Interferon and the Toll Hypothesis in Systemic Autoimmune Disease

Keith Elkon, M.D.

University of Washington

Funded in December, 2006: $600000 for 3 years


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Exploring a Common Immunological Pathway in Systemic Autoimmune Diseases

This consortium will explore whether a common process occurs in systemic autoimmune diseases that produces a cyclical pattern of inflammation and attack by the body's immune system against the body's own tissues.

Systemic autoimmune diseases include Lupus (which affects multiple organs), Polymyositis (which affects muscles), and Scleroderma (affecting the skin). Although these diseases have different clinical features, they share several similarities. All involve immune attacks by antibodies (called autoantibodies), which mistake specific proteins and nucleic acids derived from the body's own cells as foreign. All three diseases also involve activation of an immune system protein, called interferon-alpha (IFN-α, or interferon), which initiates inflammation. The researchers hypothesize that autoantibodies binding to self antigens may be responsible for inducing interferon and the resultant inflammatory response in all three of these diseases. This process involves the interaction between innate immune cells, called dendritic cells (DCs) and certain “receptors” within cells, called Toll-like receptors.

Ordinarily, DCs trigger these receptors to stimulate the production of interferon in response to foreign microbes, such as bacteria or viruses. In systemic autoimmune diseases, the researchers suggest, the process works differently. Specific errant antibodies and their cellular targets (“antigens”) trigger interferon production from a type of DC, called “plasmacytoid” DCs. Then, the interferon that is produced works on another type of DC, which presents these antigens from dying cells to other immune cells, perpetuating the autoimmune response. The Uppsala researchers will explore this hypothesis in laboratory tests of patients' samples, while the University of Washington investigators will study patients' samples to address a related hypothesis. This hypothesis suggests that, in each of these diseases, the way in which the mistakenly attacked cells die dictates whether or not interferon is stimulated again to perpetuate this cycle.

Significance: By determining how interferon is activated in these systemic autoimmune diseases, the findings could lead to development of improved therapies that block this activation.


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Interferon and the Toll Hypothesis in Systemic Autoimmune Disease

Systemic autoimmune disorders (SAD) such as Systemic Lupus Erythematosus (SLE), Scleroderma (SSc) and Polymyositis (PM) appear to be distinct clinical and pathologic entities. The pathogenesis of these diseases remains poorly defined. Nevertheless, SAD have overlapping clinical features and all are characterized by the presence of autoantibodies to deoxyribo- or ribo- nucleoproteins (DNP and RNP respectively), suggesting some similarities in mechanisms of loss of tolerance / immune response. Here we propose 2 hypotheses: (1) Systemic autoimmune disorders share the property of IFN-α induction through activation of intracellular TLRs by immune complexes containing nucleic acids (2) The mode of cell death and availability of antigen determine the ability of the immune complex to stimulate IFN-α.

In Aim 1, we will define the identities of the antigens that trigger IFN-α in the 3 SAD. We will isolate purified antigens and antibodies and determine whether the interferogenic (IFG) activity can be explained by unique modifications or other biochemical properties of the nucleic acids. The possibility that some cells such as macrophages provide inhibitory action on IFN-α production will also be investigated.

In Aim 2, we will examine how different modes of cell death influence IFG activity. Cell lines and activated lymphocytes will be induced to undergo apoptosis and necrosis by a variety of methods and release of IFG nucleoproteins monitored.

Successful completion of this proposal will elucidate whether IFN-α activation is a common property of SAD or promotes certain clinical features. In addition, it will lead to the identity and nature of the antigens that stimulate IFN and define what forms of cell death generate these antigens.


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Keith Elkon, M.D.

Keith Elkon, M.D., received his medical degree from the University of Witwatersrand in 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 the University of Washington in August, 2001 and has an adjunct appointment in the Department of Immunology at the university. Dr. Elkon's research objective is to better define the molecular and genetic basis for autoimmune diseases such as lupus and arthritis. The major focus of current research is on the innate and adaptive immune response to apoptotic cells and how abnormalities in apoptosis, or handling of dead and dying cells, leads to autoimmune diseases.

Lars Rönnblom, M.D. received his medical degree from Uppsala University, Sweden, in 1980 and a Ph.D. in immunology in 1983. He is specialist in rheumatology and internal medicine and serves as a consultant in rheumatology at Uppsala University Hospital where he is responsible for the Lupus clinic. He is Professor of Rheumatology at the Department of Medical Sciences, Uppsala University, and member of the American College of Rheumatology. He was formerly vice-president of the Swedish Society of Rheumatology.

Dr. Rönnblom's research concerns both clinical and experimental aspects of the human immune system. He has studied the type I interferon system for more than 20 years and his research group has made several pioneering observations concerning the mechanisms behind the ongoing interferon production in lupus patients. Current research interest is the genetic background to the activated type I interferon system in lupus patients, new therapeutic targets within this system and the role of type I interferon in systemic autoimmune diseases.


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Kim D., Peck A., Santer D., Patole P., Schwartz S.M., Molitor J.A., Arnett F.C., and Elkon K.B.   Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis.  Arthritis Rheum. 2008 Jul;58(7):2163-73.

Duan H., Fleming J., Pritchard D.K., Amon L.M., Xue J., Arnett H.A., Chen G., Breen P., Buckner J.H., Molitor J.A., Elkon K.B., and Schwartz S.M.  Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma.  Arthritis Rheum. 2008 May;58(5):1465-74.