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.