Elkon, Keith

Dr. Elkon's research objective is to better define the molecular and genetic basis for autoimmune diseases such as lupus and arthritis. Current areas of investigation include the following:

Apoptosis and the Immune Response – especially as it relates to lupus (SLE). Loss of tolerance leads to autoantibody production in systemic autoimmune disorders. 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 recently identified novel pathways that involve opsonization of dying cells by serum factors (complement, CRP and natural antibodies) thereby promoting the phagocytosis of apoptotic cells. The 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 the how self antigens (e.g. nucleoprotein particles such as nucleosomes, spliceosomes and ribosomes) 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. This research is applied to human lupus, especially neuropsychiatric disease as well as to murine models. In mouse lupus, attempts are being made to prevent TLR activation of IFN-a by nucleoprotein containing immune complexes.

Cytokine Regulation of Arthritis. Despite the powerful inflammatory effect of cytokines such as tumor necrosis factor (TNF)-a produced by the innate immune system, abundant evidence indicates that T cells are required for initiation and/or chronicity in both human rheumatoid arthritis (RA) and its mouse models. Interleukin (IL)-17 has emerged as a critical T cell cytokine in the pathogenesis of human RA and collagen induced arthritis in mice. IL-17 itself, is positively regulated by TGF-B and IL-6 and negatively regulated by IFN-g, IL-4 and IL-27. Current studies explore the mechanisms responsible for cytokine stimulation, the regulation of Th17 cells as well as therapeutic modalities to alter the cytokine milieu.