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: 9.81). 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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    • "To date, it is a well established fact that susceptible individuals have a complex multigenic predisposition and that environmental triggers i.e. enteroviral infections may lead to enhanced beta-cell apoptosis, dendritic cell (DC) activation and subsequent T-cell priming [8]. Immune complexes containing self nucleic acids, DNA or RNA, contribute to autoimmunity in systemic lupus erythematosus, psoriasis, polyarthritis, and diabetes [9]–[11]. Aberrant miRNA expression patterns have been associated with disease progression in T1D patients [12], [13]. "
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    • "When inoculated into the peritoneal cavity, DNA-containing amyloid fibrils induced selective pDC infiltration, which was associated with a predominant type I IFN response. After immunization with DNA-containing amyloid fibrils, non-autoimmune mice developed stable anti-nuclear autoantibodies and abroad autoreactive humoral response against DNA, RNA, Sm/RNP, and histone [145]. Proteinuria and antibody depositions in the glomeruli of the kidneys were also detected, suggesting the development of a lupus-like syndrome. "
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    04/2014; 5(2):212. DOI:10.4172/2155-9899.1000212
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    • "Recently we observed that the precursor form of amyloid, soluble protein oligomers, can efficiently bind DNA converting them into amyloids [20]. Strikingly, these nucleic acid-containing amyloids could initiate inflammation and their injection to non-autoimmune mice lead to a broad anti-autoantigen response with the generation of anti-DNA autoantibodies [21]. "
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