The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans

Abstract

The existence of long-lived IgE antibody-secreting cells (ASC) is contentious, with the maintenance of sensitization by the continuous differentiation of short-lived IgE⁺ ASC a possibility. Here, we review the epidemiological profile of IgE production, and give an overview of recent discoveries made on the mechanisms regulating IgE production from mouse models. Together, these data suggest that for most individuals, in most IgE-associated diseases, IgE⁺ ASC are largely short-lived cells. A subpopulation of IgE⁺ ASC in humans is likely to survive for tens of months, although due to autonomous IgE B cell receptor (BCR) signaling and antigen-driven IgE⁺ ASC apoptosis, in general IgE⁺ ASC probably do not persist for the decades that other ASC are inferred to do. We also report on recently identified memory B cell transcriptional subtypes that are the likely source of IgE in ongoing responses, highlighting the probable importance of IL-4Rα in their regulation. We suggest the field should look at dupilumab and other drugs that prohibit IgE⁺ ASC production as being effective treatments for IgE-mediated aspects of disease in most individuals.

Keywords: IgE; allergy; asthma; longevity; plasma cell.

FIGURE 1

Prognosis of sensitization to food allergens in infancy. Food allergies have different rates of resolution as children age, with a majority of egg and milk allergies resolving by early adulthood; by contrast, allergies to peanuts, fish, and shellfish tend to be lifelong.

FIGURE 2

Routes to sensitization modeled in mice. Mouse models typically fall on the premise of (i) chronic respiratory exposure; (ii) adjuvanted mucosal exposure through the gut or lung; or (iii) exposure through tape‐strip damaged skin (epicutaneous exposure). Each route generates IgE, but the biology of the IgE response in each case may differ.

FIGURE 3

Basic signals required for sensitization. Upon initial allergen exposure, B cells capture antigen through their B cell receptors (BCR), and process and present peptides from that allergen via MHC‐II to cognate T follicular helper (TFH) cells, which recognize peptide–MHC‐II complexes through the T cell receptor. The T cell provides the cognate B cell with IL‐4 and costimulation via CD40L (signaling through CD40 on the B cell) to drive B cell proliferation and IgE class‐switch recombination (CSR). Once a B cell is IgE class‐switched, it can then differentiate into an IgE antibody‐secreting cell (ASC), which produces IgE to bind to high‐affinity IgE receptors (FcϵRI) on the surface of mast cells and basophils, resulting in sensitization.

FIGURE 4

Potential pathways to IgE production in mice and humans. IgE class‐switch recombination (CSR) may occur during (1) the preGC phase of a B cell response, to give rise to IgE⁺ preGC B cells, which go on to become short‐lived extrafollicular IgE⁺ ASC. They also (2) likely enter GC to generate IgE⁺ B cells. Alternatively, IgM/IgG⁺ GC B cells may switch to IgE within GC to allow IgE⁺ GC B cells to then become GC‐derived IgE⁺ ASC. Which is the case has not been definitively demonstrated. (3) IgM/IgG⁺ memory B cells that can arise both directly from the preGC pool and via GC differentiation, can switch to IgE to generate IgE⁺ ASC upon allergen re‐exposure. Post‐GC IgE⁺ ASC have been convincingly demonstrated by BCR mutational profiles, but whether they arise directly from IgE⁺ GC B cells, via an IgM/IgG⁺ GC switch intermediate, or predominantly from switching at the memory B cell stage is not clear.

FIGURE 5

Regulation of IgE production by cytokines. (A) Newly identified TFH13 cells as well as TFH2 cells produce IL‐4 that promotes IgE class‐switch recombination. It is not clear if this most commonly occurs primarily prior to GC formation, once GC are established, or during recall responses in subcapsular sinus foci. By contrast, conventional TFH (conv‐TFH) and reg‐TFH produce high amounts of IL‐21 and neuritin, respectively, to suppress IgE CSR and therefore IgE⁺ ASC formation. (B) In culture, addition of neuritin to activated B cells diminishes IgE amounts in a concentration‐dependent manner. IL‐21 can suppress IgE production, or enhance it, depending on the amount of CD40 stimulation the B cells receive. (C) While IL‐13 has minimal effect on IgE amounts in murine B cell culture, in vivo its absence limits the affinity maturation of IgE antibodies such that they are not reaginic when it is genetically deleted from TFH cells, and when IL‐13‐expressing TFH are deleted.

FIGURE 6

Sites of residence of IgE⁺ ASC. IgE⁺ ASC have been identified transcriptomically in nasal polyps, peripheral blood, and stomach and duodenal sections from humans., , , , , In the case of blood and nasal polyp‐localized IgE⁺ ASC, these were defined as transcriptionally immature or plasmablasts., IgE⁺ ASC have been found in bone marrow by flow cytometry and immunohistochemistry, but their transcriptomic state has not been resolved as plasmablast, immature, or mature ASC., Similarly, in the intestine, it is not clear if IgE⁺ ASC are plasmablasts, immature, or mature ASC, despite convincing evidence they can reside at that site.,

FIGURE 7

Recent evidence of unique regulation of IgE responses by the IgE BCR. gG1⁺ B cells in mice exhibit limited autonomous signaling,, and are shown to enter quiescence as memory B cells. Upon antigen ligation of the IgG1 BCR, IgG1⁺ B cells differentiate into IgG1⁺ ASC,, which can migrate to bone marrow and mature into long‐lived IgG1⁺ ASC. In contrast, IgE⁺ B cells exhibit strong autonomous BCR signaling, which is associated with a predisposition to differentiation into ASC., , Whether IgE⁺ ASC can transition to maturity and remain as long‐lived in bone marrow is unclear; however, antigen ligation of the IgE BCR on ASC promotes SYK‐ and BCL2L11‐dependent apoptosis,, limiting the life span of most IgE⁺ ASC.