1991. that happen within several mere seconds of antigen binding. With the introduction of fresh live-cell imaging systems we are getting our first obvious views of the events that lead up to the triggering of BCR signaling cascades. These events may provide potential fresh targets D77 for restorative treatment in disease including hyper or chronic D77 activation of B cells. Specific, high-affinity antibody reactions are the result of processes based on clonal D77 selection (examined in Rajewsky 1996). In the absence of antigen, individuals generate a B-cell repertoire in which each B cell expresses a single weighty and light chain gene, the product of somatic recombination of variable and constant region gene segments. Self-reactive B cells are removed from the repertoire and when antigen enters the Kit immune system it selects those B cells expressing BCRs with highest affinity for the antigen. Under the influence of both T cell and innate immune system rules the antigen-selected B cells are induced to differentiate into short-lived antibody generating cells or enter germinal centers where they undergo the molecularly linked processes of somatic hypermutation and isotype switching. Antigen selection within the germinal centers results in high-affinity memory space B cells expressing isotype switched BCRs. These memory space B cells account, in large part, for the high titered, high affinity IgG antibody reactions observed upon re-exposure to antigen. Therefore, we presume that B cells are capable of initiating responses to the universe of foreign antigens to which individuals are revealed and do so through mechanisms that are sensitive to the affinity of the BCR for antigen and by which isotype switched BCRs are more effective. Until recently, the events by which the binding of antigen to the BCRs induced signaling remained mainly unknown due in a large part to the paucity of experimental methods that were capable to provide the spatial and temporal resolution necessary to capture the earliest events that follow the binding of antigens to BCRs that result in triggering the B cells signaling cascades. The conventional biochemical techniques that were used so successfully to describe the components of the BCR signaling cascades were too slow to study early events and could not provide spatial info. The application of fresh live-cell imaging systems that allow resolution of single molecules over a timeframe of several seconds to the study of antigen-induced B-cell reactions is providing the first views of these processes. Here we review progress in understanding the initiation of the BCR signaling using live-cell imaging systems and how this fresh knowledge may clarify in part the mechanisms that underlie hyper or chronic activation of B cells in autoimmunity and in B-cell cancers. THE WHO, HOW, AND WHERE OF ANTIGEN Demonstration TO B CELLS (BATISTA AND HARWOOD 2009) The reactions of B cells to antigens were traditionally studied by providing B cells with multivalent soluble antigens in answer. Batista et al. (Batista et al. 2001) 1st made the important observation that B cells could be efficiently activated by antigen expressed by antigen showing cells (APCs). They showed that the connection of B cells with APCs lead to the formation of a polarized bulls vision like structure in which the BCRs were concentrated in the center, surrounded from the adherence molecule LFA-1. This structure was analogous to the immune synapse earlier explained for T cells following relationships with APCs (Fooksman et al. 2010). The description of the B-cell immune synapse by Batista et alwas followed by several studies that used intravital imaging to describe the connection of B cells with APCs in lymph nodes in vivo. These studies provided evidence that small soluble antigens are able to enter follicles and activate B cells.