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


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.


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]. "
    [Show abstract] [Hide abstract] ABSTRACT: Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensive in vitro and in vivo studies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.
    Full-text · Article · Feb 2016 · Journal of Immunology Research
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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). "
    [Show abstract] [Hide abstract] ABSTRACT: Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both the pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of the pDC-IFN-α/β pathway in systemic autoimmunity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    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. "
    [Show abstract] [Hide abstract] ABSTRACT: Research on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown. We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation. This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in systemic lupus erythematosus (SLE). When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice. We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Immunity
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