2002 Dendritic Cells2002 Dendritic Cells
Dr. Rifkin was awarded an LRI Novel Research Grant to investigate whether a new pathway implicated in the activation of autoreactive B cells also leads to dendritic cell activation in lupus. The pathway involves recognition of immune complexes containing DNA and the DNA receptor TLR9.
Over the course of his LRI research, Dr. Rifkin successfully showed that TLR9 is indeed involved in dendritic cell activation by the autoantibody-DNA complexes. This has led to work to determine whether blocking TLR9 can prevent the development of disease in mouse models of SLE.
In addition, another novel pathway of dendritic cell activation has been demonstrated which leads to the production of a molecule, called BAFF, which is involved in the development of systemic lupus. Studies are in progress to delineate the exact nature of this second novel pathway.
Overall, Dr. Rifkin’s studies may provide a new understanding of the central process leading to lupus, and also appear to identify TLR9 as a target for the development of new and specific treatments for lupus.
Significantly, a number of biotechnology companies are now developing TLR9 and TLR7 inhibitors for therapeutic use in lupus and other autoimmune diseases, Dr. Rifkin reported in 2010.
Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR. J Exp Med. 2004 199(12):1631-40.
RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A. J Exp Med. 2005 202(9):1171-7.
Comparison of CpG s-ODNs, chromatin immune complexes, and dsDNA fragment immune complexes in the TLR9-dependent activation of rheumatoid factor B cells. Marshak-Rothstein A, Busconi L, Lau CM, Tabor AS, Leadbetter EA, Akira S, Krieg AM, Lipford GB, Viglianti GA, Rifkin IR. J Endotoxin Res. 2004;10(4):247-51.
DNA and RNA autoantigens as autoadjuvants. Busconi L, Lau CM, Tabor AS, Uccellini MB, Ruhe Z, Akira S, Viglianti GA, Rifkin IR, Marshak-Rothstein A. J Endotoxin Res. 2006;12(6):379-84.
Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. Immunol Rev. 2005 204:27-42.
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. Yasuda K, Richez C, Maciaszek JW, Agrawal N, Akira S, Marshak-Rothstein A, Rifkin IR. J Immunol. 2007;178:6876-6885.
Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Marshak-Rothstein A and Rifkin IR. Annu Rev Immunol. 2007;25:419-441.
TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. Richez C, Yasuda K, Watkins AA, Akira S, Lafyatis R, Van Seventer J, Rifkin IR. J Immunol. 2009;182:820-828.
Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNA-containing immune complexes. Yasuda K, Richez C, Uccelini MB, Richards RJ, Akira S, Monestier M, Corley RB, Viglianti GA, Marshak-Rothstein A, Rifkin IR. J Immunol. 2009;183:3109-3117.
Interferon regulatory factor 5 is required for disease development in the FcγRIIB–/–Yaa and FcγRIIB–/– mouse models of systemic lupus erythematosus. Richez C, Yasuda K, Bonegio RG, Watkins AA, Aprahamian T, Busto P, Richards RJ, Liu C-L, Cheung R, Utz PJ, Marshak-Rothstein A, Rifkin IR. J. Immunol. 2010;184:796-806.
In 2004, Dr. Rifkin was awarded an NIH Program Grant along with Anne Rothstein (Boston University, MA) and Mark Shlomchik (Yale University, New Haven, CT). This five-year grant represents a direct continuation of his LRI-funded work. He will examine the role of TLR9 in DCs; Dr. Rothstein will examine the role of TLR9 in B-cells; and and Dr. Shlomchik will examine the role of TLR9 in-vivo.
Along with a renewal of the NIH-funded Program Grant for another 5 years (to 2014), Dr. Rifkin’s work on Toll-like receptors and lupus has generated $9,897,658 at the NIH.
Rev. July 2010