Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.

Autor: Gertie JA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn., Zhang B; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Singapore Immunology Network (SIgN), Singapore., Liu EG; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, Conn., Hoyt LR; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn., Yin X; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn., Xu L; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn., Long LL; The Jackson Laboratory for Genomic Medicine, Farmington, Conn., Soldatenko A; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn., Gowthaman U; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Department of Pathology, University of Massachusetts Medical School, Worcester, Mass., Williams A; The Jackson Laboratory for Genomic Medicine, Farmington, Conn; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Conn. Electronic address: adam.williams@jax.org., Eisenbarth SC; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, Conn. Electronic address: stephanie.eisenbarth@yale.edu.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Jan; Vol. 149 (1), pp. 262-274. Date of Electronic Publication: 2021 May 27.
DOI: 10.1016/j.jaci.2021.05.015
Abstrakt: 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.
(Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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