A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice - 23/05/24

Doi : 10.1016/j.jaci.2024.03.027

Ellen L. Risemberg, BA ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Johanna M. Smeekens, PhD ^c,^{^{∗
These authors contributed equally to this work.}}, Marta C. Cruz Cisneros, BS ^b,^d, Brea K. Hampton, PhD ^b,^d, Pablo Hock, BS ^b, Colton L. Linnertz, MS ^b, Darla R. Miller, BS ^b, Kelly Orgel, MD, PhD ^c, Ginger D. Shaw, BS ^b,^e, Fernando Pardo Manuel de Villena, PhD ^b,^e, A. Wesley Burks, MD ^c, William Valdar, PhD ^b,^e,^{^{‡
These authors contributed equally to this work and are co–corresponding authors.},}^⁎ , Michael D. Kulis, PhD ^c,^{^{‡
These authors contributed equally to this work and are co–corresponding authors.},}^⁎ , Martin T. Ferris, PhD ^b,^⁎,^{^{‡
These authors contributed equally to this work and are co–corresponding authors.}}
^a Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
^b Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
^c Division of Allergy and Immunology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC
^d Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
^e Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

^∗Corresponding author: Martin T. Ferris, PhD, Department of Genetics, UNC Chapel Hill, CB 7292, Chapel Hill, NC 27599.Department of GeneticsUNC Chapel HillCB 7292Chapel HillNC27599^∗∗Michael D. Kulis, PhD, Department of Pediatrics, UNC Chapel Hill, CB 7231, Chapel Hill, NC 27599.Department of PediatricsUNC Chapel HillCB 7231Chapel HillNC27599^∗∗∗William Valdar, PhD, Department of Genetics, UNC Chapel Hill, CB 7264, Chapel Hill, NC 27599.Department of GeneticsUNC Chapel HillCB 7264Chapel HillNC27599

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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.