Ontogeny of human IgE-expressing B cells and plasma cells

Abstract

BackgroundIgE-expressing (IgE+) plasma cells (PCs) provide a continuous source of allergen-specific IgE that is central to allergic responses. The extreme sparsity of IgE+ cells in vivo has confined their study almost entirely to mouse models.ObjectiveTo characterize the development pathway of human IgE+ PCs and to determine the ontogeny of human IgE+ PCs.MethodsTo generate human IgE+ cells, we cultured tonsil B cells with IL-4 and anti-CD40. Using FACS and RT-PCR, we examined the phenotype of generated IgE+ cells, the capacity of tonsil B-cell subsets to generate IgE+ PCs and the class switching pathways involved.ResultsWe have identified three phenotypic stages of IgE+ PC development pathway, namely (i) IgE+ germinal centre (GC)-like B cells, (ii) IgE+ PC-like ‘plasmablasts’ and (iii) IgE+ PCs. The same phenotypic stages were also observed for IgG1+ cells. Total tonsil B cells give rise to IgE+ PCs by direct and sequential switching, whereas the isolated GC B-cell fraction, the main source of IgE+ PCs, generates IgE+ PCs by sequential switching. PC differentiation of IgE+ cells is accompanied by the down-regulation of surface expression of the short form of membrane IgE (mIgES), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgEL), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice.ConclusionGeneration of IgE+ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgEL/mIgES ratio may be implicated in survival of IgE+ B cells during PC differentiation and allergic disease.

B Cell Responses: Cell Interaction Dynamics and Decisions

“…A particularly striking case is that of the IgE BCR, which in mouse studies was shown to have an antigen-independent constitutive activity leading to increased PC differentiation, reduced GC B cell responses, and virtually undetectable Bmems (Haniuda et al, 2016;He et al, 2015;Yang et al, 2014. Recent evidence from cultured human B cells (Ramadani et al, 2017) and singlecell RNA-seq of blood samples from allergic patients (Croote et al, 2018) provides further evidence for a bias of IgE B cells to differentiate into PCs. Another factor that can influence the propensity to become a PC versus a GC cell is the chronic exposure to low avidity autoantigen.…”

Memory control by the B cell antigen receptor

“…Whether the two isoforms of primate mIgE are differentially used by certain B cell populations is insufficiently investigated. Experiments using in vitro cultures of human tonsillar B cells indicated that the EMPD‐containing long mIgE isoform may be predominantly expressed in freshly switched germinal center‐like B cells, whereas the EMPD‐deficient short isoform seems to be predominantly used in more differentiated plasmablast‐like cells …”

BCR analysis of single-sorted, putative IgE+memory B cells in food allergy:an ephemeral existence?

“…To validate that our enhanced staining technique was capable of detecting IgE + MBCs, we stimulated PBMCs in culture with IL-4 + anti-CD40, which is known to induce IgE class-switching (34). As expected, culturing under these conditions resulted in the robust emergence of IgEsecreting cells and IgE as detected by total IgE ELISPOT and ELISA, respectively (Fig.…”