Dr. Keith Elkon's research objective is to better define the molecular and genetic basis for autoimmune diseases such as lupus and arthritis.
Apoptosis and the Immune Response
Loss of tolerance leads to autoantibody production in systemic autoimmune disorders such as systemic lupus erythematosus (SLE). There is considerable evidence to support the concept that autoantibodies are generated in response to impaired clearance of dead and dying cells.
Dr. Elkon's laboratory has identified novel pathways that involve opsonization of dying cells by serum factors (complement, CRP and natural antibodies) thereby promoting the phagocytosis of apoptotic cells. One hypothesis currently being explored is that deficiencies of these serum opsonins leads to delayed clearance of dying cells sequentially facilitating necrosis, an inflammatory response to self antigens and loss of tolerance. Current studies explore how self antigens (e.g. nucleoprotein particles such as nucleosomes, spliceosomes and ribosomes) are processed and activate the innate immune system, especially plasmacytoid dendritic cells (pDCs) to induce IFN-a. In addition, the molecular signals whereby apoptotic cells turn off inflammatory cytokines such as IL-12 in DCs and anergize T cells under homeostatic conditions, are also being investigated.
Removal of inflammatory nucleoprotein complexes
A related line of investigation explores how the debris derived from apoptotic cells, nucleoprotein particles, can be rendered less immunogenic. The research involves the creation of transgenic mice expressing "cleanup: molecules as well as biologics that have nuclease activity and that can be administered exogenously.
Neuropsychiatric Lupus (NPSLE)
The pathogenesis of NPSLE is poorly understood. This laboratory has had a longstanding interest in NPSLE. We are currently examining the role of type 1 interferons in the induction of certain clinical manifestations of NPSLE. Regulation of inflammation by serologic factors is also under investigation.