The Journal of Experimental Medicine
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Published online 14 June 2004 doi:10.1084/jem.20031942
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1631-1640
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Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes

Melissa W. Boulé1, Courtney Broughton1, Fabienne Mackay3, Shizuo Akira4, Ann Marshak-Rothstein2, and Ian R. Rifkin1

1 Renal Section, Department of Medicine and 2 Department of Microbiology, Boston University School of Medicine, Boston, MA 02118
3 Department of Arthritis and Inflammation, Garvan Institute of Medical Research, New South Wales 2010, Australia
4 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Address correspondence to Ian R. Rifkin, Boston University School of Medicine, EBRC 5th Floor, 650 Albany Street, Boston, MA 02118. Phone: (617) 638-7325; Fax: (617) 638-7326; email: irifkin{at}bu.edu

Dendritic cell (DC) activation by nucleic acid–containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor Fc{gamma}RIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.

Key Words: systemic lupus erythematosus • innate immunity • Fc receptor • BAFF • tumor necrosis factor

Abbreviations used in this paper: chromatin IC, chromatin immune complex; protein IC, protein immune complex; sODN, phosphorothioate oligodeoxynucleotide; TLR, Toll-like receptor.


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