Article

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

Departments of Immunology and Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2012; 109(36):14550-14555. DOI: 10.1073/pnas.1206923109
Source: PubMed

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.

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Available from: Dipyaman Ganguly
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    • "Albeit rare, amyloid fibrils have been found to be associated with SLE cases and complicate lupus nephritis [144] . Immunization of healthy mice with DNAcontaining amyloid fibrils induces lupus-like disease, promoting autoantibody production and lupus nephritis [143]. C-reactive protein (CRP), an acute-phase reactant produced by liver in response to inflammation, can suppress IFNí µí»¼ production from normal pDC by increasing the trafficking to ICs into late endosomes in pDC [132]. "
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    • "Among PEC populations, both SPMs and neutrophils transcribed IL-1b (Figure S1E), suggesting that the resident SPM, other than LPM, is likely the primary source of IL-1b upon sensing amyloid. Given the dual infiltration of pDCs and neutrophils and the importance of these cells in systemic autoimmunity, we expected that neutrophils might facilitate a pDC-mediated humoral autoimmunity that is triggered by immunization with DNA-containing amyloid (Di Domizio et al., 2012a). To examine the functional role of neutrophils, we pre-injected BALB/c mice with anti-Ly6G monoclonal antibody (mAb) (clone 1A8), which selectively and transiently depleted neutrophils in vivo (Figure 1E). "
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    Preview · Article · Aug 2015 · Cell Reports
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    • "Human prototypic amyloidogenic peptides, prion fragment and amyloid-b 1-42 can directly bind to DNA (Di Domizio et al., 2012b; Jimé nez, 2010). Immunization with amyloid fibers complexed with nucleic acids, in the presence of the classic adjuvant CFA, can induce autoantibodies in nonautoimmune mice within 12 weeks (Di Domizio et al., 2012a). Although groundbreaking, the amyloid-DNA composites used in the latter study were made from human serum albumin and salmon sperm DNA—an artificial composite to which the immune system would not normally be exposed. "
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