The production of pathogenic autoantibodies is the cause of a number of autoimmune diseases. However, the cellular and molecular mechanisms underlying the production of pathogenic autoantibodies is incompletely understood. The purpose of the proposed research program is to develop a better understanding of the mechanisms underlying the generation of autoantibodies. These projects are designed to understand the mechanisms controlling generation of the repertoire, selection of the repertoire by peripheral stimuli, immunoglobulin class switching to IgG antibodies with higher pathogenic significance, and the regulation of the production of autoantibodies by these molecular processes in transgenic animals expressing human immunoglobulin genes. These projects interrelate in that each focuses on an important aspect of the development of pathogenic autoantibodies and their role in disease pathogenesis. The first project, of which Dr. Peter Lipsky is the principal investigator, will examine a potential role of superantigens in biasing the B cell repertoire toward autoantibody formation. The second project, of which Dr. J. Donald Capra is the principal investigator, will utilize transgenic mice expressing a human Ig heavy chain minilocus to determine the influence of an autoimmune background on production of autoantibodies encoded by the human genes. In the third project, Dr. Katheryn Meek will examine mechanisms of immunoglobulin class switching, especially those driven by members of the CD40 ligand family of interaction molecules. Finally, mechanisms of repertoire generation and particularly induction of expression of Vh genes thought to encode autoantibodies will be examined in project 4, with Dr. Philip Tucker as the principal investigator. It is anticipated that as a result of the proposed work, comprehensive new insights into the mechanisms of autoimmunity will arise that should provide approaches to therapeutic interventions in the future.
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