The biology of IgEIn 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 (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 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 n...
The classical allergic reaction starts within seconds or minutes after antigen contact and is induced by antibodies produced by a special subset of B lymphocytes. These antibodies belong to the IgE subclass and are responsible for Type I hyper-reactivity reactions. IgE plays a minor role in healthy individuals. In allergic individuals, however, IgE antibodies trigger allergic responses through allergen-mediated cross-linking on effector cells followed by mediator release. The mechanisms inducing a switch to IgE production are not fully understood with the consequence that allergies are mainly treated with antisymptomatic drugs. To develop basic therapies, many questions concerning the very complex regulation of IgE expression have to be understood. Positive and negative regulators influence the synthesis of IgE. Experiments in our laboratory could show that not only regulatory molecules, but also the membrane bound IgE itself controls the quantity and quality of the IgE produced. This fact becomes more and more interesting, because the signals generated by the B-cell receptor may be important targets for interference in allergic patients, in whom the titer and the affinity of the IgE antibodies for the allergen are directly related to disease activity.
A recent development in immunomanipulation involves the targeting of cytotoxic T lymphocytes (CTL) to cell-bound antigens using bispecific antibodies. These antibodies have been engineered such that specificity is directed against the T cell receptor (TCR) or TCR-associated T3 molecules, as well as against the chosen antigen. The present study was aimed to force interactions between T and B cells by bridging their receptors. F23.1 antibodies, which are specific for gene products of the TCR V beta 8 gene family, were conjugated with TNP (2,4,6-trinitrophenyl) and this construct was used to bridge the receptors of V beta 8+ T cells with the receptors of TNP-specific B cells. The bridging was demonstrated by direct killing of both a TNP-specific B hybridoma and of blast cells from mice transgenic for mu, kappa of the TNP-specific antibody Sp6. Further, F23.1-TNP constructs in conjunction with V beta 8+ CTL were shown to specifically deplete Ig-secreting B cells from Sp6 transgenic mice. Conjugates of TCR-specific antibodies and antigen are theoretically useful in vivo to either deplete or expand B cells of a given specificity by coupling their receptors to the TCR of CTL or T helper cells, respectively.
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