Type 2 <scp>IgG</scp> Memory B Cells as Precursors of <scp>IgE</scp> Plasma Cells
Authors: Larissa Nogueira de Almeida, Janina Petry, Christopher C. Udoye
Journal: Allergy (2025)

Immunoglobulin E (IgE) is a major mediator of allergic reactions and can activate mast cells and basophils via the high-affinity IgE receptor. Some IgE-mediated allergies can last a lifetime, but IgE-secreting plasma cells (PCs) and IgE+ memory B cells (MBCs) are rare, leading to questions about the origin of allergen-specific IgE antibodies (Abs). In recent years, studies have suggested that allergen-specific B cell memory is predominantly held by IgG(1) MBCs, which can become IgE-secreting PCs during a recall response [1, 2]. A recent article by Koenig and colleagues proposed a novel class-switched MBC population with type 2 immune markers, which they termed MBC2, as a major progenitor of IgE PCs [3]. The most important findings of their work are highlighted in Figure 1. Using single-cell RNA sequencing (scRNA-seq), the authors identified 21 MBC clusters in both allergic and non-allergic subjects (Figure 1, upper panel). Two MBC clusters, collectively termed MBC2, expressed high levels of the low-affinity IgE receptor (CD23) and receptors for the type 2-associated cytokines IL-4 (IL4R) and IL-13 (IL13RA1). MBC2s contained two subsets, IGHE+ and IGHE- MBC2s, which differed in the expression of IgE germline transcripts (εGLTs), but barely expressed productively rearranged IgE transcripts. Instead, both subsets expressed predominantly IgG1 B cell receptors (BCRs), and a relatively high proportion of IgG4 in the IGHE+ MBC2s. Importantly, the frequency of IGHE+ MBC2 cells was independent of the allergic status and did not correlate with allergic disease. The authors confirmed this MBC2 phenotype at the protein level with additional elevated expression of CD40 and HLA-DR/DQ genes and a unique down-regulation of the inhibitory IgG receptor FcγRIIB compared to other MBC subsets. The authors also found a similar IL-4-dependent CD23hi/IL-4Rαhi MBC2-like population in mice, which emerged in the context of type 2 but not type 1 sensitization, with 2% of antigen-specific, class-switched MBCs showing the IGHE+ MBC2 phenotype (the majority of which expressed an IgG1 BCR) upon type 2 sensitization. Importantly, the authors also showed that antigen-specific MBC2 generation in mice was primarily dependent on germinal center (GC) reactions, with less than 10% of antigen-specific MBC2s appearing to develop independently of GCs. Finally, an analysis of birch allergic patients undergoing sublingual immunotherapy (SLIT) revealed a clonal connection between IgE-producing PCs analyzed 1 month after the start of SLIT and MBC2s analyzed before or 1 month after the start of SLIT, although it remained unclear what percentage of IgE+ PC clones were found in MBC2 clones (Figure 1, lower panel). Together with an independent article in the same issue [4], Koenig and colleagues provide insights into allergen-specific B cell memory by identifying class-switched IGHE+ MBC2s with a strong type 2 phenotype, which appears to be generated mainly in GCs, as potential precursors of IgE PCs in allergen-specific recall responses in allergy, but also after allergen-specific immunotherapy (AIT). Their work characterizes in detail the phenotype of such MBC2s for the first time and raises multiple questions that should be explored in the near future. Notably, it remains unclear which factors influence IGHE+ MBC2s to switch to IgE- instead of IgG1- or IgG4-secreting PCs during an allergic or AIT recall response, especially considering that IGHE+ MBC2s may also be present in non-allergic individuals. Furthermore, it remains unclear what proportion of IgE-secreting PCs develop directly from re-activated IGHE+ MBC2s or instead from IgE+ MBCs (expressing a functional IgE BCR), or whether all or some of the re-activated IGHE+ MBC2s or instead IgE+ MBCs re-enter the GC to become "long-lived" IgE-secreting PCs, or what proportion of IgE-secreting PCs develop independently of GCs and GC-derived MBCs. Accordingly, IgE+ GC B cells have been described as precursors of IgE+ MBCs and IgE-secreting PCs [5], and long-lived IgE-secreting PCs have also been reported [6]. Interestingly, it has been suggested in the context of IgG Abs that direct re-activation of (IgG+) MBCs induces IgG+ PCs that, like extrafollicular IgG+ PC responses, generate short-lived and highly galactosylated and sialylated IgG Abs, whereas re-activated MBCs re-entering the GC generate IgG+ PCs that produce long-lived and less galactosylated and sialylated IgG Abs, with the level of galactosylation and sialylation of the latter IgG Abs further dependent on co-stimulatory signals in the GC reaction, and that these different IgG Abs may play different roles [7, 8]. Whether these differences also play a role for IgE is still unclear, but individual IgE compositions of such different pathways may influence the overall quality and effector function of IgE. The identification of class-switched allergen-specific IGHE+ MBC2s supports and concretizes recent suggestions that at least part of IgE-secreting PCs are derived from (IgG+) MBCs. (IGHE+) MBC2s may therefore represent a potential biomarker and therapeutic target for IgE-mediated allergic diseases, which requires further investigation. The authors thank Dr. Anna Globinska for her support in figure creation and Dr. Marc Ehlers for general support and fruitful discussion. Dr. Larissa Nogueira de Almeida and Dr. Janina Petry are members of the labs of Dr. Stefanie Derer-Petersen and Dr. Marc Ehlers, respectively, at the Institute of Nutritional Medicine of the University of Lübeck and the University Hospital Schleswig-Holstein, Germany. Dr. Christopher C. Udoye is a member of the lab of Dr. Rudolf Manz at the Institute for Systemic Inflammation Research of the University of Lübeck and the University Hospital Schleswig-Holstein, Germany. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.