B cells that produce self reactive antibodies are normally deleted centrally or silenced in the periphery. However auto-antibody production is a characteristic pathologic feature of a number of autoimmune disorders. Elegant studies with transgenic mice have demonstrated that deletion of auto-reactive B cells in the bone marrow and peripheral silencing are triggered by antigen receptor engagement. But despite the central role of the antigen receptor in the induction of tolerance to self antigens little is known about the mechanism by which this receptor regulates clonal anergy and clonal deletion. Progress in this area has been hindered in part by the complex multisubunit structure of the B cell antigen receptor. Membrane immunoglobulins are composed of a clonotypic receptor and two other polypeptides, Igalpha and Igbeta. We, and others, have shown that in addition to a transport function Igalpha and Igbeta also serve as the signal transducers for the B cell antigen receptor. The signaling activity has been localized to cytoplasmic domains of Igalpha and Igbeta which had distinct functions in mature B cell lines. Although our tissue culture experiments have helped to define the structural features of the immunoglobulin receptor required for signaling in mature B cells, they do not address the problem of antigen receptor function in deletion and anergy. The long-range goal of the proposed research is to elucidate the molecular requirements for producing the signals that result in anergy and clonal deletion in B cells. The working hypothesis is that the signals that result in deletion and anergy are delivered by either Igalpha or Igbeta or both. The first part of the proposed project will be to establish whether Igalpha and Igbeta are involved in producing the signals that lead to tolerance in vivo. For this purpose we will produce lines of transgenic mice that carry auto-reactive immunoglobulins with specific mutations that have been shown to prevent the association of immunoglobulin with Igalpha and Igbeta. In the second part of the project we will explore how individual B cell receptor components induce tolerance. Finally the role of tyrosine phosphorylation as well as individual tyrosine kinases in deletion and tolerance will be examined. These studies have significant implications for understanding how auto- antigens can trigger the B cell receptor to produce tolerance, and together with other components of the proposed program will identify new pathways to tolerizing B and T cells.
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