The role of allergen-specific IgE, IgG and IgA in allergic disease

Abstract

Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. Exposure to even minute quantities of allergens can lead to the production of IgE antibodies in atopic individuals. This is termed allergic sensitization, which occurs mainly in early childhood. Allergen-specific IgE then binds to the high (FcεRI) and low-affinity receptors (FcεRII, also called CD23) for IgE on effector cells and antigen-presenting cells. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE, even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared with IgE and do not efficiently interfere with allergen-induced inflammation. However, IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mast cells and basophils. Here, we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.

Keywords: IgE; allergy treatment; basic mechanisms in allergy; biologics; biomarkers; immunotherapy; tolerance induction; vaccines and mechanisms.

FIGURE 1

IgE and its receptors. IgE antibody uses two identical light and heavy chains and the constant region has four domains (Cε1‐Cε4). The two antigen‐binding sites are formed by pairing of the variable region of light and heavy chains. IgE is asymmetrically bent at the Cε2‐3 linker and folds on itself with the two Cε2 domains folded back and almost touching the Cε4 domains. IgE interacts with the high‐affinity IgE‐receptor FcεRI with the Cε2 and Cε3 domains, and with the low‐affinity IgE‐receptor CD23 with the Cε3 and Cε4 domains. Anti‐IgE antibodies like omalizumab bind to the Cε3 domain of IgE and can therefore inhibit the binding of IgE to both FcεRI as well as to CD23. IgE binding to FcεRI occurs in a 1;1 stoichiometry of 1:1, and IgE binding to CD23 in a stoichiometry of 2:1 or larger

FIGURE 2

IgE‐mediated Th2 and Mast cell/basophil activation and inhibitory effects of allergen‐specific IgG and IgA as well as anti‐IgE. Inhibition of IgE‐mediated Th2‐cell activation (left panel) and basophil/mast cell degranulation (right panel) by allergen‐specific IgG and ‐IgA (purple), and anti‐IgE (red) treatment. Whereas allergen‐specific IgG and IgA compete with IgE for binding to allergens, anti‐IgE antibodies bind to IgE and block binding of IgE to both the high‐affinity (FcεRI) and low‐affinity (CD23) receptors for IgE expressed on antigen‐presenting cells and basophils/mast cells. In this way, they can inhibit IgE‐mediated activation of allergen‐specific T cells as well as the release of inflammatory mediators by basophils/mast cells induced by IgE‐mediated cross‐linking of FcεRI after allergen exposure

FIGURE 3

Maternal immunoglobulin‐mediated imprinting of allergic responses in the offspring. Maternal IgG (blue) to airborne allergens and food allergens reach the offspring in utero by a transfer across the placenta and after birth through breast milk and transfer across the gut. The neonatal Fc receptor (FcRn) carries maternal IgG either free or bound to allergen. Free IgG can inhibit allergic sensitization in offspring by modulating B‐cell reactivity. Allergen‐IgG immune complexes can induce immune tolerance by promoting allergen‐specific Treg expansion. Maternal IgE (purple) might also be transported across the placenta by FcRn. Foetal mast cells bear the IgE receptor (FcεR1) and bind maternal IgE. In mice, these IgE‐loaded foetal mast cells are functionally competent, degranulate upon exposure to allergen and persist in neonates, in whom they may mediate allergic disease in early life. Maternal secretary IgA (orange) are also found in human breast milk and might decrease allergic sensitization by controlling allergen transfer across offspring gut. Evidence in mice also suggests they might control the expansion of Tregs in offspring