Keith Elkon, M.D.
Professor, Medicine and Head, Division of Rheumatology
Adjunct Professor, Immunology

Department of Medicine
University of Washington
Box 356428
1959 NE Pacific, BB-561 Health Sciences
Seattle, WA 98195-6428
Phone: 206.543-3414
Fax: 206.685-9397
email: elkon@u.washington.edu

Elkon Lab Members

Dr. Elkon received his medical degree from the University of Witwatersrand, Johannesburg South Africa in 1974 and membership to the Royal College of Physicians (MRCP) in 1978. He received postdoctoral training at the Hammersmith Hospital, London and at the Weill Medical College of Cornell University, New York. Dr. Elkon was formerly Director of the Graduate Program in Immunology and Professor of Medicine at Cornell. He was appointed as Head, Division of Rheumatology, at UW in August, 2001.

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. 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.

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.

Students currently training in the Elkon lab: Deanna Santer

Recent publications:

Di Cristofano A, Kotsi P, Peng YP, Cordon-Cardo C, Elkon KB, Pandolfi PP. Impaired Fas response and autoimmunity in Pten (+/-) mice. Science, 285:2122-2125, 1999.

Gershov D, Kim S-J, Brot N, Elkon KB. C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components and sustains an anti-inflammatory innate immune response: implications for systemic autoimmunity, J Exp Med, 192: 1353-1363, 2000.

Kim S-J, Gershov D, Brot N, Elkon KB. I-PLA2 activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural IgM antibodies and complement activation. J Exp Med, 196: 655-665, 2002.

Layer K, Lin G, Wei H, Schmucker A, Antov A, Li X, Takamatsu S, Chevassut T, Dower NA, Stang SL, Beier D, Buhlmann J, Bronson RT, Elkon KB, Stone JC, Lim B. A spontaneous mutation in RasGRP1 uncovers an essential role for Ras signaling in the maintenance of T cell tolerance. Immunity, 19: 243-255, 2003.

Philpott NJ, Nociari M, Elkon KB Falck-Pedersen, E. Adenovirus-induced maturation of dendritic cells through a tumor necrosis factor-a induction pathway mediated by phosphoinositide-3-OH kinase. Proc Natl Acad Sci, 101, 6200-6205, 2004.

Kim SJ, Elkon KB, Ma X. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 2004;21:643-53.

Martin, D.A., and K.B. Elkon. 2005. Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity. J Exp Med 202:1465-1469, 2005.

Martin, D.A., Elkon, KB. Intracellular mammalian DNA stimulates myeloid dendritic cells to produce Type I interferons independently of MyD88 or TLR9. Arthritis Rheum, 54:951-962., 2006.

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Updated 4/2/07