Eosinophil-associated Gastrointestinal Disorders Research Articles

Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders.

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed invitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101+ CD274+ tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct invivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.

Isospora belli superinfection in a patient with eosinophilic gastroenteritis—A diagnostic challenge

Isospora belli infection, characterized by peripheral blood eosinophilia, is often seen as an opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). It is also reported in patients with underlying lymphoproliferative disorders including lymphoma and leukemia. Eosinophil-associated gastrointestinal disorders (EGID), including eosinophilic gastroenteritis (EGE), is characterized by eosinophilic infiltration of the gastrointestinal (GI) tract with various GI symptoms. We report a case of a 50-year-old male who developed Isospora superinfection of the small bowel while receiving systemic corticosteroids for EGE. He presented with worsening diarrhea, abdominal pain, nausea and vomiting with worsening peripheral eosinophilia. I. belli infection was diagnosed by the detection of oocysts in stool samples and by the presence of the parasite on duodenal biopsy in the background of tissue eosinophilia. I. belli can cause severe chronic diarrhea in immunocompromised patients on corticosteroids. Trimethoprim–sulfamethoxazole often provided rapid cure. Even though peripheral blood eosinophilia was seen in both EGE and Isospora infection, the identification of subnuclear protozoal inclusions as a new histologic finding, as well as the absence of this finding in previous duodenal biopsies coupled with the continued presence of tissue eosinophilia, favored a parasitic superinfection in the setting of underlying EGE.

Psychological Functioning of Children and Adolescents With Eosinophil-Associated Gastrointestinal Disorders

This study examined health-related quality of life (HRQOL) and adjustment among children with eosinophil-associated gastrointestinal disorders (EGID) compared with an age-matched sample without acute or chronic illness. Participants were youths aged 2 to 18 years. Children and caregivers completed measures of psychological symptoms and HRQOL. Significant group differences were found for child report of depressive, as well as anxiety, symptoms. Significant group differences were also found for caregiver report of psychological symptoms and social skills. Finally, based on parent and youth report, HRQOL and greater school absenteeism were associated with EGID diagnosis.

Transmural eosinophilic gastritis with gastric outlet obstruction: case report and review of the literature

Eosinophil-associated gastrointestinal disorders (EGIDs) are uncommon conditions whose aetiologies are unclear, but which are characterised by eosinophilic infiltration and inflammation of the gastrointestinal tract in the absence of other causes of eosinophilia. We report the case of a 65-year-old woman with eosinophilic gastritis who underwent a Polya gastrectomy for a suspected gastric tumour with gastric outflow obstruction. Subsequent histological examination showed a non-malignant transmural eosinophilic infiltration of the stomach wall, a rare pathological entity. We present a review of the literature and discuss the management of such cases.

Eosinophilic Gastrointestinal Disease and Peanut Allergy are Alternatively Associated With IL-5+ and IL-5- Th2 Responses

RATIONALE: Both anaphylactic food allergy and eosinophil associated gastrointestinal disorders (EGIDs) are associated with Th2 responses and food specific IgE, yet are clinically different. We determined if the clinical differences between these diseases are reflected in different Th2 responses to foods. METHODS: Peanut allergic (PA), allergic eosinophilic gastroenteritis (AEG) and nonatopic (NA) subjects were enrolled. Antigen specific IL-4, IL-5, IFN-γ and TNF T cell responses to peanut, soy and shrimp were measured using intracellular cytokine staining and polychromatic flow cytometry. RESULTS: Two distinct subpopulations of Th2 cells were found: IL-5+ Th2 (IL-4+, IL-5+) and IL-5- Th2 (IL-4+, IL-5-) cells. Peanut specific IL-5+ Th2 cells were present at a 20-fold greater frequency in AEG vs. PA (81 vs. 4 per 106 CD4 cells, p = 0.05), whereas similar frequencies of IL-5- Th2 cells were found (67 vs. 41 per 106). IL-5+ Th2 cells accounted for a significantly greater fraction of the food antigen specific cells in AEG relative to PA (29% vs. 4%, p < 0.0001). In PA, but not AEG, IL-5- Th2 responses to peanut were highly correlated with peanut specific IgE (r= 0.87 vs. 0.55, respectively). All subject groups elicited similar very low magnitude Th1 responses to food Ags. CONCLUSION: Th2 responses are composed of two subpopulations: IL-5+ Th2 and IL-5- Th2 cells. IL-5+ Th2 food allergen specific T cells are singularly associated with AEG, whereas PA is associated with a dominant IL-5- Th2 response. These results suggest heterogeneity within the Th2 cytokine response, with different Th2 responses alternatively favoring IgE mediated or eosinophil dominant immunopathology.

