Abstract
Background: In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy. Objective: We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods: F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and TH2 responses, were assessed. Results: F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic TH2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI). Conclusion: Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.
| Original language | English |
|---|---|
| Pages (from-to) | 795-805 |
| Number of pages | 11 |
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 127 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 1 2011 |
| Externally published | Yes |
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Keywords
- anaphylaxis
- Food allergy
- IgE
- IL-4
- tolerance
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling. / Mathias, Clinton B.; Hobson, Suejy A.; Garcia-Lloret, Maria; Lawson, Greg; Poddighe, Dimitri; Freyschmidt, Eva Jasmin; Xing, Wei; Gurish, Michael F.; Chatila, Talal A.; Oettgen, Hans C.
In: Journal of Allergy and Clinical Immunology, Vol. 127, No. 3, 01.03.2011, p. 795-805.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling
AU - Mathias, Clinton B.
AU - Hobson, Suejy A.
AU - Garcia-Lloret, Maria
AU - Lawson, Greg
AU - Poddighe, Dimitri
AU - Freyschmidt, Eva Jasmin
AU - Xing, Wei
AU - Gurish, Michael F.
AU - Chatila, Talal A.
AU - Oettgen, Hans C.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Background: In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy. Objective: We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods: F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and TH2 responses, were assessed. Results: F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic TH2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI). Conclusion: Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.
AB - Background: In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy. Objective: We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods: F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and TH2 responses, were assessed. Results: F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic TH2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI). Conclusion: Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.
KW - anaphylaxis
KW - Food allergy
KW - IgE
KW - IL-4
KW - tolerance
UR - http://www.scopus.com/inward/record.url?scp=79952310804&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952310804&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2010.11.009
DO - 10.1016/j.jaci.2010.11.009
M3 - Article
VL - 127
SP - 795
EP - 805
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 3
ER -