Elegant studies of central T and B cell tolerance have been performed, leading to the identification of multiple mechanisms that remove or silence autoreactive cells during their maturation, but also reminding us that some autoreactive cells do mature to immunocompetence in all individuals. Furthermore, studies of the B cell response to antigen have clearly demonstrated that autoreactivity can arise de novo in antigen-activated cells, which also requires silencing. Finally, it has now been established in studies of multiple autoimmune diseases that a critical checkpoint exists between autoreactivity and tissue injury, one of the issues about which we remain most ignorant. Understanding peripheral mechanisms for maintaining self-tolerance offers promise for better therapies for autoimmune disease. The proper implementation of this new knowledge requires an understanding of similarities and differences between animal models and human disease. Specific Issues: Translating results from studies of animal models to human studies Peripheral and central tolerance T cells and B cells The relationship between autoimmunity and immunodeficiency The role of dendritic cells in autoimmunity What dictates generation of autoreactive antibody in one individual and not in another? How much autoreactivity must occur in order to progress to disease and what governs this? What exactly is "pathogenic autoreactivity", i.e, are all investigators talking about the same thing? How much of pathogenesis is due to autoreacting antibodies per se versus the tissue`s response to antibody? What role is innate immunity playing in all of this?
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