Once an individual has developed IgE antibodies to certain antigen epitopes, multiple mechanisms can lead to a more robust and diverse IgE responses to both the original as well as other antigens. Some of these mechanisms are mediated by CD23 (ref. 1
), which can be expressed on cells such as epithelial cells, B cells and myeloid cells (). CD23 is a C-type lectin that can exist in a membrane-bound form that has three lectin domain “heads” separated from the membrane by a triple α-helix coiled-coil stalk, as well as in various soluble forms whose functions depend on whether these soluble forms are monomeric or trimeric1,17
(). The CD23 sheddase, ADAM metallopeptidase domain 10 (ADAM10), is the main protease that releases soluble CD23 from the membrane-associated form3,18
. CD23 is sometimes called a low-affinity receptor for IgE, but when the three lectin head domains of CD23 interact with a single IgE molecule, the resulting affinity constant (Ka
) approaches that of the high-affinity receptor for IgE, Fcε receptor I (FcεRI)(~1010
Expression and major functions of IgE-binding receptors or molecules
CD23 is thought to contribute to both positive and negative regulation of IgE production (), but the mechanisms responsible for this, and the role of CD23 in the pathology of allergic diseases, are not fully understood1
. Moreover, some effects of CD23 on IgE production may be influenced by other CD23 binding partners, including CD21, which can permit CD23 to participate simultaneously in biological networks involving either the complement system or IgE, and various integrins1
. However, certain functions of CD23 clearly have the potential to influence the biology of IgE-associated allergic disorders.
For example, CD23 on epithelial cells might amplify IgE responses by moving IgE and antigen-IgE complexes across the epithelium by transcytosis19,20
(‘1’ in , right), where they can bind to and activate FcεRI on mast cells, macrophages and dendritic cells, thereby promoting allergic inflammation, and, by inducing the secretion of IL-4 and/or IL-13 by mast cells, contribute to local IgE production (‘2’ in , right). IgE- and antigen-activated mast cells also release mediators such as histamine, tumor necrosis factor (TNF) and prostaglandin D2 (PGD2
) that can, in turn, promote the maturation, functional activation and migration of dendritic cells, favoring the development of sensitization to additional antigens (‘3’ in , right).
IL-4 and IL-13 also can increase CD23 expression on B cells and myeloid cells21
, thereby enhancing facilitated antigen presentation (FAP). In FAP, antigen-IgE complexes bound to the CD23 that is expressed on antigen-activated B cells can favor the presentation of such antigens to TH
cells (‘4’ in , right and ). The presentation of antigen-derived peptides initiated by the recognition of an antigen by membrane-associated B cell receptors is by definition effected only by interactions of cognate B cells with TH
cells (, left). By contrast, FAP of antigens bound to secreted IgE can permit any antigen-activated, CD23-expressing B cells, regardless of the specificity of the cells’ B cell receptors, to present diverse peptides (from related or unrelated antigens) to cognate T cells (, right). Thus, FAP is an efficient mechanism for so-called epitope spreading, in which the presence of an antibody response to one epitope can ultimately result in the production of antibodies to other epitopes on the same or unrelated antigens1
Epitope spreading is thought to contribute to the progressive development of allergies to multiple antigens in individuals with allergy. Epitope spreading may also contribute to the ‘atopic march’, wherein individuals who first present in early childhood with atopic dermatitis later develop allergic rhinitis and then atopic asthma22
, and may help explain how genetic abnormalities affecting one epithelium (for example, the epidermis) can predispose to allergic disorders affecting other epithelia. Notably, a large fraction of Europeans and Asians with atopic dermatitis have loss-of-function mutations in the gene encoding filaggrin, which results in impaired barrier function of the skin23
. Filaggrin is expressed in the epidermis of the skin and in other squamous epithelia but not in the airway or gastrointestinal mucosae24
, however, individuals with filaggrin mutations that are associated with the development of atopic dermatitis are also at increased risk for the later development of atopic asthma25
Additional functions of CD23 include the clearance of antigen-IgE complexes, the killing of pathogens by IgE-bearing monocytes and eosinophils26
, involvement in IgE-independent27
monocyte-mediated toxicity against target cells and, through CD23 expressed on intestinal epithelial cells, the transportation of IgE and antigen-IgE complexes directly across the intestinal epithelium19,29
, which may account for delivery of maternal IgE to the fetus by swallowed amniotic fluid30
(). By moving IgE in the opposite direction across the intestinal31,32
epithelium, CD23 can favor the formation of antigen-IgE complexes in the lumen that can then be transported by CD23 back across the epithelium, resulting in the activation of local mast cells (or other FcεRI-bearing effector cells), a process that may both exacerbate allergic inflammation and impair mucosal epithelial function at the affected site.
It has been reported that local IgE synthesis and expression of CD23 can occur concurrently in the fetus30,33
and that a parental history of atopy and high titers of IgE in the cord blood are predictive of early atopy34
. Moreover, CD23
gene polymorphisms have been associated with effects on the development of atopy in mice and humans35
. It is thus tempting to attribute to CD23 at least some role in the development and, through epitope spreading and other mechanisms, the exacerbation of allergic disorders.