Keith

Elkon

MD

Education & Training: 

M.B., B.Ch. (M.D. equivalent), University of the Witwatersrand, Johannesburg, South Africa (1974)

Residency, Hammersmith Hospital and Guy's Hospital, London, UK

Fellowship, Weill Medical College, Cornell University, Ithaca, NY

Research Interests: 

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 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. 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) are processed and activate the innate immune system, especially plasmacytoid dendritic cells (pDCs) to induce IFN-a. In addition, apoptotic cell processing and the downstream molecular signals in DCs that lead to anergy or T cell activation are 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 can be administered exogenously. 

 

Type I interferons are the major inflammatory proteins made by the innate immune system following virus infections. Surprisingly overexpression of type I interferon is very prominent feature observed in about three quarters of Lupus (SLE) patients as well as in related autoimmune diseases such as scleroderma, polymyositis and primary Sjogren’s syndrome. There is also some suggestion that this pathway may be implicated in organ specific autoimmune diseases such as Type 1 Diabetes and some cases of rheumatoid arthritis. Nucleic acids from dying cells are strongly implicated in stimulating interferon in autoimmune diseases. 

 

Major Goals of Research

 

The two major goals of Dr. Elkon’s research are to understand the abnormalities in the innate immune system responsible for initiating the autoimmune diseases such as lupus and to use this knowledge to design new forms of therapy that could work on the earliest stages of disease to prevent severe inflammation.

Current research projects address the following questions:

• What are the cell death abnormalities that provoke an immune response?
• How does the cell debris released from dying cells stimulate inflammation - especially the type 1 interferon response?
• Which interferon pathways are specifically abnormal in lupus and related autoimmune disorders?
• Can environmental triggers such as sunlight be used to uncover differences in the interferon response in lupus versus controls?
• How can rheumatologists develop therapeutics to abrogate early activation of interferon pathways?

PubMed: 

PubMed Bibliography

Publications: 

Selected-

Elkon KB. Cell Death, Nucleic Acids and Immunity: Inflammation beyond the Grave. Arthritis Rheumatol, 70:805-816, 2018. PMID: 29781188.

An J, Woodward JJ, Lai W, Minie M, Sun X, Tanaka L, Snyder JM, Sasaki T, Elkon KB. A novel anti-malarial drug derivative inhibits cyclic GMP-AMP synthase in Trex1 deficient mice. Arthritis Rheumatol, 70:1807-1819, 2018. PMID: 29781188

Akilesh HM, Buechler MB, Duggan JM, Hahn WO, Matta B, Sun X, Gessay G, Whalen E, Mason M, Presnell SR, Elkon KB, Lacy-Hulbert A, Barnes BJ, Pepper M, Hamerman JA. Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes.  Science. 2019 Jan 11;363. PMID: 30630901

Sontheimer, C., Liggitt, D., and Elkon, KB. UVB irradiation causes STING-dependent production of protective Type 1 Interferon in the skin by recruited inflammatory monocytes. Arthritis Rheumatol,69:826-836, 2017. PMID: 27863141

An J, Durcan L, Karr RM, Briggs TA, Rice GI, Teal TH, Woodward JJ, Elkon KB. Expression of Cyclic GMP-AMP in patients with systemic lupus erythematosus. Arthritis Rheumatol. 69:800-807, 2017. PMID: 27863149

Lood C, Arve S, Ledbetter J, Elkon KB. TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA. J Exp Med, 214:2103-2119, 2017. PMID: 28606989

Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C , De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ (co-last authors). Mitochondrial ROS generate NETs enriched in oxidized interferogenic mitochondrial DNA and contribute to lupus-like disease. Nature Medicine, 22:146-53, 2016. PMID: 26779811.

Sisirak V, Sally B, D'Agati V, Martinez-Ortiz W, Özçakar ZB, David J, Rashidfarrokhi A, Yeste A, Panea C, Chida AS, Bogunovic M, Ivanov II, Quintana FJ, Sanz I, Elkon KB, Tekin M, Yalçınkaya F, Cardozo TJ, Clancy RM, Buyon JP, Reizis B. Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell. 2016 Jun 9. pii: S0092-8674(16)30585-2. doi: 10.1016/j.cell.2016.05.034. [Epub ahead of print]. PMID: 27293190

Barrat FJ, Elkon KB, Fitzgerald KA. Importance of nucleic acid recognition in inflammation and autoimmunity, Ann Rev Med, 67:323-336, 2016 PMID: 26526766.

Han CY, Tang C, Guevara ME, Wei H, Wietecha T, Shao B, Subramanian S, Omer M, Wang S, O’Brien KD, Wight TN, Vaisar T, de Beer MC, de Beer FC, Osborne WR, Elkon KB,  Chait A  Serum Amyloid A contributes to inflammation-induced impairment in HDL function. J Clin Invest, 126:796, 2016.

An J, Woodward JJ, Sasaki T, Minie M, Elkon KB. Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase-DNA Interaction. J Immunol. 194:4089-93, 2015.

Sisirak V, Ganguly D, Lewis KL, Couillault C, Tanaka L, Bolland S, D’Agati V, Elkon KB, Reizis B. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med, 2011:1969-1976, 2014.

Giltiay NV, Chappell CP, Sun X, Kolhatkar N, Teal T, Wiedeman A, Kim J, Tanaka L, Buechler MB, Hamerman JA, Imanishi-Kari T, Clark EA, Elkon KB. Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med, 210:2713-23, 2013.