Chimaeric IgE/IgG1 antigen receptor knock in mice

The number of allergic diseases increases annually. However, the investigation of the molecular cause of the disease was not possible with classical medical techniques up to now. The modern molecular biology allows us to answer questions concerning these topics. Normally, our immune system is able to estimate the source of danger and distinguish between harmless and pathogenic substances. But sometimes the estimation fails and a harmless substance is recognized as a dangerous one. In this case, the substance acts as antigen and activates the immune system. The classical allergic reaction starts seconds or minutes after antigen contact and is committed by antibodies, produced by a special class of lymphocytes. These antibodies belong to the IgE subclass and are responsible for the hyper reactivity reaction. In healthy individuals, IgE plays only a minor role. However, in allergic people the situation is completely different and IgE antibodies trigger the allergic response. The mechanisms behind are not completely understood which in the past mainly resulted in therapeutic possibilities restricted to symptom control. To develop basic therapies a lot of questions concerning the regulation of IgE expression have to be investigated. IgE itself can be secreted into the blood or expressed as membrane receptor on the surface of specific B-lymphocytes. In the membrane form, IgE is responsible for the induction of immunological memory and differentiation of IgE producing plasma cells. In the secreted form, the antibodies fulfil all tasks of the immune response: they trace the antigen and contribute to its destruction. The regulation of the production of IgE is very complex. A lot of regulators, positively and negatively, influence the synthesis of IgE. Experiments in our laboratory could show that not only regulatory molecules but also the membrane IgE itself controls the quantity and quality of the IgE produced. Thus, the IgE antigen receptor itself mediates a signal transduction that finally expresses a high level of IgE which is responsible for the induction of allergic diseases. The aim of the present project proposal is the construction of three different "knock-in" mouse strains, which carry chimaeric IgE/IgG1 antigen receptors. We expect, differences in the polyadenylation pattern of the membrane transcripts compared to the wildtype, resulting in dramatic differences between the serum IgE levels. In contrast to mIgG1 cells, mIgE B cells, due to their low number, are hardly to detect. If, additionally to the transcriptional up- regulation, class specific factors are involved in that tight regulation, the introduction of the IgG1 tail could lead to an increased number of IgE memory B cells and plasma cells. In summary, we want to focus on the regulatory function of the mIgE antigen receptor on the quantity of serum IgE expression. By constructing mouse lines, expressing IgE antigen receptors chimaeric for their transmembrane and cytoplasmic tails, we can not only investigate the post-transcriptional processing of the transcript coding for the membrane form of IgE, but also study the influence of the signal transduction on the later recruitment of IgE secreting plasmacells. The quantity of IgE produced becomes more and more interesting, because the signals generated by the cytoplasmic tail may be an important target 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.