SIGNAL TRANSDUCTION BY IGM IN B LYMPHOCYTES

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DESCRIPTION (Adapted from Investigator's abstract): B cell antigen receptors (BCR) regulate many different physiologically important processes in the antibody system. These physiologic responses can be divided into two categories, those which are antigen independent and those which are induced by antigen. During the first funding period for this grant we have defined essential interactions between mIgM and the Iga-Igb signal transducers. This information was then used to show that the antigen independent events include several distinct transitions that are regulated by membrane immunoglobulin (mIgm) through the Iga-Igb signal transducers. Although it is understood how binding to antigen might crosslink mIgM and activate Iga-Igb signal transducers, the molecular mechanisms by which mIgM is triggered to induce antigen independent events remain to be elucidated. Progress in understanding how antigen independent events are activated has been hindered by a lack of understanding of the nature of the crosslinker, the structural features of the BCR that are recognized, and whether the nascent mIgM needs to be expressed on the cell surface to trigger these responses. The long range goal of the proposed research is to elucidate the molecular mechanisms that activate allelic exclusion and the pre-B cell transition. The first part of the project will examine the structural features of Iga and Igb required for B cell development and B cell responses to antigen. The second part of the project will be to try to determine the cellular and molecular requirements for mIgM signaling in developing B cells. The third part of the project will aim to try to define the relationship between mIgM expression and allelic exclusion. These studies have potential implications for understanding how B cells develop and produce immune responses in vivo.