DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic life-threatening autoimmune disorder that currently afflicts up to 2,000,000 individuals within the United States each year. Therapeutic options for treating patients with SLE include agents such as steroids, cytotoxic drugs, and anti-malarials. Although these therapies can reduce disease severity, they often have deleterious side effects that limit their extended use. A better understanding of the factors that trigger disease onset could facilitate the development of drugs that specifically target the autoreactive effector cells without the debilitating side effects and general immunosuppression associated with curent treatment protocols. This proposal is based on recent studies that identify a novel pathway involved in the activation of both autoreactive B cells and (auto)antigen presenting dendritic cells. Our group has shown that chromatin-containing immune complexes (chromatin- IC), bound by either the BCR or an FcgammaR, are delivered to an internal compartment where they activate the cells via a MyD88-dependent Toll-like receptor 9 (TLR9) pathway. Thus, inhibition of the TLR9 pathway may specifically block the development and/or progression of systemic autoimmune disease without interfering with immune responses to foreign proteins. To take advantage of this potential therapeutic opportunity, it will be necessary to further delineate the mechanism and general applicability of this dual receptor paradigm. The goal can best be met by combining the research endeavors of program investigators with diverse research backgrounds - B cell regulation (Marshak-Rothstein), antigen uptake and vesicle trafficking (Corley), chromatin remodeling (Viglianti), dendritic cell activation (Rifkin), and transgenic models of autoimmune disease (Shlomchik) - to address the following questions: (a) What are the unique functional consequences of chromatin-IC engagement of B cells and dendritic cells (project 1 and 2)? (b) What aspects of chromatin structure determine immunogenicity in this system (project 1)? (c) How are chromatin-IC processed and how does TLR9 affect the persistence and site of these events (project 1)?; (d) Do TLR other than TLR9 mediate responses to non-chromatin associated autoantigens (project 2, 3,)? (e) What is the in vivo role of TLRs in systemic autoimmunity (project 3)? and finally (f) Can this pathway be specifically targeted therapeutically with agents that block the TLR9 signaling pathway (project 1,2)? The results of these studies should provide important insights that will facilitate the development of non-invasive therapies for the treatment of systemic autoimmune diseases such as SLE.