Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity.

Details

Serval ID
serval:BIB_5209DF708DD4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Di Domizio J., Dorta-Estremera S., Gagea M., Ganguly D., Meller S., Li P., Zhao B., Tan F.K., Bi L., Gilliet M., Cao W.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
2012
Volume
109
Number
36
Pages
14550-14555
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of self-antigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2012 19:53
Last modification date
20/08/2019 15:07
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