At least two cell-derived signals have been shown to be necessary for the induction of
immunoglobulin isotype switching in B-cells. The first signal is given by either of the soluble
lymphokines,
interleukin (IL)-4 or
IL-13, which induce germline epsilon transcript expression, but this alone is insufficient to trigger secretion of
immunoglobulin E (
IgE). The second signal is provided by a physical interaction between B-cells and activated T-cells, basophils and mast cells, and it has been shown that the CD40/
CD40 ligand (
CD40L) pairing is crucial for mediating
IgE synthesis. In hyper-
immunoglobulin M1 (
HIGM1) syndrome, which is characterized by greatly decreased levels of
immunoglobulin G, A and E (
IgG,
IgA and
IgE), there are mutations in the
CD40L resulting in a completely non-functional extracellular domain. The
CD40L is, therefore, playing a central role in
immunoglobulin isotype switching. Amongst the numerous pairs of surface adhesion molecules, the CD23-CD21 pair seems to play a key role in the generation of
IgE. The CD23 molecule is positively and negatively regulated by factors which increase or decrease
IgE production, respectively.
Antibodies to CD23 have been shown to inhibit IL-4-induced human
IgE production in vitro and to inhibit
antigen-specific
IgE responses in a rat model, in an isotype selective manner. CD23 interacts with CD21 on B-cells, preferentially driving
IgE production. CD23 recognizes two main
epitopes on the CD21 molecule. One region consists of short consensus repeat (SCR) sequences 1-2 and the other of SCR 5-8. In the latter region, Asn 370 and 295 are critical in the interaction with the
lectin CD23. Therefore, a restricted number of
cytokines and surface molecules seems to selectively regulate human
immunoglobulin E synthesis.