Deleterious allergen-specific IgE responses underlie atopic disease. Defining the nature of IgE memory has fundamental clinical implications in the era of cytokine-targeting biologic therapies. Current dogma holds that signaling through the IgE BCR enforces either apoptosis or plasmablast differentiation upon IgE+ B cells. A subset of IgG1+ memory B cells (MBC2s) has been proposed to undergo sequential IgE switching and plasmablast differentiation to maintain serum IgE in atopic individuals. Interestingly, even in patients who respond to biologic therapies targeting Th2 cytokines, IgE levels fall substantially but can continue to persist at elevated levels. Moreover, disease recurrence can follow cessation of treatment, suggesting an ongoing need for continual therapy.
To address these uncertainties, we examined circulating B cells in patients with IEI associated with atopy, as well as disease controls. Our cohort included patients with dominant negative (DN) variants in STAT3 or IL6ST, GOF variants in STAT6 and STAT1, biallelic LOF variants in DOCK8 or ZNF341, and individuals with severe atopic dermatitis.
An optimized highly sensitive flow cytometric assay to detect intracellular IgE revealed discrete populations of IgE+ B cells that corresponded to either memory-type B cells (IgElo CD27+ Ki67-) or plasmablasts (IgEhi CD27+ CD38+ Ki67+). scRNAseq and BCR (scVDJseq) analyses verified the expression of productive IGHE transcripts in putative IgE+ B cells. While present at extremely low frequencies in healthy donors, IgE+ B cells were greatly enriched in individuals with STAT3 hyper IgE syndrome.
Regardless of donor genotype, the phenotype and transcriptional profile of IgE+ B cells resembled that of IgG1+ MBC2s. IgE+ B cells were neither clonally expanded nor related to B cells of other Ig isotypes. Crucially, IgE+ B cells downregulate SYK, suggesting a mechanism to avoid BCR-induced apoptosis identified in murine studies. A broad range of SHM in IgE+ B cells suggested several developmental trajectories and provided evidence of selection pressure in IgE+ B cells comparable with other switched isotypes. Interestingly, IgE+ B cells survived IL-4R/IL-13R blockade in some STAT3 HIES patients.
These data elucidate the phenotype of human IgE+ B cells and suggest approaches which may further reveal their ontogeny and pathological relevance.
