A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice - 23/05/24
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Abstract |
Background |
The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized Collaborative Cross strain CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, in contrast to C3H/HeJ (C3H) mice.
Objective |
This study aimed to determine the genetic basis of orally induced anaphylaxis to peanut in CC027 mice.
Methods |
A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 mice and 5 additional Collaborative Cross strains.
Results |
Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis and 4% having severe anaphylaxis. There were 8 genetic loci associated with variation in response to peanut challenge—6 associated with anaphylaxis (temperature decrease) and 2 associated with peanut-specific IgE levels. There were 2 major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis gene. Consistent with described functions of Themis, we found that CC027 mice have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127− regulatory T cells.
Conclusions |
Our results demonstrate a key role for Themis in the orally reactive CC027 mouse model of peanut allergy.
Le texte complet de cet article est disponible en PDF.Key words : Food allergy, peanut allergy, QTL, genetics, genotype-phenotype correlation, Themis, T cells, C3H, CC027, Collaborative Cross
Abbreviations used : AAC, C3H, CC, CC027, Chr, DNT, GWAS, PNsIgE, QTL, SNP, Treg, UNC
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