Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity.
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.
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jeremy
J
Di Domizio
Stephanie
S
Dorta-Estremera
Mihai
M
Gagea
Dipyaman
D
Ganguly
Stephan
S
Meller
Ping
P
Li
Bihong
B
Zhao
Filemon K
FK
Tan
Liqi
L
Bi
Michel
M
Gilliet
Wei
W
Cao
D000682:Amyloid / Q000737:chemistry / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009696:Nucleic Acids / Q000032:analysis / Q000276:immunology*; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction
D000682:Amyloid; D017931:DNA Primers; D007370:Interferon Type I; D009696:Nucleic Acids; D009841:Oligonucleotides