AB0139 Type i interferon production by plasmacytoid dendritic cells is essential for instigating systemic autoimmunity

Background Complex genetic, host-derived and environmental factors contribute to the immunepathophysiologic development of systemic autoimmunity. In Systemic Lupus Erythematosus(SLE), type I interferons (IFN) produced by plasmacytoid dendritic cells (pDCs) is clinically associated with the disease (1-4). IFN production by pDCs is induced by autoantibodies complexed with self-nucleic acids and associated proteins or NETs, which exacerbates the ongoing autoimmune pathology. However, how pDCs and IFN participate in early lupus development remains to be elucidated. Objectives Previously we found that amyloid precursor proteins readily form amyloid fibrils in the presence of nucleic acids, which can potently induce IFN production by pDCs (5,6). Furthermore, immunization of non-autoimmune mice with DNA-containing amyloid fibrils leads tothe development of stable anti-nuclear serology and lupus-like disease (6). Here we characterized the IFN response and its functional significance in lupus initiation in vivo. Methods Non-autoimmune mice were immunized with DNA-containing amyloid fibrils or controls as described (6). The development of autoantibodies was measured by antigen-specific ELISA, or standard tests with Hep-2 cells or C. luciliae. Acute peritonitis induced by DNA-containing amyloid fibrils or controls was analyzed as described (6). Transcript expression was examined by quantitative PCR. Results Mice received DNA-containing amyloid fibrilsmounted rapid IFN response, which was correlated with selective peritoneal pDC infiltration. Interestingly, type I interferon and IFN-inducible genes are also detected in the peripheral blood, suggesting an acute systemic response. Mice deficient of IFNAR were resistant to the induction of lupus by DNA-containing amyloid fibrils, consistent with the effect of pDC depletion which abolished the IFN production. Moreover, while female Balb/c mice eventually developed anti-dsDNA antibodies, male mice failed to establish stable autoimmune disease, a phenomenon resonant with clinical lupus. Conclusions Type I interferon production and signaling is essential to induce systemic autoimmunity. Targeting IFN pathway thus would be effective to prevent the development of autoimmunity. References Ronnblom, L., and Pascual, V. (2008) Lupus 17 , 394-399 Theofilopoulos, A. N., Baccala, R., Beutler, B., and Kono, D. H. (2005) Annu. Rev. Immunol. 23 , 307-336 Marshak-Rothstein, A. (2006) Nat Rev Immunol 6 , 823-835 Mark J, S. (2009) Curr. Opin. Immunol. 21 , 626-633 Di Domizio, J., Zhang, R., Stagg, L. J., Gagea, M., Zhuo, M., Ladbury, J. E., and Cao, W. (2012) J Biol Chem 287 , 736-747 Di Domizio, J., Dorta-Estremera, S., Gagea, M., Ganguly, D., Meller, S., Li, P., Zhao, B., Tan, F. K., Bi, L., Gilliet, M., and Cao, W. (2012) Proc Natl Acad Sci U S A 109 , 14550-14555 Acknowledgements This research is supported by the University of Texas MD Anderson Cancer Center Institutional Research Grant (to W.C.), National Institutes of Health (NIH) Grant AI074809 (to W.C.), and NIH MD Anderson ’s Cancer Center Support Grant CA016672. Disclosure of Interest None Declared