What's New in Eosinophilic Homing? Something Is in the Air

Combined Program in Pediatric Gastroenterology and Nutrition Boston, Massachusetts, U.S.A. A Pathologic Function for Eotaxin and Eosinophils in Eosinophilic Gastrointestinal Inflammation. Hogan SP, Mishra A, Brandt EB, et al. Nat Immunol. 2001;2:353–601. Summary: Hogan et al. have previously demonstrated that after intraperitoneal sensitization to ovalbumin and subsequent oral challenge with enteric-coated ovalbumin beads, mice developed mucosal eosinophilia within the small intestine (Proc Natl Acad Sci U S A. 2000;97:6681–6). In this most recent article, the authors further characterize the histopathologic features of the affected mice and also begin to address the mechanisms by which eosinophils participate in gastric dysfunction (Nat Immunol. 2001;2:353–60). Allergen-challenged mice developed cachexia and peripheral eosinophilia. Eosinophils were identified in the squamous epithelium of the esophagus and were increased in the lamina propria of the stomach and small intestine compared with control mice. In the small bowel, reduced villous/crypt ratios were found, but eosinophil degranulation was not consistently identified. Eosinophils were seen adjacent to neurons that were undergoing axonal necrosis. At the time of killing, the stomachs of challenged mice were noted to be markedly larger than those of the unchallenged mice, and the organ weight was consistently increased. In an effort to assess gastric function associated with these morphologic findings, “gastric emptying” studies using fluorescent microspheres were performed. Two hours after receiving intragastric microspheres, antigen-challenged mice had a higher concentration of intragastric microspheres, suggesting a delay in their gastric emptying. These histologic and functional results were completely dependent on eotaxin, an eosinophil-specific chemokine. These findings demonstrate that allergic gastric eosinophilia results in an altered phenotype with reproducible organ dysfunction. Combined Program in Pediatric Gastroenterology and Nutrition Boston, Massachusetts, U.S.A. An Etiological Role for Aeroallergens and Eosinophils in Experimental Esophagitis. Mishra A, Hogan SP, Brandt EB, et al. J Clin Invest. 2001;107:83–90. Summary: Many patients with eosinophilic gastrointestinal diseases do not respond to diet restriction or the use of an elemental formula. Therefore, investigators have suggested that alternative antigens may induce mucosal eosinophilia (J Pediatr Gastroenterol Nutr. 1998;27:90–3;J Pediatr Gastroenterol Nutr. 2000;30:S28–35). In an effort to address this hypothesis, Mishra et al. (J Clin Invest. 2001;107:83–90) present new evidence demonstrating that esophageal eosinophilia can result from sensitization and challenge with an aeroallergen. While sedated, mice were sensitized with an intranasal application of Aspergillus fumigatas, a ubiquitous aeroallergen implicated in the pathogenesis of rhinopulmonary allergic diseases. After sensitization and challenge, histologic assessments of the esophageal, gastric, and small intestinal mucosa were performed. Mucosal eosinophilia was seen in the esophagus but not in the stomach or small intestine. Electron micrographic evidence of eosinophil degranulation was consistently found in esophagi of challenged mice. Likewise, squamous epithelial proliferation, as assessed by 5` bromodeoxyuridine (BrdU) incorporation analysis, was increased in the distal esophagus of challenged mice. In contrast to the findings in the model system by Hogan et al. of eosinophilic gastroenteritis, these results were completely dependent on interleukin 5, an eosinophil growth and activating factor. Great care was taken to describe the method of sensitization. For instance, oral or gastric application of the allergen did not result in the induction of mucosal eosinophilia. These data demonstrate that sensitization and challenge through the rhinopulmonary route can result in esophageal disease. Comment: We are beginning to recognize the clinicopathologic findings associated with eosinophilic gastroenteritis and eosinophilic esophagitis. What remains unclear are the mechanisms by which eosinophils contribute to symptoms and gastrointestinal dysfunction. Confounding the picture is a recent study that identified large numbers of eosinophils (> 40/high-power field) present in the cecal mucosa of otherwise healthy children who died of trauma, which suggests that fairly large numbers of eosinophils may be normal in certain areas of the intestine (Mod Pathol. 1996;9:110–4). Although eosinophils increase in disease states and are present in healthy tissue, the factors controlling their homing from the vascular space and their patterns of activation within the intestinal mucosa remain elusive. Both of these recent studies from the laboratory of Rothenberg et al. (Nat Immunol. 2001;2:353–60;J Clin Invest. 2001;107:83–90), which describe novel murine models of eosinophilic gastroenteritis and esophagitis, have shed light on the role of this enigmatic cell within the gut. Where do these findings leave us in searching for the meaning of gut eosinophilia? First, they have provided models that may allow dissection of basic questions around eosinophil homing and effector function. Previously, the lack of reproducible models of noninfectious mucosal eosinophilia significantly retarded the effort to investigate intestinal eosinophilia. Now there may be two models. Several differences exist between these model systems, making them valuable resources for the investigator. For instance, the esophageal eosinophilia in the aeroallergen model is completely dependent on interleukin 5, whereas the eosinophilic gastroenteritis model is dependent on eotaxin. These findings suggest that the homing patterns in rhinopulmonary sensitization and challenge may differ from that occurring in the gastrointestinal tract, therefore providing valuable insight regarding the seemingly distinct attraction of eosinophils to the squamous mucosa in eosinophilic esophagitis. Second, the evidence from the aeroallergen model suggests that in addition to food allergens, airborne antigens are capable of inducing gastrointestinal mucosal eosinophilia. The previous use of diet restriction to treat eosinophilic diseases may be too limited. Perhaps the topical administration of fluticasone to the nasal mucosa, as is used in the treatment of allergic rhinitis, could function as a prophylactic measure in esophageal eosinophilia. Immunotherapy (antigen desensitization) may prove to be an alternative resource to treat affected patients. Third, there is evidence that eosinophils may truly be linked to gastric dysfunction (i.e., delayed gastric emptying). Yet to be determined are the mechanisms by which this functional response occurs. Eosinophil degranulation is not consistently seen on histologic sections from the gastric mucosa of antigen-challenged mice making, mediators such as the eosinophil-derived granule proteins (i.e., major basic protein) unlikely culprits. Eosinophils are potent sources of leukotrienes (LT), including LTC4 and LTD4, molecules known to induce eosinophil chemotaxis, smooth muscle contraction, mucous secretion, and mucosal edema. Perhaps the release of these molecules results in antral dysfunction, precluding the passage of ingested foods. These data should turn our thinking about and treatments for eosinophilic gastrointestinal diseases along new avenues. To date, our practice has been somewhat blindly based on dietary manipulation (to reduce antigenic exposure), corticosteroids (to reduce eosinophil survival), and cromolyn (to inhibit eosinophil activation). Further consideration should be given to agents, such as leukotriene inhibitors, that provide a more targeted approach to eosinophil-derived products. In fact, montelukast, a leukotriene receptor antagonist, abolished symptoms and reduced peripheral eosinophilia in one pediatric patient with eosinophilic gastroenteritis (J Allergy Clin Immunol 1999;104:506–7). We will continue to benefit from interactions with our colleagues in allergy/immunology, dermatology, and pulmonology who care for many patients with eosinophilic diseases. Basic investigations and clinical use of therapeutic agents that affect eosinophil differentiation and proliferation (anti-interleukin 5 antibodies), transmigration (antiadhesion antibodies, anti-chemokine molecules), and effector function (lidocaine, leukotriene inhibitors) may eventually be applied in a rigorous, well-defined fashion to improve the care and quality of life for pediatric patients with eosinophilic gastrointestinal diseases.

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