The goal of this program is to understand the regulation and disregulation of the immune system in autoimmunity. The program involves collaborative interactions between members of three Departments, and is organized into four projects supported by three Core facilities. Expertise in the field of immunology, molecular biology, and biochemistry will focus on the events that initiate and sustain autoimmune responses, and the regulatory processes which contain autoimmunity. We will address the following questions? What are the requirements to initiate autoimmune responses? Are autoimmune responses regulated, and if so, by what mechanisms? Does immune regulation contain autoimmune responses under normal circumstances? Finally, do sustained autoimmune responses remain chronic because they diversify from a single initiating response to responses to other autoantigens from the same tissue? These questions will be addressed by collaborative interactions between the Principal Investigators of these projects, which are as follows: (1) R.A. Flavell, PI - Using transgenic mice expressing SV40-T antigen in the acinar pancreas, and T cell receptor transgenic mice which recognize antigen, mechanisms that lead to autoimmunity in this system will be determined, as well as mechanisms which regulate that autoimmune response. The role of diversification of the immune response from SV40-T antigen to other acinar antigens will be investigated. (2) C. A. Janeway, Jr. PI - This project will test the hypothesis that regulation of autoimmune T cells can prevent a monoclonal T cell attack on tissues, but cannot contain a polyclonal attack. It will also test the hypothesis that the autoimmune T cells response diversifies through the action of autoreactive B cells that recruit T cells of novel specificities to the response. Finally, it will characterize the interplay between regulation and diversification in generating autoimmunity. (3) M. J. Shlomchik, PI - Transgenic mouse models will be used to study the regulation of B cells expressing a disease-related autoantibody, rheumatoid factor (RF), in normal and autoimmune mice. In contrast to some other autoantibody models, RF B cells from the first series of transgenics appear competent to initiate an immune response. Thus, studies will focus on why RF B cell escape tolerance and what prevents chronic autoimmunity in RF transgenic mice. (4) M. J. Mamula, PI - This project will examine the role of self peptides in the initiation and perpetuation of both B and T cell autoimmunity in models of systemic lupus erythematosus (SLE). Autoreactive T cells will be investigated for their fine specificity to SLE autoantigens in spontaneous and antigen-induced autoimmunity. Finally, we will study how autoimmunity may diversify from a single initiating determinant to other sites on autoantigens; a mechanism that may exacerbate lupus autoimmunity. These four projects will be supported by a genetically modified mouse core to provide gene targeted and transgenic rodents essential to most of these studies, and a FACS core, to allow us to separate cells for analysis and to analyze cells in all of these projects. The program is coordinated by frequent meetings of the program facility bringing together these diverse approaches to address a common goal.