CD23⁺IgG1⁺ memory B cells are poised to switch to pathogenic IgE production in food allergy.

Abstract

Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23⁺IgG1⁺ memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of CD23⁺IgG1⁺ memory B cells correlated with circulating concentrations of IgE in children with peanut allergy. A corresponding population of "type 2-marked" IgG1⁺ memory B cells was identified in single-cell RNA sequencing experiments. These cells differentially expressed interleukin-4 (IL-4)- and IL-13-regulated genes, such as <i>FCER2</i>/<i>CD23</i>⁺, <i>IL4R</i>, and germline <i>IGHE</i>, and carried highly mutated B cell receptors (BCRs). In children with high concentrations of serum peanut-specific IgE, high-affinity B cells that bind the main peanut allergen Ara h 2 mapped to the population of "type 2-marked" IgG1⁺ memory B cells and included clones with convergent BCRs across different individuals. Our findings indicate that CD23⁺IgG1⁺ memory B cells transcribing germline <i>IGHE</i> are a unique memory population containing precursors of high-affinity pathogenic IgE-producing cells that are likely to be involved in the long-term persistence of peanut allergy.