE and CRP elevation together with clinical features and pathology can be incorporated into a diagnostic scoring criteria system to improve the accuracy of diagnosing this uncommon condition in the future.

Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis.

GOALS: To assess the predictive value of baseline peripheral absolute eosinophil counts (AECs) for proton pump inhibitor (PPI) response in eosinophilic esophagitis (EoE). BACKGROUND: PPI leads to histologic remission in ~50% of EoE patients, although there are few distinguishing clinical features between PPI-responsive (PPI-r-EoE) and nonresponsive (PPI-nr-EoE) diseases. Peripheral eosinophilia is present in ~50% of EoE cases and is associated with eosinophil density on esophageal biopsy and worse clinical outcomes. The association between peripheral eosinophilia and PPI-responsiveness in EoE remains unclear. STUDY: This is a retrospective cohort study of adult EoE patients at a tertiary center between 2012 and 2016. All patients underwent twice daily PPI trials for ≥8 weeks followed by repeat esophageal biopsies and were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response (<15 eosinophils/high power field). Baseline peripheral AEC was obtained within 1 month before index endoscopy. Analyses were performed using Fisher exact/Student t test (univariate) and logistic regression (multivariable). RESULTS: One hundred eighty-three patients (91 PPI-nr-EoE and 92 PPI-r-EoE) were included. Mean peripheral AEC was higher among PPI-nr-EoE patients (0.41 vs 0.24 K/µL, P = 0.013). Baseline peripheral eosinophilia (>0.5 K/µL) was more prevalent among patients with PPI-nr-EoE (70.4% vs 45.5%, P = 0.023) and a history of food impaction (51.9% vs 23.7%, P = 0.0082). On multivariable analyses, peripheral eosinophilia remained an independent predictor for PPI response (adjacent odds ratio = 2.86, CI: 1.07-7.62, P = 0.036) and food impaction (adjacent odds ratio = 2.80, CI: 1.07-7.35, P = 0.037). CONCLUSIONS: Baseline peripheral eosinophilia independently predicts PPI nonresponse and food impaction in EoE patients. Peripheral AEC may help therapy selection in EoE and prevent delays in achieving histologic remission.

Molecular pathways underlying lung-brain axis signaling in asthma: Relevance for psychopathology and neuroinflammation.

BACKGROUND: Accumulating evidence indicates that asthma has systemic effects and affects brain function. Although airway inflammation is proposed to initiate afferent communications with the brain, the signaling pathways have not been established. OBJECTIVE: We sought to identify the cellular and molecular pathways involved in afferent lung-brain communication during airway inflammation in asthma. METHODS: In 23 adults with mild asthma, segmental bronchial provocation with allergen (SBP-Ag) was used to provoke airway inflammation and retrieve bronchoalveolar lavage fluid for targeted protein analysis and RNA sequencing to determine gene expression profiles. Neural responses to emotional cues in nodes of the salience network were assessed with functional magnetic resonance imaging at baseline and 48 hours after SBP-Ag. RESULTS: Cell deconvolution and gene coexpression network analysis identified 11 cell-associated gene modules that changed in response to SBP-Ag. SBP-Ag increased bronchoalveolar lavage eosinophils and expression of an eosinophil-associated module enriched for genes related to TH17-type inflammation (eg, IL17A), as well as cell proliferation in lung and brain (eg, NOTCH1, VEGFA, and LIF). Increased expression of genes in this module, as well as several TH17-type inflammation-related proteins, was associated with an increase from baseline in salience network reactivity. CONCLUSIONS: Our results identify a specific inflammatory pathway linking asthma-related airway inflammation and emotion-related neural function. Systemically, TH17-type inflammation has been implicated in both depression and neuroinflammation, with impacts on long-term brain health. Thus, our data emphasize that inflammation in the lung in asthma may have profound effects outside of the lung that may be targetable with novel therapeutic approaches.

Determination of Optimal Eosinophil Thresholds for Diagnosis of Eosinophilic Gastritis and Duodenitis: A Pooled Analysis of 4 Prospective Studies.

