Chronic allergen exposure drives accumulation of long-lived IgE plasma cells in the bone marrow, giving rise to serological memory

Summary: Long-lived IgE plasma cells reside in the bone marrow of allergic mice and atopic humans, confer IgE serological memory and produce allergen-specific IgE that can drive anaphylaxis. Abstract: Immunoglobulin E (IgE) plays an important role in allergic diseases. Nevertheless, the source of IgE serological memory remains controversial. We re-examined the mechanism of serological memory in allergy using a dual-reporter system to track IgE plasma cells (PCs) in mice. Short-term allergen exposure resulted in the generation of IgE plasma cells that resided mainly in secondarylymphoid organs and produced IgE that was unable to degranulate mast cells. In contrast, chronic allergen exposure led to the generation of long-lived IgE plasma cells that were primarily derived from sequential class switching of IgG1, accumulated in the bone marrow (BM) and produced IgE capable of inducing anaphylaxis. Most importantly, IgE plasma cells were found in the BM of human allergic, but not non-allergic donors, and allergen-specific IgE produced by these cells was able to induce mast cell degranulation when transferred to mice. These data demonstrate that longlived IgE BMPCs arise during chronic allergen exposure and establish serological memory in both mice and humans. Overall design: To study the IgE response in vivo, a house dust mite (HDM) driven lung inflammation model was conducted in WT, membrane-IgEvenus/Blimp-1mCherry single or dual reporter mice. Cellular responses were tracked by harvesting lymphoid tissues from the mice at the end of each experiment and analyzing them by flow cytometry. Molecular readouts were assessed using prepared RNA from harvested cells. Serum readouts, such as IgE or IgG1 levels, were assessed using ELISA. Pathogenicity of serum IgE derived from short-term and chronic HDM exposed mice was determined by passive cutaneous and passive systemic anaphylaxis assays (PCA and PSA). The human IgE response was also examined ex-vivo using BM samples from allergic and non-allergic donors. Human IgE-producing BMPCs were quantified using intracellular IgE staining, secretion of IgE was determined by ELISA from cultured BM supernatant and the capacity of the IgE to induce anaphylaxis was determined by PCA.