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5 + and IL-5 − T H2 responses

Both anaphylactic food allergy and eosinophil-associated gastrointestinal disorders are associated with T(H)2 responses and food-specific IgE, yet they have very different clinical presentations. To determine whether the clinical differences between anaphylactic food allergy and eosinophil-associated gastrointestinal disorders are reflected in different T(H)2 responses to foods. Subjects with peanut allergy (PA), subjects with allergic eosinophilic gastroenteritis (AEG), and nonatopic subjects were enrolled. Antigen-specific IL-4, IL-5, IFN-gamma, and TNF T-cell responses to peanut, soy, and shrimp were measured by using intracellular cytokine staining and polychromatic flow cytometry. Two distinct subpopulations of T(H)2 cells were found: IL-5+ T(H)2 (IL-4+, IL-5+) and IL-5(-) T(H)2 (IL-4+, IL-5(-)) cells. Peanut-specific IL-5+ T(H)2 cells were present at a 20-fold greater frequency in AEG versus PA (81 vs 4 per 10(6) CD4 cells; P = .05), whereas there were similar frequencies of IL-5(-) T(H)2 cells (67 vs 41 per 10(6)). For all foods, IL-5+ T(H)2 cells accounted for a significantly greater fraction of the antigen-specific cells in AEG relative to PA (29% vs 4%; P < .0001). In PA but not AEG, IL-5(-) T(H)2 responses to peanut were highly correlated with peanut-specific IgE (r = 0.87 vs 0.55, respectively). All subject groups elicited similar very low-magnitude T(H)1 responses to food antigens. T(H)2 responses are composed of 2 subpopulations: IL-5+ T(H)2 and IL-5(-) T(H)2 cells. IL-5+ T(H)2 food allergen-specific T cells are singularly associated with AEG, whereas PA is associated with a dominant IL-5(-) T(H)2 response. These results suggest heterogeneity within the T(H)2 cytokine response, with different T(H)2 responses alternatively favoring IgE-mediated or eosinophil-dominant immunopathology.

Eosinophil-Associated Gastrointestinal Disorders with Asthma: Immunohistochemical Analyses

We report 5 patients with eosinophil-associated gastrointestinal disorders (EGIDs) and asthma. All patients developed EGIDs while asthma remained clinically stable. Asthma severity was moderate persistent and severe persistent and 2 patients had intolerance to nonsteroidal anti-inflammatory drugs. By immunohistochemical analysis of the mucosa, eosinophils, macrophages, and T cells were found to be the major infiltrating cells. There was a lesser degree of infiltration of mast cells and B cells but no neutrophils. Compared with normal controls, increased counts of eosinophils and CD8+ T cells were found in the duodenum, and eosinophils, macrophages, and CD4+ T cells in the colon.

Immunomodulatory therapy of eosinophil‐associated gastrointestinal diseases

Eosinophil-associated gastrointestinal disorders (EGIDs), including eosinophilic esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of increasingly recognized inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Significant morbidity is associated with the development of esophageal strictures in some patients. Immune-mediated reactions to food allergens appear to drive the inflammation in a subset of patients, especially those with solitary EE, but dietary interventions remain difficult in EE and are less effective in EG. Despite the increasing incidence of these disorders and their increased recognition by physicians, there are currently no medications that either United States or European Union regulatory agencies have specifically approved for use in EGIDs. This lack of safe and effective therapies for EGIDs is a major obstacle in the care of these patients and underscores the need for new therapeutic approaches. This review briefly discusses the currently available 'off label' drug treatments for EGIDs, most notably topical and systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible therapeutic targets, and conversely, clinical trials of mechanistically-targeted therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is discussed as an introduction to mechanistically-targeted immunotherapeutics. The two biologic categories that have been used in EGIDs, anti-IgE (omalizumab) and anti-IL-5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis, biologic therapeutics currently in early trials for asthma management are also briefly discussed as potential therapeutic agents for EGIDs. Given the deficiencies of current therapeutics and the rapidly advancing knowledge of the pathogenesis of these disorders, EGIDs are an ideal model for translating recent advances in understanding immunopathogenesis into mechanistically-based therapeutics. Further understanding of the early events in pathogenesis is also needed to develop preventive and disease-modifying treatments.

2007 E. Mead Johnson Award: Scientific Pursuit of the Allergy Problem

My research has focused on elucidating the allergy problem over the past two decades. The primary approach has been to uncover critical mechanisms of allergic inflammation, with particular focus on eosinophils, a hallmark cellular constituent of allergic responses. Molecular processes that bridge T helper cell type 2 (TH2) immunity with eosinophilia and key checkpoints for regulating eosinophilia have been uncovered. Notably, interleukin (IL)-5 (derived from TH2 cells) has been identified as the chief hematopoietin responsible for eosinophil expansion in the circulation. Pathways for selective eosinophil mobilization from the blood stream to the tissue have been uncovered by defining the role of the eotaxin subfamily of chemokines in eosinophil chemoattraction and activation. Finally, TH2 cell derived IL-4 and IL-13 have been defined as chief inducers of the eotaxins, and upstream orchestrators of eosinophilic inflammation. These translational studies have formulated novel therapeutic strategies (currently being tested) for a variety of eosinophilic conditions, with particular attention on hypereosinophilic syndromes and eosinophil-associated gastrointestinal disorders such as eosinophilic esophagitis.

