Ontogeny of human IgE-expressing B cells and plasma cells

Abstract

Background: IgE-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.

Objective: To characterize the development pathway of human IgE⁺ PCs and to determine the ontogeny of human IgE⁺ PCs.

Methods: To 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.

Results: We 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 (mIgE_S ), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgE_L ), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice.

Conclusion: Generation of IgE⁺ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgE_L /mIgE_S ratio may be implicated in survival of IgE⁺ B cells during PC differentiation and allergic disease.

Keywords: IgE class switching; allergy; germinal centre; human B cells; plasma cell.