Molecular and cellular targets of anti-IgE antibodies (original) (raw)

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 e-heavy chains and can be detected in two forms, a secreted and a membrane-bound form ). 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 ¼ 10 9 M) to receptors (FceRI) on the surface of human basophils and mast cells (6). IgE cross-linking of FceRI + 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 Immunoglobulin E (IgE) was the last of the immunoglobulins discovered. It is present in very low amounts (nano-to micro-gram per ml range) in the serum of normal healthy individuals and normal laboratory mouse strains and has a very short half-life. This contrasts with the other immunoglobulin classes, which are present in much higher concentrations (micro-to milligram per ml range) and form a substantial component of serum proteins. Immunoglobulins play a role in homeostatic mechanisms and they represent the humoral arm of defence against pathogenic organisms. Since IgE antibodies play a key role in allergic disorders, a number of approaches to inhibit IgE antibody production are currently being explored. In the recent past the use of nonanaphylactic, humanized anti-IgE antibodies became a new therapeutic strategy for allergic diseases. The therapeutic rational beyond the idea derives from the ability of the anti-IgE antibodies to bind to the same domains on the IgE molecule that interact with the highaffinity IgE receptor, thereby interfering with the binding of IgE to this receptor without cross-linking the IgE on the receptor (nonanaphylactic anti-IgE antibodies). Treatment with anti-IgE antibodies leads primarily to a decrease in serum IgE levels. As a consequence thereof, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells reducing the release of inflammatory mediator such as histamine, prostaglandins and leukotrienes. Experimental studies in mice indicate that injection of some monoclonal anti-IgE antibodies also inhibited IgE production in vivo. The biological mechanism behind this reduction remains speculative. A possible explanation may be that these antibodies can also interact with membrane bound IgE on B cells, which could interfere the IgE production.