Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Lang, Karl S.; Recher, Mike; Junt, Tobias; Navarini, Alexander A.; Harris, Nicola L.; Freigang, Stefan; Odermatt, Bernhard; Conrad, Curdin; Ittner, Lars M.; Bauer, Stefan; Luther, Sanjiv A.; Uematsu, Satoshi; Akira, Shizuo; Hengartner, Hans; Zinkernagel, Rolf M.

doi:10.1038/nm1176

Cited by 346 publications

(278 citation statements)

References 52 publications

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“…Exposure to TLR3 or TLR7 ligands is required, for example, to induce autoimmune diabetes in transgenic mice that harbour large numbers of pancreatic islet-reactive cytotoxic T cells. In this model, TLR-induced local production of IFN-α triggers the recruitment of autoreactive T cells into the pancreatic islets [140]. TLR3 and TLR9 ligation are also key events in the development of autoimmune myocarditis by inducing the maturation of DCs pulsed with heart-specific self-peptide [14].…”

Section: Toll-like Receptor (Tlr) Ligands and Autoimmunitymentioning

confidence: 99%

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Blanco

Palucka

Pascual

et al. 2008

Cytokine & Growth Factor Reviews

453

362

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Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.

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Section: Toll-like Receptor (Tlr) Ligands and Autoimmunitymentioning

confidence: 99%

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Blanco

Palucka

Pascual

et al. 2008

Cytokine & Growth Factor Reviews

453

362

View full text Add to dashboard Cite

show abstract

“…However, MyD88-deficient mice raised in a germ-free environment develop disease, indicating that MyD88 signalling is not required for diabetogenesis and that TLRmediated changes in gut flora may prevent diabetes in a MyD88-independent fashion [37]. Previous work has demonstrated that exogenous TLR7 or TLR3 agonists increase IFN-α and pancreatic islet expression of MHC class I and transgenic islet antigens [38]. In this paper we show that administration of a single dose of TLR7/8 agonist +CD40 agonist in 8.3 NOD mice and repeated administration of TLR7 agonist in NOD mice accelerates the development of spontaneous diabetes.…”

Section: Tlr7/9 Agonists Activate Nod-derived Bmdcs and Cause The Secmentioning

confidence: 99%

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

et al. 2011

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Aims/hypothesis The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8 + T cells. Methods We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8 + T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). Results TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. Conclusions/interpretation TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.

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“…TLR agonists have been shown to induce autoimmune diseases, for example, EAE and diabetes. 41,42 On the other hand, TLR stimulation can also suppress autoimmune pathogenesis, showing a more complex role for TLR in autoimmune diseases. 43,44 Vectors based on herpes simplex virus type 1 (HSV-1) have several features making them a good candidate for gene therapy of CNS disease.…”

Section: Multiple Sclerosis (Ms) Is a Demyelinating Autoimmune Diseasmentioning

confidence: 99%

Treatment of experimental autoimmune encephalomyelitis in SJL/J mice with a replicative HSV-1 vector expressing interleukin-5

et al. 2011

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Experimental autoimmune encephalomyelitis (EAE) is an autoimmune inflammation of the central nervous system and is used as the experimental model of multiple sclerosis (MS). The exact mechanism behind the disease is still unknown, but interleukin (IL)-17 expressing T cells are thought to mediate the disease. Toll-like receptors (TLRs) are known to have a role in the innate immune response against pathogens, and several TLRs have also a role in the disease course of EAE. Here, we show that treatment with a herpes simplex virus type 1 vector expressing the Th2 cytokine IL-5 ameliorates EAE and decreases the numbers of infiltrating lymphocytes in the brain. The effect involves downregulation of TLR 2, 3 and 9 mRNA expression and upregulation of type I interferons (IFNs) in brains during onset of disease. The elevated expression of type I IFNs was also observed during recovery.

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Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Cited by 346 publications

References 52 publications

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

Treatment of experimental autoimmune encephalomyelitis in SJL/J mice with a replicative HSV-1 vector expressing interleukin-5

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