Allergic disease is driven by plasma cells that produce allergen-specific IgE, which binds to high-affinity receptors on mast cells and basophils and causes their degranulation after allergen cross-linking. Allergies can be lifelong, but IgE-producing plasma cells are short-lived and IgE+ memory B cells (MBCs) are very rare. The current consensus is that allergen-specific B cell memory is maintained by non-IgE MBCs, but their phenotype is not well described. Two simultaneous preprints (not peer-reviewed) now characterize the primary reservoir of allergen-specific IgE-producing plasma cells.

Using new and pre-existing single-cell datasets in human allergy, Koenig et al. identify a type 2-polarized MBC subset they term ‘MBC2s’. MBC2s are CD23hiIL-4RαhiCD32low and express IgE germline transcript (eGLT). These cells are polarized by IL-4, have gene signatures of adaptive immune activation, and have a transcriptional programme that retains them in a memory state. The authors report that MBC2s are enriched in IgG1 and IgG4 expression and, based on the expression of eGLT, seem poised to switch to IgE.

In individuals with allergic rhinitis and food allergy, Koenig et al. found that the allergen-specific MBCs were mainly MBC2s, whereas this was not the case for SARS-CoV-2-specific MBCs. They also identified mouse homologues of human MBC2s in allergy models. Finally, they provide in vivo evidence that human MBC2s are primary clonal relatives of allergen-specific IgE-producing plasma cells after 1 month of allergen sublingual immunotherapy in individuals allergic to birch.

The preprint by Ota et al. describes a similar allergen-specific MBC reservoir using single-cell transcriptomics of children with peanut allergies. They show that these MBCs also express CD23, IL-4R and eGLT, and produce mainly IgG1 and IgG4. Sorted peanut-specific B cells were consistent with the type 2-polarized MBC population. In addition, the peanut allergen-specific reservoir of MBCs had highly mutated B cell receptors (BCRs). Furthermore, in a subset of highly sensitized, peanut-allergic individuals, they could identify MBCs with convergent high-affinity BCRs specific for the main peanut allergen, the conglutin Ara h 2.

Together, these preprints provide compelling evidence of a new phenotype of type 2-polarized MBCs that can retain allergen-specific IgE memory. Future work to understand how these cells develop and generate IgE-producing plasma cells could help to enable reprogramming of allergen-specific memory for therapeutic benefit.