Monali Manohar, Kari Christine Nadeau, Maya Kasowski

J Clin Invest.; 2022 Jan 4;132(1):e155609.  doi: 10.1172/JCI155609.

Abstract

The rising incidence of food allergy in children underscores the importance of environmental exposures; however, genetic factors play a major role. How the environment and genetics interact to cause food allergy remains unclear. The landmark Learning Early About Peanut Allergy (LEAP) clinical trial established that early peanut introduction protects high-risk infants, consistent with the tolerizing effects of gut exposure. In this issue of the JCI, Kanchan et al. leveraged the LEAP trial data to examine molecular genetic mechanisms of early sensitization. A previously identified HLA risk allele for peanut allergy (DQA1*01:02) was associated with peanut-specific IgG4 levels in consumers. Notably, IgG4 antibodies likely provide protection by reducing the binding of allergen to IgE. The association of the same allele with peanut allergy in avoiders while potentially conferring protection in consumers reinforces the need to integrate genetic information toward a personalized therapeutic strategy for the best outcome in addressing food allergies.

See https://pubmed.ncbi.nlm.nih.gov/34981779/

Figure 1

Tipping the balance in favor of peanut tolerance in the face of risk alleles.

Genetic alleles, such as HLA-DQA*01:02, MALT-1, and FLG, predispose the carrier to the risk of developing peanut allergy. In the absence of oral peanut introduction in early infanthood (left panel), antigen presentation by HLA-DQA*01:02, barrier dysfunction caused by LFG mutations, and dysregulated NF-κB signaling due to MALT1 SNP together may promote polarization of naive CD4⁺ T cells to Th2 and Tfh13 cells. Th2 and Thfh13 secrete type 2 cytokines, including IL-4, IL-5, and IL-13, which induce IgE class switching in B cells. Peanut and peanut component–specific IgE thus generated leads to peanut allergy pathogenesis. With early oral peanut introduction (right panel), peanut-derived epitopes, specifically Ara h 2 epitopes presented in the context of HLA-DQA*01:02, likely counter Th2 polarization of naive CD4⁺ T cells. Attenuation of Th2 phenotype favors peanut epitope–specific IgG4 production over IgE production and could dampen the atopy-provoking effects of other risk alleles, thus leading to peanut tolerance.