PAIRS OF SURFACE MOLECULES INVOLVED IN HUMAN IGE REGULATION - CD23-CD21 AND CD40-CD40L

At least two cell-derived signals have been shown to be necessary for the induction of immunoglobulin isotype switching in B-cells. The firs t signal is given by either of the soluble lymphokines, interleukin (I L)-4 or IL-13, which induce germline epsilon transcript expression, bu t 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 b een shown that the CD40/CD40 ligand (CD40L) pairing is crucial for med iating IgE synthesis. In hyper-immunoglobulin M1 (HIGM1) syndrome, whi ch 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, the refore, playing a central role in immunoglobulin isotype switching. Am ongst the numerous pairs of surface adhesion molecules, the CD23-CD21 pair seems to play a key role in the generation of IgE, The CD23 molec ule is positively and negatively regulated by factors which increase o r decrease IgE production, respectively, Antibodies to CD23 have been shown to inhibit IL-4-induced human IgE production in vitro and to inh ibit antigen-specific IgE responses in a rat model, in an isotype sele ctive manner, CD23 interacts with CD21 on B-cells, preferentially driv ing IgE production. CD23 recognizes two main epitopes on the CD21 mole cule. 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 restric ted number of cytokines and surface molecules seems to selectively reg ulate human immunoglobulin E synthesis.