Microparticles as a Source of Nuclear Antigens in Systemic Lupus Erythematosus

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DESCRIPTION (provided by applicant): The goal of these investigations is to elucidate the role of microparticles (MPs) as a key source of nuclear antigens in systemic lupus erythematosus (SLE) and characterize these structures as components of pathogenic immune complexes (ICs). MPs are small membrane-structures that are released from cells during cell activation or death. These particles contain DNA and RNA in a form that is protected from extracellular nucleases and allows binding of antinuclear antibodies (ANAs). As such, MPs may form immune complexes that can either deposit in the tissue or promote cytokine production including interferon- 1 (IFN). Because of the value of assessing MPs as target antigens in SLE and their effector function, we are proposing studies to address fundamental questions concerning the nature of ANA binding to MPs and their immunological effects. Three specific aims are proposed: 1) To analyze the binding of antinuclear antibodies to MPs generated in in vitro and in vivo model systems as well as those circulating in patient blood. The MPs in patient blood will be analyzed for binding to a panel of monoclonal anti-DNA and anti- nucleosome antibodies; 2) To analyze the expression of MPs in the blood of patients with SLE, focusing on particles with bound antibody, and determine the relationship to clinical manifestations and disease activity. Using plasma from lupus patients, circulating MPs will be quantified by flow cytometry in terms of cell surface markers, including bound Ig. The number and properties of MPs will be related to disease activity and organ-specific manifestations. Sera of patients with SLE will also be screened for binding to the in vitro-generated particles; and 3) To investigate the effects of ANAs on the immunological activities of microparticles in in vitro systems. The immunological effects of MPs on cytokine production by macrophage cell lines and peripheral blood cells will be assessed in vitro, characterizing effects of monoclonal ANA as well as IgG purified by patient sera. Together, these experiments will provide important new information on a novel group of subcellular signaling structures relevant to the pathogenesis of SLE as well as the development of novel biomarkers and new therapies. PUBLIC HEALTH RELEVANCE: These studies will focus on the role of microparticles in systemic lupus erythematosus (SLE), a prototypic autoimmune disease characterized by inflammation and damage of multiple organ systems. An important mechanism of this disease concerns the formation and deposition of immune complexes that contain nucleic acids. In these studies, we will explore the role of cellular microparticles as a source of this nucleic acid. Understanding the role of microparticles in the immune complex disease will provide information to allow the development of new treatments as well as markers to assess the course of SLE and its renal and vascular complications.