Whence and wherefore IgE?

Abstract

Despite the near ubiquitous presence of Ig-based antibodies in vertebrates, IgE is unique to mammals. How and why it emerged remains mysterious. IgE expression is greatly constrained compared to other IgH isotypes. While other IgH isotypes are relatively abundant, soluble IgE has a truncated half-life, and IgE plasma cells are mostly short-lived. Despite its rarity, IgE is consequential and can trigger life-threatening anaphylaxis. IgE production reflects a dynamic steady state with IgG memory B cells feeding short-lived IgE production. Emerging evidence suggests that IgE may also potentially be produced in longer-lived plasma cells as well, perhaps as an aberrancy stemming from its evolutionary roots from an antibody isotype that likely functioned more like IgG. As a late derivative of an ancient systemic antibody system, the benefits of IgE in mammals likely stems from the antibody system's adaptive recognition and response capability. However, the tendency for massive, systemic, and long-lived production, common to IgH isotypes like IgG, were likely not a good fit for IgE. The evolutionary derivation of IgE from an antibody system that for millions of years was good at antigen de-sensitization to now functioning as a highly specialized antigen-sensitization function required heavy restrictions on antibody production-insufficiency of which may contribute to allergic disease.

Keywords: IgE; IgG; allergen immunotherapy; allergy; class switch recombination; plasma cells.

Figure 1.. Divergent evolutionary functions in IgG and IgE

As IgY (green) underwent a gene duplication to generate IgG (blue) and IgE (purple), there was a compartmentalization of humoral function. IgG occupies the role of defender against most pathogens in the systemic circulation, including bacteria, viruses, and fungi, and can be produced with impressive rapidity. In contrast, IgE, owing to its low systemic concentrations and constrained production, serves as a tissue-localized sensitizer, functioning in the skin and specific mucosal tissues to sensitize to parasites and venoms and at times pathogenically to benign triggers such as dietary antigens.

Fig. 2.. Models of antigen-dependent and antigen-independent apoptosis of IgE+ cells

In IgE plasma cells, upon antigen stimulation of the IgE BCR (purple), there is induction of a signaling cascade involving Syk, BLNK, and PLCγ2 which results in increased calcium flux and activation of Cas3 caspases, ultimately triggering apoptosis. In comparison, IgE+ B cells, induced autonomously by the IgE receptor, undergo a signaling cascade involving the BLNK-Jnk-p38 axis, resulting in chronic calcium signaling and BIM-mediated apoptosis. BCR, B cell receptor. BCL2L11, BIM. Ca, calcium.

Fig. 3.. Determinants of IgE-mediated mast cell degranulation and anaphylaxis

Multiple factors modulate the capacity of IgE (purple) to induce mast cell degranulation and anaphylaxis. Higher IgE specific activity, defined as the ratio of allergen-specific IgE levels to total IgE levels, is associated with heightened mast cell and basophil activation. Polysensitization of IgE, wherein IgE binds multiple protein components of a given allergen, has also been associated with the clinical development of allergies. Increased ratio of allergen-specific IgE to IgG (blue) may also facilitate IgE outcompeting with IgG for binding to allergen, facilitating allergic disease. Lastly, the generation of high affinity IgE through the contribution of T_FH13 cells and stepwise CSR from IgG to IgE is important for mast cell degranulation and allergic disease. CSR, class switch recombination. MHC, major histocompatibility complex. Phl p, Phleum pratense. T_FH, T follicular helper cell. TCR, T cell receptor.

Fig. 4.. Induction of long-lived IgE+ bone marrow plasma cells

A recent study highlighted that in short term exposure to HDM (4 weeks), IgE+ short-lived PCs were sequestered in secondary lymphoid organs such as the spleen and were unable to generate IgE (purple) capable of triggering mast cell degranulation and anaphylaxis. In comparison, with prolonged HDM exposure (15 weeks), there was induction of a population of IgE+ long-lived PCs that express the homing chemokine receptor CXCR4 and localize to the bone marrow and lung mucosa. These long-lived PCs generated IgE derived from sequential CSR from IgG1 (blue) and were able to robustly trigger mast cell degranulation and anaphylaxis. CSR, class switch recombination. HDM, human dust mite. PC, plasma cell.

Fig. 5.. Therapeutic strategies for the elimination of reservoirs of IgE memory.

IgE memory resides in two sources: (1) type 2 memory B cells that are poised to undergo CSR to IgE+ PCs upon allergen re-exposure and (2) a rare population of bone-marrow resident, long-lived IgE+ PCs induced by chronic allergen exposure. To target type 2 memory B cells that rely on IL-4 and IL-13 for undergoing CSR to IgE, dupilumab is utilized to disrupt IL-4 and IL-13 signaling, preventing the generation of new IgE+ PCs. Secondly, to address the rare population of IgE+ long-lived PCs, a novel bispecific antibody BCMAxCD3 has been developed that causes T-cell mediated elimination of PCs. The coadministration of dupilumab and BCMAxCD3 depletes both reservoirs of IgE memory, durably suppressing IgE-mediated responses. CSR, class switch recombination. IL4R, IL-4 receptor. PC, plasma cell.

Fig. 6.. Local class switch recombination in mucosal tissues

In atopic disease, local CSR to IgE in mucosal tissues has been demonstrated, yielding high concentrations of IgE in tissues in contact with allergens. In allergic rhinitis, there is evidence of CSR from IgG (blue), IgA (orange), and IgM (black) to IgE (purple) in nasal mucosa.^– In the stomach and duodenal mucosa in food allergic patients, CSR from IgA1 appears to the major source of IgE generation. In the bronchial mucosa of asthmatics, CSR from IgM and IgG appears to be the primary source of IgE. CSR, class switch recombination.

Fig. 7.. Proposed mechanism of IgA-mediated mast cell inhibition

Binding of IgA (orange) to mast cells depends on ambient calcium concentrations and the presence of sialic acid residues (pink) on the IgA molecule. Binding results in diminished phosphorylation of the Syk kinase, restricting mast cell degranulation as well as the generation of IL-13, TNF-α, and IL-6. Ca, calcium. P, phosphorylated. TNF-α, Tumor Necrosis Factor alpha.