3. IgE targeting to the CD23 pathway
The importance of CD23 as a target of IgE is not entirely clear. However, even though CD23 binds IgE with clearly lower affinity compared to FcεRI, It was shown that CD23 can oligomerize on the surface of B cells leading to enhanced IgE binding through an avidity effect (43) (Fig. 1A and 1B). The leucine zipper region in the stalk was proposed to play an important role in CD23 oligomerisation (44). In turn, a more recent study has suggested a direct involvement of the CD23 stalk region in IgE binding potentially explaining why IgE binds well to B cells despite the relatively poor affinity binding to the previous described lectin domain binding site (45). Another important aspect that may regulate CD23 targeting is the valency of IgE. The binding of IgE in complex with allergen (IgE-immune complex) was shown to impact binding of IgE to CD23 (46). Furthermore, we recently showed that IgE in complex with allergen is preferentially bound by CD23, whereas the binding to FcεRI is diminished by IgE complexation (47). The physiological relevance of IgE-allergen immune complexes in healthy and allergic patients is not entirely clear, even though their existence has been described a long time ago (48,49). Similarly to IgE-allergen immune complexes, the well documented presence of natural anti-IgE antibodies could also lead to multivalent IgE complexes that could potentially regulate CD23 versus FcεRI targeting (50–53).
IgE binding to CD23 may also be enhanced by other receptors. The complement receptor CD21, which has been shown to bind CD23 is an interesting co-receptor for IgE-IC. Even though IgE itself does not fix complement, the inclusion of complement fixing IgG could impact immune complex to CD23. It was shown that IgE-immune complexes formed in allergic patients include IgE, IgG1 and IgG4 leading to the activation of the complement system resulting in the fixation of complement components to the complexes that bind to peripheral B cells via CD21 (54) (Fig. 1C). Surprisingly, IgG binding via FcγRII was not found to play a role in that study. The role of IgG and complement factors in regulating IgE-IC binding to CD23 on B cells or other cell types requires more detailed investigations.
CD23 as a regulator of IgE levels
A main function attributed to CD23 has been the regulation of IgE synthesis. Both in vitro and in vivo studies have shown that CD23 plays a central role in regulating IgE synthesis. However, the exact mechanism of IgE down-regulation is a matter of debate. It was shown quite some time ago that mice overexpressing CD23 display reduced IgE levels after primary immunization with antigen in alum (55,56) while CD23-/- mice show enhanced IgE production (57). Furthermore, anti-CD23 antibodies have been shown to inhibit antigen-specific IgE responses in mice (58).
In human B cells, it was shown that IgE synthesis can be inhibitedin vitro by direct targeting of CD23 (59). This supports a model which predicts a positive and a negative feedback mechanism depending on the concentration of IgE and cleavage of membrane CD23 (63). Thus, high levels of IgE or antibodies against the lectin head of CD23 stabilize membrane CD23 preventing its proteolytic cleavage and thereby inhibits IgE synthesis. In turn, the cleavage of CD23 by allergens has been a proposed mechanism of enhanced IgE responses (60). Allergen-cleaved CD23 would lose the ability to suppress IgE synthesis and hence lead to eleveated IgE levels. CD23 binding by antibodies recognizing the stalk region of CD23 or metalloproteinases such as ADAM10 are additional ways in which CD23 cleavage and production of soluble CD23 can occur.
It has been proposed that CD23 cleavage not only prevents negative regulation but may even enhance IgE synthesis by acting on other cells as soluble CD23. However, the mechanisms by which sCD23 enhances IgE synthesis are unclear. Potentially, released soluble CD23 may up-regulate IgE synthesis by cross-linking membrane IgE and CD21. The activity of the soluble fragments depends on their oligomeric state namely soluble CD23 monomers inhibit whereas oligomers stimulate IgE synthesis (61). The fact that IgE and CD21 have distinct binding sites and bind CD23 simultaneously supports this hypothesis (41). In contrast the co-ligation of of membrane IgE and membrane-bound CD23 via allergen-IgE complexes has been suggested as negative feedback mechanism of IgE synthesis but more experiments need to be performed to confirm this hypothesis.
A further mechanism by which CD23 may regulate IgE levels, is by acting as a direct decoy receptor for FcɛRI. It was shown in mice, that B cells regulate serum IgE levels directly by absorbing free IgE molecules, thus preventing FcɛRI loading and allergic sensitization (47,62,63), This more novel model of IgE regulation fits well with the generally higher IgE levels in CD23 deficient mice.