Ian R. Rifkin, M.D., Ph.D.
Associate Professor of Medicine
650 Albany Street
Office: X514; 617-638-7325
Lab: E-5; 617-414-3338
M.D. University of the Witwatersrand, South Africa.
Ph.D. University of Cambridge, England.
There are two main research aims in my laboratory. The first aim is to understand the pathogenesis of the systemic autoimmune disease systemic lupus erythematosus (SLE), with the ultimate goal of identifying new therapeutic targets. We mainly use mouse models and in-vitro systems for these studies, although we also work with human cells and patient material. Specific projects include: 1) Studying mechanisms and signaling pathways responsible for the activation of dendritic cells in SLE. This project is based on our original observation that dendritic cell activation by nucleic acid autoantigen-containing immune complexes occurs through the dual engagement of an Fc receptor and a Toll-like receptor (TLR9 for DNA autoantigens and TLR7 for RNA autoantigens). Ongoing studies aim to characterize the precise nature of the stimulatory autoantigens in more detail, and to determine the overall contribution of TLR-mediated dendritic cell activation to SLE pathogenesis. 2) Determining the role of interferon regulatory factor 5 (IRF5) in lupus pathogenesis. IRF5 has recently been identified as a major susceptibility gene for SLE in humans and plays an important role in TLR signaling. We are using a combination of in vivo and in vitro approaches to evaluate the biological role of IRF5 in SLE.
The second main aim of our research is to determine the mechanisms responsible for the premature atherosclerosis seen in SLE. Premature atherosclerosis is a major cause of morbidity and mortality in patients with SLE, although the lupus-specific risk factors responsible for this are poorly understood. In collaboration with Dr. Walsh in Molecular Cardiology, we have developed a novel mouse model of premature atherosclerosis and SLE, and are using this model to explore underlying pathogenic mechanisms and test new therapeutic approaches.
- Rifkin IR, Channavajhala PL, Kiefer HLB, Carmack AJ,,Landesman-Bollag E, Beaudette BC, Jersky B, Salant DJ, Ju S-T, Marshak-Rothstein A, Seldin DC. 1998. Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2a. J. Immunol. 161:5164-5170.
- Rifkin IR, Leadbetter EA, Beaudette BC, Kiani C, Monestier M, Shlomchik MJ, Marshak-Rothstein A. 2000. Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells. J. Immunol. 165:1626-1633.
- Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603-607.
- Aprahamian T, Rifkin I, Bonegio R, Hugel B, Freyssinet JM, Sato K, Castellot JJ Jr, Walsh K. 2004. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J. Exp. Med. 199:1121-1131.
- Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR. 2004. TLR9 dependent and independent dendritic cell activation by chromatin-IgG complexes. J. Exp. Med. 199:1631-1640.
- Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. 2005. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. 204:27-42.
- Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A. 2005. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202:1171-1177.
- Beaudette-Zlatanova BC, Ling T, Shlomchik MJ, Marshak-Rothstein A, Rifkin IR. 2006. B cells and dendritic cells from Vk8 light chain transgenic mice activate MRL-lpr/gld CD4+ T cells. J. Immunol. 177:45-52.
- Aprahamian T, Bonegio R, Rizzo J, Lefer DJ, Rifkin IR, Walsh K. 2006. Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J. Immunol. 177:3028-3034.
- Yasuda K, Richez C, Maciaszek JW, Agrawal N, Akira S, Marshak-Rothstein A, Rifkin IR. 2007. Murine dendritic cell type I interferon production induced by human IgG-RNA immune complexes is IRF5- and IRF7-dependent, and is required for IL-6 production. J. Immunol. 178:6876-6885.
- Marshak-Rothstein A and Rifkin IR. 2007. Immunologically active autoantigens: the role of Toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25:419-441.
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