Patients with lupus develop extremely high levels of autoantibodies to self-antigens ribonucleoproteins and DNA. It is unclear how the B cells producing these autoantibodies escape self-tolerance. Lymphoid neogenesis, the formation of ectopic lymphoid tissue in response to inflammation, is associated with autoantibody production in many situations. We have shown that intraperitoneal exposure of non- autoimmune-prone mice such as BALB/c to tetramethylpentadecane (TMPD) causes lymphoid neogenesis tissue and lupus-like autoimmune disease. Within the ectopic lymphoid tissue induced by TMPD are CD11c+, CD86+ dendritic cells producing large amounts of Type I interferon (IFN-I). In contrast, ectopic lymphoid tissue generated in response to mineral oil contains little IFN-I and does not cause lupus. We hypothesize that autoreactive B cells arise with increased frequency and/or have a survival advantage in ectopic lymphoid tissue and that interfering with lymphoid neogenesis may prevent autoimmunity. Furthermore, we hypothesize that the production of IFN-I in tertiary lymphoid tissue is a co-factor in lupus. Three Specific Aims are proposed. Aim 1 is to examine the role of IFN-I in the pathogenesis of TMPD- induced lupus by determining the susceptibility of interferon receptor deficient and other mutant mice. Conversely, blockade of IFN-I signaling will be evaluated as a means of preventing/treating lupus. Aim 2 is to determine if germinal center-like reactions occur in ectopic lymphoid tissue by studying the T cell and B cell responses to the exogenous antigen NP-KLH. Aim 3 is to examine the role of ectopic lymphoid tissue in the generation of lupus autoantibodies. Of particular interest is the possibility that autoantibodies arise preferentially in the ectopic lymphoid tissue due to less efficient censoring during the course of germinal center-like reactions or due to the local production of IFN-I. The cells responsive to IFN-I will be identified and the possibility that therapeutic intervention to inhibit lymphoid neogenesis might prevent lupus will be investigated. As we have found virtually identical abnormalities in SLE patients and mice with TMPD- induced lupus, the information gained from these studies may provide insight into the immune pathways involved in SLE as well as suggesting new therapeutic approaches. In addition, what we learn here may have wider applicability to the many other autoimmune diseases associated with lymphoid neogenesis. [unreadable] [unreadable] [unreadable]