Anti-IgE treatment of eosinophil-associated gastrointestinal disorders

Eosinophil-associated gastrointestinal disorders (EGIDs) are commonly associated with atopy and are being recognized with increasing frequency. Current therapy for EGIDs is inadequate. We sought to determine the efficacy of anti-IgE therapy in EGIDs and investigate the role of IgE in disease pathogenesis. Nine subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE levels were serially measured. Allergen skin testing and flow cytometry for basophil activation and FcepsilonRI were determined at baseline and at week 16. Omalizumab was associated with a decrease in absolute eosinophil count at both the week 16 (34%, P = .004) and combined weeks 12 to 16 (42%, P = .012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%) but did not reach statistical significance (P = .074 and .098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell FcepsilonRI expression and free IgE levels were all significantly decreased (P < .005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (P < .005 for both). These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs and suggest that anti-IgE therapy might be effective in these disorders. Anti-IgE might be a potential therapy for EGIDs.

Eosinophil function in eosinophil-associated gastrointestinal disorders

Eosinophil-associated gastrointestinal disorders (EGIDs) are characterized by a rich eosinophilic inflammation of the gastrointestinal tract in the absence of known causes for eosinophilia or other gastrointestinal disorders. These disorders include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis, and are being recognized with increasing frequency. Clinical studies suggest that eosinophils have a pathogenic role in EGID; however, the function of eosinophils in these disorders remains an enigma. In this review, we briefly describe the clinical features of EGID of the esophagus, small bowel, and colon. We summarize recent experimental analysis examining the underlying contribution of eosinophils to disease pathogenesis and discuss possible therapeutic approaches for the treatment of these diverse diseases.

Epicutaneous Antigen Exposure Primes for Experimental Eosinophilic Esophagitis in Mice

Eosinophilic esophagitis (EE) is frequently associated with atopic disease, including dermatitis and asthma. Data are emerging that atopic skin may provide an early entry point for antigen sensitization. We aimed to test the hypothesis that epicutaneous exposure to antigen primes for subsequent respiratory antigen-induced EE. Wild-type and genetically engineered mice were subjected to epicutaneous antigen sensitization and the development of experimental EE, and immune responses were examined. We show that exposure to antigen via the epicutaneous route primes for marked eosinophilic inflammation in the esophagus triggered by a single airway antigen challenge. The development of experimental EE is associated with significant skin eosinophilia, accelerated bone marrow eosinophilopoiesis, blood eosinophilia, and large increases in serum antigen-specific immunoglobulin G1/immunoglobulin E using ovalbumin or Aspergillus fumigatus as the epicutaneous antigen. Mechanistic analysis with gene-targeted mice showed that interleukin-5 was required for esophageal eosinophilia and that interleukin-4, interleukin-13, and STAT6 contributed to a lesser extent. These findings provide the first evidence that epicutaneous exposure to allergens potently primes for EE via a Th2-dependent mechanism.

Chemokines in eosinophil-associated gastrointestinal disorders

Eosinophil-associated gastrointestinal disorders (EGDs) are characterized by a pronounced cellular inflammation. Recent clinical and experimental investigations have implicated a family of molecules known as chemokines in the regulation of leukocyte recruitment in these diseases. The underlying cellular and molecular mechanisms involved in chemokine-mediated cellular infiltration are largely unknown. In this review, we describe the role of CD4+ T cells and eosinophils in the clinical manifestations of EGDs and discuss the current understanding of the role of chemokines in the recruitment of these cells in the expression of diseases.

Eosinophil-associated gastrointestinal disorders: A world-wide-web based registry

A world wide web database was established that tracked features of eosinophil-associated gastrointestinal disorders; 80% had coexisting atopic disease, 62% had food sensitization, and 16% had an immediate family member with a similar disorder. Developmental delay, seizure disorders, and congenital anomalies were seen in a proportion of respondents. The world wide web has proven to be an efficient tool to gather patient information, allowing us to define distinguishing features of various eosinophil-associated gastrointestinal disorders and to establish that these disorders have strong genetic and allergic components. (J Pediatr 2002;141:576-81)

Experimental analysis of eosinophil-associated gastrointestinal diseases.

Eosinophil infiltration into the gastrointestinal tract occurs in a wide range of diseases. However, the underlying cellular and molecular mechanisms involved in eosinophil migration and the role of eosinophils in disease pathogenesis are largely unknown. Recent studies using experimental models of eosinophil-associated gastrointestinal allergy have revealed differential roles for IL-5 and eotaxin in the modulation of eosinophil accumulation into various regions of the gastrointestinal tract. Furthermore, such studies have revealed a possible role for eosinophils in the pathogenesis of gastrointestinal disorders. The present review describes the clinical manifestations of various eosinophil-associated gastrointestinal disorders and the current understanding of the role of IL-5 and eotaxin in the allergic inflammatory response, and the participation of the eosinophilic granulocyte in the expression of disease.

A novel approach at evaluating eosinophil-associated gastrointestinal disorders using a world-wide-web based registry

A novel approach at evaluating eosinophil-associated gastrointestinal disorders using a world-wide-web based registry