Evidence from experimental models indicate that defects in programmed cell death, or apoptosis of lymphocytes can contribute to autoimmunity by interfering with normal lymphoid death pathways. Recent studies from our laboratory suggest that bcl-x, a member of the bcl-2 family of apoptosis regulatory genes, provides important life signals for lymphocytes. Bcl-x mRNA and protein expression are induced following crosslinking of the CD4O receptor on B cells or mitogen activation of both T and B lymphocytes. Furthermore, overexpressed bcl-x protects an immature B lymphocyte cell line from apoptosis triggered by crosslinking of surface immunoglobulin M (IgM) in a model for negative selection of B cells. In this study we propose to directly examine the role of bcl-x in mediating an autoimmune phenotype, and to explore the influence of bcl-x in negative selection, tolerance induction, and somatic mutation of B cells.
Our specific aims are to: l). Generate two lines of B cell transgenic mice, one expressing the Long isoform (bcl-xL), a life protein, and the other expressing Short (bcl-xS), a death protein. The influence of dysreguIated bcl-xL expression on the development and activation of B cells will be studied, with the prediction that these mice will be predisposed to autoimmunity and/or lymphoma. In contrast, mice transgenic for bcl-xS within the B lineage may have impaired development or diminished B cell immune responses. 2). The influence of bcl-xL on anergy induction and negative selection will be examined in the hen egg lysozyme model system for B cell tolerance, and the role for bcl-xL on somatic mutation within germinal centers will be assessed. 3). Finally, bcl-xL and bcl-xS B cell transgenic mice will be backcrossed onto the NZW genetic background. Congenic bcl-x/NZW mice will be bred with NZB mice, and the resulting BWF1 females will be examined to test whether the transgenes accelerate (Long) or abrogate (Short) disease onset and severity in this model for systemic lupus. New insights into the pathophysiology of systemic autoimmune disease are required if we are to make significant improvements in treatment of our patients with autoimmunity. The proposed experiments will test the straightforward hypothesis that dysregulation of the death repressor gene bcl-x in B cells can lead to autoimmune disease. These experiments are likely to improve our understanding of the role of bcl-x as an antidote to death in the immune system. Furthermore, these studies may suggest gene therapy approaches to treat autoimmunity by targeting apoptotic pathways in B lymphocytes.
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