INTRODUCTION: Consensus is lacking regarding the number of eosinophils (eos) required for the diagnosis of eosinophilic gastritis (EoG) and eosinophilic duodenitis (EoD). In addition, thresholds that require multiple high-power fields (HPFs) may not be practical for clinical use, resulting in delayed or missed diagnoses. This pooled analysis of 4 prospective studies assessed thresholds for multiple and single HPFs used to diagnose EoG and EoD. METHODS: Studies included the phase 2 ENIGMA1, the phase 3 ENIGMA2, an EoG/EoD prevalence study and a healthy volunteer study. Eos were quantified in the epithelium and lamina propria for controls and symptomatic participants. Symptomatic participants were further divided by histologic diagnosis of EoG/EoD. Peak eos counts were assessed, and the area under the receiver operating characteristic curve was analyzed to identify eos cutoffs for detection of EoG/EoD using the Youden index and sensitivity and specificity equality approaches. RESULTS: Based on the highest specificity analysis in 740 patients, the optimal eos threshold was determined to be 20 eos/HPF in 5 gastric HPFs for EoG (71% sensitivity and 94% specificity) and 33 eos/HPF in 3 duodenal HPFs for EoD (49% sensitivity and 100% specificity). For single-field analysis, the optimal eos thresholds were 33 eos/HPF (EoG) and 37 eos/HPF (EoD), both corresponding to 93% sensitivity and 93% specificity. DISCUSSION: Highly specific single gastric and duodenal HPF thresholds may have more clinical applicability than thresholds requiring multiple HPFs and could better facilitate development of practical histopathologic guidelines to aid pathologists and clinicians in the detection and diagnosis of EoG and/or EoD.

Chronic rhinosinusitis with nasal polyps: eosinophils versus B lymphocytes in disease pathogenesis.

PURPOSE OF REVIEW: To highlight the current evidence that supports the view that eosinophils may not drive disease in chronic rhinosinusitis with nasal polyps (CRSwNP) and the emerging evidence for B cells as an important player in this disease. RECENT FINDINGS: Eosinophil depletion studies in CRSwNP do not fully support a critical role for eosinophils in CRSwNP. Almost complete eosinophil depletion with dexpramipexole had no impact on polyp size reduction or clinical improvement. Anti-interleukin (IL)-5 and IL-5Rα inhibition were more effective though with less clinical impact when compared to anti-immunoglobulin E (IgE) or IL-4Rα inhibition strategies. As IL-5Rα is also expressed on CRSwNP derived IgE+ and IgG4+ plasma cells to the same extent as eosinophils, improvements in CRSwNP with IL-5 inhibition may suggest a role for B cells over eosinophils in CRSwNP. We review both eosinophils and B cells in the context of CRSwNP and highlight the current evidence that supports an emerging role for B cells. SUMMARY: Despite many aspects of immunopathology in CRSwNP explainable by B cell dysfunction, B cells have so far been ignored in CRSwNP. Further work is needed, as targeting B cells may offer an exciting new therapeutic option in the future.

Persistent esophageal changes after histologic remission in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by persistent or relapsing allergic inflammation, and both clinical and histologic features of esophageal inflammation persist over time in most individuals. Mechanisms contributing to EoE relapse are not understood, and chronic EoE-directed therapy is therefore required to prevent long-term sequelae. OBJECTIVE: We investigated whether EoE patients in histologic remission have persistent dysregulation of esophageal gene expression. METHODS: Esophageal biopsy samples from 51 pediatric and 52 adult subjects with EoE in histopathologic remission (<15 eosinophils per high-power field [eos/hpf]) and control (48 pediatric and 167 adult) subjects from multiple institutions were subjected to molecular profiling by the EoE diagnostic panel, which comprises a set of 94 esophageal transcripts differentially expressed in active EoE. RESULTS: Defining remission as <15 eos/hpf, we identified 51 and 32 differentially expressed genes in pediatric and adult EoE patients compared to control individuals, respectively (false discovery rate < 0.05). Using the stringent definition of remission (0 eos/hpf), the adult and pediatric cohorts continued to have 18 and 25 differentially expressed genes (false discovery rate < 0.05). Among 6 shared genes between adults and children, CDH26 was upregulated in both children and adults; immunohistochemistry demonstrated increased cadherin 26 staining in the epithelium of EoE patients in remission compared to non-EoE controls. In the adult cohort, POSTN expression correlated with the endoscopic reference system score (Spearman r = 0.35, P = .011), specifically correlating with the rings' endoscopic reference system subscore (r = 0.53, P = .004). CONCLUSION: We have identified persistent EoE-associated esophageal gene expression in patients with disease in deep remission. These data suggest potential inflammation-induced epigenetic mechanisms may influence gene expression during remission in EoE and provide insight into possible mechanisms that underlie relapse in EoE.

