Immune Activation by Bacterial DNA: A New Genetic Code

Pisetsky, David S.

doi:10.1016/s1074-7613(00)80256-3

Cited by 283 publications

(146 citation statements)

References 65 publications

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“…Previous attempts to immunize nonautoimmune mice with self-antigens, such as DNA, apoptotic cells, or purified nucleosome, only resulted in limited or transient autoantibody generation (36)(37)(38). Tetramethylpentadecane (TMPD) induces an array of autoantibodies and glomerulonephritis in BALB/c mice (39).…”

Section: Discussionmentioning

confidence: 99%

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

Domizio¹,

Dorta‐Estremera²,

Gagea

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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 selfantigens. 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.autoimmune disease | innate immune response | disease model

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Section: Discussionmentioning

confidence: 99%

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

Domizio¹,

Dorta‐Estremera²,

Gagea

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, it is tempting to speculate that the resulting migration, which was significantly higher than that after delivery of gold particles alone, was a result of a combination of both mechanical injury and non-specific activation of LC by the presence of DNA, probably induced by immunostimulatory sequences contained in the plasmid backbone. [24][25][26] Although in the epidermis, luciferase activity and EGFP expression were found mainly in keratinocytes, the analysis of transgenic protein expression in epidermal cell suspensions clearly demonstrated luciferase expression in CD1a + LC. In contrast, we were unable to demonstrate luciferase activity in the migratory DC collected 72 h after transfection.…”

Section: (A) Most Of the Luciferase Expression Was Detected In Epidermentioning

confidence: 92%

Direct transfection and activation of human cutaneous dendritic cells

et al. 2001

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Gene therapy techniques can be important tools for the induction and control of immune responses. Antigen delivery is a critical challenge in vaccine design, and DNA-based immunization offers an attractive method to deliver encoded transgenic protein antigens. In the present study, we used a gene gun to transfect human skin organ cultures with a particular goal of expressing transgenic antigens in resident cutaneous dendritic cells. Our studies demonstrate that when delivered to human skin, gold particles are observed primarily in the epidermis, even when high helium delivery pressures are used. We demonstrate that Langerhans cells resident in the basal epidermis can be transfected, and that

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“…Immunostimulatory sequences are bacterial DNA or synthetic oligonucleotides that stimulate the innate immune system through toll-like receptor-9 (TLR-9). 19,20 1018 is a 22-mer phosphorothioate oligodeoxyribonucleotide with immunostimulatory activity. 21 An investigational hepatitis B vaccine, HBsAg adjuvanted with 1018 (HBsAg-1018), has been shown to provide a higher and more rapid antibody response after one and two doses than a marketed alum-adjuvanted hepatitis B vaccine in healthy adults.…”

Section: Introductionmentioning

confidence: 99%