In 1966 Ishizaka et al. (1) opened a new era in the pathophysiology of immunological disorders when they identified and purified IgE from the serum of allergic patients. Like other immunoglobulins, IgE consists of two light chains and two ɛ-heavy chains and can be detected in two forms, a secreted and a membrane-bound form (Fig. 1). mIgE is a transmembrane protein which behaves like a classical antigen receptor on B lymphocytes (2). Previous experiments in our and other laboratories showed that the expression of functional mIgE is essential for generating a humoral IgE and IgG1 response in mice (3, 4). The transmembrane domain and the cytoplasmic tail are encoded by two exons M1 (transmembrane domain) and M2 (cytoplasmic tail). The cytoplasmic domains of mIgs are different in size and range from only three amino acid residues in the case of mIgM and mIgD to 28 residues for the mIg subclasses. The mIg transmembrane segments are about 25 amino acids long, are highly homologous between all Ig-subclasses and have the potential for interaction with other polypeptides (5). Beside these 25 membrane-spanning amino acids, M1 additionally encodes isotype specific extracellular spacer segments. The spacers differ in lengths (13–21 amino acids) and show high variability between the different Ig isotypes. In the early nineties it became evident that human IgE molecules, unlike other immunoglobulin classes, bind specifically and with a very high affinity (Ka = 109 M) to receptors (FcɛRI) on the surface of human basophils and mast cells (6). IgE cross-linking of FcɛRI+ cells by specific antigens results in the release of a variety of preformed (e.g. histamine) and de novo synthesized chemical mediators (e.g. prostaglandins) and cytokines that exert their effects by interacting with specific receptors on target organs. Despite the fact that IgE is known for more than 30 years, we must admit that, so far, we failed to define significant biological functions for the IgE molecule. Because IgE titres are elevated in individuals suffering from helminthic infestations, IgE was thought to play a role in the defence against worms (7, 8). It was surprising to realize that treatment with anti-IgE antibodies of mice infected with Schistosoma mansoni or Nippostrongylus brasiliensis resulted in accelerated elimination of parasites and in a decreased worm burden and reduction in the number of eggs, which paralleled the decrease of serum IgE. High serum IgE levels seem not to be related to host defence but may be the consequence of Th2 cells by the parasite leading to increased IL4-levels. Thus, what remains is the knowledge, that IgE is the key molecule of the allergic response and current drugs for allergic diseases, such as antihistamines, corticosteroids, and bronchodilators, are not able to affect the basic causes of the disease but mainly treat allergic symptoms and concomitant inflammatory reactions. Conventional desensitization immunization with total extracts of allergenic sources (9) often are not effective and go in parallel with anaphylactic reactions. Therefore, a systemic treatment that targets the allergic process, that prevents it from occurring, and has fewer side effects than current drugs, is desirable. Because IgE is the central macromolecular mediator responsible for the progression of allergic reactions, neutralizing it and inhibiting its synthesis would appear to be a rational approach for the treatment of various allergic diseases. However, we must be aware that by systemically blocking the IgE response, we resign on an antibody class without the knowledge of its biological function and its natural biological function during immune reactions.
Figure 1. Like all other immunoglobulins, IgE can be found in two forms. In the secreted form (sIg) immunoglobulins represent the effector arm of the humoral immune system. Alternatively, they can also be expressed on the surface of a B lymphocyte in a membrane-bound form (mIg), and, in this physical state, they most likely convey signals to steer the B-cell along its differentiation pathway. The production of the two types are determined by alternative splicing or rather, alternative polyadenylation. The constant parts of the epsilon heavy chains are encoded by six exons. The last two exons code for the transmembrane (M1) and cytoplasmic domain (M2). The fourth exon (CH4) which is located 5′ of the membrane exons is a composite exon: it contains an internal splice donor site which is used when mRNA for membrane-bound Ig is made.
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