ANCA-negative EGPA: only eosinophils without vasculitis? Insights from anti-T2 biologics.

The pathogenic role of p-ANCA in eosinophilic granulomatosis with polyangiitis (EGPA) is a long-standing matter of debate. In this work, we report our real-life experience with EGPA patients, treated with biologics targeting type 2 (T2)-eosinophilic inflammation (Mepolizumab, Benralizumab, Dupilumab). Interestingly, we observed EGPA extrarespiratory relapses only in p-ANCA-positive patients (2/5 cutaneous vasculitis, 3/5 constitutional symptoms), with new rise of p-ANCA and normal eosinophil blood count. Notably, revising our cohort with the new ACR 2022 criteria, these five patients were the only ones to satisfy the entry criterion of vasculitis' defined diagnosis at disease onset. These observations may suggest that biologics, selectively turning off T2 inflammation, may have unmasked p-ANCA exclusive role in the pathogenesis of vasculitis in EGPA. Therefore, we raise the question whether EGPA vasculitis exists only in p-ANCA-positive patients, and whether p-ANCA-negative disease is "only eosinophils without vasculitis".

Study of cytokine-induced immunity in bullous pemphigoid: recent developments.

Bullous pemphigoid (BP) is an organ-specific disease. Its pathogenesis has not been clearly studied yet; However, studies in recent years have shown that its pathogenesis is related to T helper cells. The pathogenesis of BP is mainly related to Th2 and Th17-related cytokines. IL-4, IL-5 and IL-13 cause eosinophil recruitment, promote antibody production, trigger pruritus and promote blister formation and other symptoms. IL-17 and IL-23 promote the production of matrix metalloproteinase-9 (MMP-9) by related cells, which causes dermo-epidermal junction (DEJ) separation to form bullae and blisters, and can persist in BP inflammation. The serum concentrations of IL-17 and IL-23 are related to the prognosis of BP. In this paper, we focus on the role of related cytokines in the pathogenesis of bullous pemphigoid and the relationship between the related cytokine populations secreted by three major T helper cells-helper T lymphocytes 1 (Th1), Th2, and Th17. A better understanding of the biological and immunological functions of cytokines associated with BP patients will provide opportunities for therapeutic targets in BP.

Vulval superficial myofibroblastoma with lymphocytic and eosinophilic infiltrate.

We present the case of a vulval superficial myofibroblastoma with a lymphocytic and eosinophilic rim in a woman in her late 20s. The tumour presented in pregnancy as a cystic lesion with pain and increasing size. While the histopathology of superficial myofibroblastomas has been well defined in the literature, to our knowledge, there has been no documentation of the presence of an inflammatory infiltrate of lymphocytes and eosinophils surrounding and within the tumour. This may potentially act as a diagnostic or prognostic reference.

[Research progress on eosinophils in lung cancer].

Eosinophils are important immune cells that contain eosinophilic particles and play a key role in allergic diseases such as asthma and helminth infections. An increasing number of studies have confirmed that eosinophils infiltrate a variety of tumor tissues, which can synthesize and secrete a large number of bioactive substances under certain circumstances, such as cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes and so on, which may affect angiogenesis and matrix remodeling or change the tumor microenvironment, thereby affecting tumor progression. This review focused on the role of eosinophils in lung cancer and provided an outlook on the issues in clinical and basic research.