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.

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Available from: Dipyaman Ganguly,
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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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    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.
    Cell Reports 08/2015; 12(7). DOI:10.1016/j.celrep.2015.07.021 · 8.36 Impact Factor
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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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    ABSTRACT: In addition to important regulatory roles in gene expression through RNA interference, it has recently been shown that microRNAs display immune stimulatory effects through direct interaction with receptors of innate immunity of the Toll-like receptor family, aggravating neuronal damage and tumour growth. Yet no evidence exists on consequences of microRNA immune stimulatory actions in the context of an autoimmune disease. Using microRNA analogues, we here show that pancreatic beta cell-derived microRNA sequences induce pro-inflammatory (TNFa, IFNa, IL-12, IL-6) or suppressive (IL-10) cytokine secretion by primary mouse dendritic cells in a sequence-dependent manner. For miR-29b, immune stimulation in RAW264.7 macrophages involved the endosomal Toll-like receptor-7, independently of the canonical RNA interference pathway. In vivo, the systemic delivery of miR-29b activates CD11b+B220- myeloid and CD11b-B220+ plasmacytoid dendritic cells and induces IFNa, TNFa and IL-6 production in the serum of recipient mice. Strikingly, in a murine model of adoptive transfer of autoimmune diabetes, miR-29b reduces the cytolytic activity of transferred effector CD8+ T-cells, insulitis and disease incidence in a single standalone intervention. Endogenous miR-29b, spontaneously released from beta-cells within exosomes, stimulates TNFa secretion from spleen cells isolated from diabetes-prone NOD mice in vitro. Hence, microRNA sequences modulate innate and ongoing adaptive immune responses raising the question of their potential role in the breakdown of tolerance and opening up new applications for microRNA-based immune therapy.
    PLoS ONE 09/2014; 9(9):e106153. DOI:10.1371/journal.pone.0106153 · 3.23 Impact Factor
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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. "
    Wei Cao ·
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) were initially identified as the prominent natural type I interferon-producing cells during viral infection. Over the past decade, the aberrant production of interferon α/β by pDCs in response to self-derived molecular entities has been critically implicated in the pathogenesis of systemic lupus erythematosus and recognized as a general feature underlying other autoimmune diseases. On top of imperative studies on human pDCs, the functional involvement and mechanism by which the pDC-interferon α/β pathway facilitates the progression of autoimmunity have been unraveled recently from investigations with several experimental lupus models. This article reviews correlating information obtained from human in vitro characterization and murine in vivo studies and highlights the fundamental and multifaceted contribution of pDCs to the pathogenesis of systemic autoimmune manifestation.
    04/2014; 5(2):212. DOI:10.4172/2155-9899.1000212
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