A central and essential feature of the immune system is its ability to distinguish and """"""""tolerate"""""""" self anitgens while responding to and eliminating foreign antigens. One of the mechanisms by which this discriminatory capability is generated appears to be by tolerance induction and thus functional deletion of individual antigen specific lymphocytes. We wish to further our understanding of signal discrimination by lymphocytes, and to this end propose to study the molecular basis of antigen driven B lymphocyte activation, tolerance induction and antiidiotypic antibody mediated suppression. In view of the roles of cell surface IgM and IgD as antigen receptors, and Ia as a restriction marker, we will examine changes in their expression during these processes. In addition, we will define changes in membrane potential, and levels of intracellular calcium, calmodulin and calmodulin binding proteins during tolerance induction, suppression and transition of Go B cells into G1 in response to immunogen. We propose to examine these parameters in particular because of findings which suggest a second messenger role for calcium in lymphocyte activation. We will attempt to determine to what extent each of the changes and events defined correlates with a commitment to and/or is causally related to entry into G1, proliferation and differentiation into antibody secreting cells. These studies will be conducted using isolated antigen binding cells in combination with in vitro immune induction and flow cytometric assays for marker expression, membrane potential, intracellular free calcium, and cell cycle state. Biochemical assays for calmodulin and calmodulin binding proteins will be used. These studies should provide valuable information regarding mechanisms of signal discrimination by B lymphocytes.
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