A switch to pathogenic IgE production in food allergy found in memory B cells

Good news! Perhaps a breakthrough! Two independent studies come to similar conclusion.

From the editor's summary and abstract:

"Editor’s summary

IgE is the key mediator of allergic responses in the context of both food allergy and allergic rhinitis. However, most IgE-producing cells are short-lived, begging the question: What population replenishes the IgE-producing cell pool? In a pair of papers, Ota et al. and Koenig et al. independently identified a population of type 2–polarized memory B cells expressing IgG1 or IgG4, CD23, and IL-4Rα that also express germline IGHE. Ota et al. found that these cells were enriched in children with peanut allergy as compared with non-allergic pediatric controls, expressed highly mutated B cell receptors specific to peanuts, and had a high ability to switch to IgE in vitro. Koenig et al. identified a comparable cell type in adults with birch allergy, house dust mite allergy, or peanut allergy and found that these memory B cells generated allergen-specific IgE during early sublingual allergen immunotherapy. Together, these studies implicate type 2–polarized memory B cells expressing IgG, CD23, and IL-4Rα as the source of pathogenic, allergen-specific IgE-producing cells. ...

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 FCER2/CD23+, IL4R, and germline IGHE, 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 IGHE 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."

From the abstract:

"Abstract

Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2–polarized MBCs defined as CD23hi, IL-4Rαhi, and CD32low at both the transcriptional and surface protein levels. These MBC2s are enriched in IgG1- and IgG4-expressing cells while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. Furthermore, MBC2s generated allergen-specific IgE during sublingual immunotherapy, thereby identifying these cells as a major reservoir for IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases but could be beneficial in protection against venoms and helminths."

CD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy | Science Translational Medicine (no public access)

Type 2–polarized memory B cells hold allergen-specific IgE memory