The study of tolerance to self-antigen in B-cells is of the utmost importance to understand how the immune system is regulated in health and disease. Unfortunately, the study of human B-cell tolerance has been hampered by the inability of investigators to identify an abundant population of autoreactive B-cells with homogenous antigenic reactivity and surface markers. We have identified such a population (termed VH4- 34 cells) and over the last three years we have validated the use of these cells for the study of human B-cell tolerance. ? ? VH4-34 cells recognize glycolipid autoantigens widely expressed in the surface of multiple cell types as well as microbial glycolipid antigens and probably play a homeostatic role in host defense by connecting the innate and adaptive immune systems. In healthy individuals, VH4-34 cells are prevented from inducing autoimmunity by positive selection into the marginal zone of the spleen and negative selection form the germinal centers. The latter mechanism prevents VH4-34 cells from expanding into the long-lived postgerminal center memory and plasma cell compartments thereby inhibiting the production of significant amounts of pathogenic autoantibodies. ? ? In this application we propose to study the phenotypic and functional properties of VH4-34 cells in healthy individuals and to compare them to VH4-34 cells obtained with patients with Systemic Lupus Erythematosus (SLE) in whom B-cell tolerance is defective. This will be accomplished by using multiparameter flow cytometry and immunocytochemistry. Furthermore, we will analyze the signaling processes responsible for the biological responses observed with VH4.34 cells and again determine how signaling differs in patients with SLE. Finally, we will ascertain what type of T-cells regulate the behavior of VH4-34 cells both in healthy subjects and SLE patients. ? ? The studies proposed herein should yield important insights into the regulation of autoimmunity and the pathogenesis of autoimmune diseases such as SLE. Furthermore, we believe that our results will improve our ability to treat patients with SLE and similar diseases. ? ?
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