PMID- 34051223
OWN - NLM
STAT- MEDLINE
DCOM- 20220303
LR  - 20240226
IS  - 1097-6825 (Electronic)
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 149
IP  - 1
DP  - 2022 Jan
TI  - Oral anaphylaxis to peanut in a mouse model is associated with gut permeability 
      but not with Tlr4 or Dock8 mutations.
PG  - 262-274
LID - S0091-6749(21)00820-4 [pii]
LID - 10.1016/j.jaci.2021.05.015 [doi]
AB  - 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.
CI  - Copyright (c) 2021 American Academy of Allergy, Asthma & Immunology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Gertie, Jake A
AU  - Gertie JA
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, 
      Conn.
FAU - Zhang, Biyan
AU  - Zhang B
AD  - 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.
FAU - Liu, Elise G
AU  - Liu EG
AD  - 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.
FAU - Hoyt, Laura R
AU  - Hoyt LR
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, 
      Conn.
FAU - Yin, Xiangyun
AU  - Yin X
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, 
      Conn.
FAU - Xu, Lan
AU  - Xu L
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, 
      Conn.
FAU - Long, Lauren L
AU  - Long LL
AD  - The Jackson Laboratory for Genomic Medicine, Farmington, Conn.
FAU - Soldatenko, Arielle
AU  - Soldatenko A
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, 
      Conn.
FAU - Gowthaman, Uthaman
AU  - Gowthaman U
AD  - 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.
FAU - Williams, Adam
AU  - Williams A
AD  - 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.
FAU - Eisenbarth, Stephanie C
AU  - Eisenbarth SC
AD  - 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.
LA  - eng
GR  - R01 AI136942/AI/NIAID NIH HHS/United States
GR  - T32 AR007107/AR/NIAMS NIH HHS/United States
GR  - T35 HL007649/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210527
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (Dock8 protein, mouse)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
CIN - J Allergy Clin Immunol. 2022 Jan;149(1):58-59. PMID: 34599978
CIN - J Allergy Clin Immunol. 2022 Aug;150(2):489. PMID: 35568593
MH  - Administration, Oral
MH  - Animals
MH  - Arachis/immunology
MH  - Disease Models, Animal
MH  - Female
MH  - Gastrointestinal Microbiome
MH  - Genetic Predisposition to Disease
MH  - Guanine Nucleotide Exchange Factors/genetics
MH  - Intestinal Mucosa/*metabolism
MH  - Male
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - Mutation
MH  - *Passive Cutaneous Anaphylaxis/genetics
MH  - Peanut Hypersensitivity/genetics/*metabolism/microbiology
MH  - Permeability
MH  - Species Specificity
MH  - Toll-Like Receptor 4/genetics
MH  - Mice
PMC - PMC8626534
MID - NIHMS1716934
OTO - NOTNLM
OT  - C3H/HeJ
OT  - DOCK8
OT  - TLR4
OT  - anaphylaxis
OT  - food allergy
OT  - gut permeability
OT  - peanut
EDAT- 2021/05/30 06:00
MHDA- 2022/03/04 06:00
PMCR- 2023/01/01
CRDT- 2021/05/29 20:09
PHST- 2020/07/08 00:00 [received]
PHST- 2021/05/06 00:00 [revised]
PHST- 2021/05/10 00:00 [accepted]
PHST- 2021/05/30 06:00 [pubmed]
PHST- 2022/03/04 06:00 [medline]
PHST- 2021/05/29 20:09 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - S0091-6749(21)00820-4 [pii]
AID - 10.1016/j.jaci.2021.05.015 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2022 Jan;149(1):262-274. doi: 10.1016/j.jaci.2021.05.015. 
      Epub 2021 May 27.