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A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation

Nature Immunology volume 2, pages 353–360 (2001)Cite this article

Abstract

Although eosinophils have been implicated in the pathogenesis of gastrointestinal disorders, their function has not been established. Using a murine model of oral antigen–induced eosinophil-associated gastrointestinal disease, we report the pathological consequences of eosinophilic inflammation and the involvement of eotaxin and eosinophils. Exposure of mice to enteric-coated antigen promotes an extensive T helper 2–associated eosinophilic inflammatory response involving the esophagus, stomach, small intestine and Peyer's patches as well as the development of gastric dysmotility, gastromegaly and cachexia. Electron microscopy shows eosinophils in proximity to damaged axons, which indicated that eosinophils were mediating a pathologic response. In addition, mice deficient in eotaxin have impaired eosinophil recruitment and are protected from gastromegaly and cachexia. These results establish a critical pathological function for eotaxin and eosinophils in gastrointestinal allergic hypersensitivity.

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Figure 1: Oral antigen–induced recruitment of eosinophils into the gastrointestinal tract.
Figure 2: Oral antigen–induced gastromegaly and cachexia in wild-type and eotaxin-deficient mice.
Figure 3: Oral antigen–induced pathological changes in the gastrointestinal tract.
Figure 4: Electron microscopic analysis of the jejunum from oral antigen–challenged mice.
Figure 5: Eosinophil quantification in the Peyer's patches and esophagus of wild-type and eotaxin-deficient mice.

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Acknowledgements

We thank A. Dvorak for review of the electron microscopy; M. Cohen, S. Wert, D. Witte, F. Finkelman and G. Khurana Hershey for discussions and review of the manuscript; A. Emley for graphic assistance; and I. Hofman for technical assistance with electron microscopy. Supported in part by the National Health Medical Research Council (Australia) C. J. Martin Postdoctoral Fellowship (to S. P. H.), National Institutes of Health grants R01 AI42242-02 (to M. E. R.), R01 AI45898-01 (to M. E. R.) and the Human Frontier Science Program (to M. E. R. and P. S. F.).

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Authors and Affiliations

  1. Division of Pulmonary Medicine, Department of Pediatrics, Allergy and Clinical Immunology, Children's Hospital Medical Center, Cincinnati, 45229, OH, USA

    Simon P. Hogan, Anil Mishra, Eric B. Brandt, Michael P. Royalty, Samuel M. Pope, Nives Zimmermann & Marc E. Rothenberg

  2. Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, 0200, ACT, Australia

    Paul S. Foster

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Correspondence to Marc E. Rothenberg.

Supplementary information

Web Figure 1.

Experimental regime and oral antigen–induced TH2 immunity. (a) Mice were intraperitoneally (i.p.) injected with 50 μg OVA/1mg alum (OVA/Alum) on day 0. On days 12 and 15, mice were challenged orally with 20 mg placebo or OVA enteric-coated beads (placebo beads or OVA bead, respectively), or by intragastric administration (i.g.) of 200 μl PBS or soluble OVA (1 mg)–PBS. Four days after the last challenge, mice were killed and parameters were measured. (b) Eosinophil numbers in peripheral blood were determined by Discombe's analysis of femoral artery blood. (c) The serum allergen-specific IgG1and IgG2a ratio is shown for unchallenged and challenged mice. Amounts of allergen-specific IgA (c) and IgG1 (d) in fecal extracts of sensitized mice challenged with placebo or allergen beads are shown. (f-–g) Mesenteric lymph nodes from placebo- and oral allergen-–challenged mice were cultured for 72 h with anti-CD3 (5 μg/ml) and anti-CD28 (1 μg/ml) or OVA (50 μg/ml). Culture supernatants were collected and assessed for IL-5 (f), IL-4 (g) and IFN-γ (h) by ELISA. Data represent mean±s.e.m. for groups of 4-–5 per group. (GIF 67 kb)

Web Figure 2.

Anti-MBP immunostaining of the intestine in allergen-challenged mice. Allergen-sensitized mice were challenged with OVA enteric-coated beads. Four days later, the jejunum was analyzed. Anti-MBP staining shows intracellular granule and extracellular-associated immunoreactivity. (a,b) Two sections that highlight extracellular MBP localization are shown. (JPG 56 kb)

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Hogan, S., Mishra, A., Brandt, E. et al. A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation. Nat Immunol 2, 353–360 (2001). https://doi.org/10.1038/86365

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