Following stimulation with antigen or polyclonal mitogen, resting human B lymphocytes become activated, proliferate, and sequently differentiate into antibody secreting cells. This sequence can be delineated by a series of morphologic, metabolic, molecular, and cell surface antigenic events. The focus of this proposal is to study the cellular expression and function of those cell surface structures which are not expressed on the resting B cell but appear with activation. These activation antigens (ActAgs) are excellent candidates for receptors for growth or differentiation factors, molecules involved in localization in microenvironments, or molecules involved in cell-cell interaction.
The aims of the present proposal are: 1) to identify and characterize distinct populations of human B lymphocytes expressing B cell ActAgs with attention to the stimuli that induce them, 2) to attempt to identify the functions of B cell ActAgs by studying their biochemical and molecular structures as well as studying the effects of MoAbs directed against ActAgs on proliferation, differentiation, and cell-cell interaction, and 3) to attempt to develop new MoAbs to ActAgs. To achieve these aims, activated B cell populations will be induced in vitro, isolated from normal lymphoid tissues, and isolated from patients with diseases characterized by activated B lymphocytes. The expression of activation antigens on these populations will be extensively studied and the major activated subpopulations of human B lymphocyte identified. These activated B cell populations will be isolated, phenotypically characterized, and analyzed for their response to growth and differentiation factors. B cell ActAgs will be structurally characterized by standard techniques and their genes will be cloned. MoAbs to ActAgs will be added to in vitro systems to determine whether they induce proliferation or differentiation, block cytokine induced proliferation or differentiation, or inhibit cell-cell association. New MoAbs to B cell ActAgs will be developed in an attempt to define new functionally important molecules. Activated B cells are involved in the pathogenesis of the majority of autoimmune diseases, graft rejection, allergy, and immunity to infection. This study hopes to provide a strong foundation with which to study the etiology and pathophysiology of these diseases.
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