Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations - 05/01/22
, Stephanie C. Eisenbarth, MD, PhD a, b, c, ⁎ Abstract |
Background |
The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain’s susceptibility is not known.
Objective |
We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy.
Methods |
We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability.
Results |
In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine.
Conclusions |
Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : C3H/HeJ, food allergy, anaphylaxis, peanut, TLR4, DOCK8, gut permeability
Abbreviations used : CT, DC, DOCK8, Dock8C3H/HeJ, Dock8WT, FITC, LPS, mMCP1, OVA, PCA, TLR4, Tlr4C3H/HeJ, Tlr4Het, WT
Plan
| Funding for this study was provided by Food Allergy Research & Education, The Ira & Diana Riklis Family Research Award in Food Allergy (to S.C.E.), National Institute of Allergy and Infectious Diseases grant AI136942 (to S.C.E.), a gift from the Colton Foundation (to S.C.E.), 5T32AR007107 (to E.G.L.), NCATS grant UL1TR001863 (to E.G.L.), National Science Scholarship from Agency for Science, Technology and Research, Singapore (to B.Z.), and a generous philanthropic gift from Francoise Haasch-Jones and Rhett Jones (to A.W.). |
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| The first 2 authors contributed equally to this article, and both should be considered first author. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 1
P. 262-274 - janvier 2022 Retour au numéro
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