Endosomal Toll-like receptors in autoimmunity: mechanisms for clinical diversity

Trivedi, Sapna; Greidinger, Eric L.

doi:10.2217/thy.09.2

Cited by 34 publications

(37 citation statements)

References 75 publications

(76 reference statements)

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“…This may suggest that the endosomal TLR pathway activation could play a key role in the development of lung cancer. Stimulation of endosomal TLRs has been shown to induce a Th1/Th17 type of immune response through activation of NF-κB, mitogen activated protein kinase and an upregulation of IFN-1 and IFN-inducible genes (27,28). NF-κB plays a critical role in the development of tumors in the context of chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of Toll-like receptors in non-small cell lung cancer and idiopathic pulmonary fibrosis

et al. 2012

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Abstract.Patients with idiopathic pulmonary fibrosis (IPF) have a higher incidence of lung cancer. The role of Toll-like receptors (TLRs), a key component of the innate immunity, in interstitial lung diseases (ILDs) and lung cancer pathogenesis is not clarified. TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9 mRNA expression was quantitatively measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in bronchoalveolar lavage fluid (BALF) of 16 IPF patients, 16 non-small cell lung cancer (NSCLC) patients and 9 control subjects. TLR2, TLR3, TLR4 and TLR9 protein expression was assessed on BALF T-lymphocytes using flow cytometry. TLR3 mRNA expression was significantly higher in NSCLC compared to IPF (p= 0.023) and controls (p= 0.001). TLR7 mRNA expression levels were significantly higher in both NSCLC and IPF groups compared to controls (p= 0.029, p= 0.009). TLR9 expression at the mRNA level was significantly higher in both NSCLC and IPF groups compared to controls (p=0.01, p=0.001). Finally, TLR2 mRNA expression was significantly higher in IPF patients compared to controls (p= 0.042). Flow cytometry revealed decreased TLR3 and TLR9 expression in IPF patients compared to the NSCLC group (p= 0.02, p= 0.014) and decreased TLR9 expression in IPF compared with the controls (p= 0.04). TLR2 protein expression was significantly higher in IPF patients compared to NSCLC (p=0.04). Increased expression of endosomal TLRs in NSCLC patients and elevated expression of TLR2 in pulmonary fibrosis are the main results of this study. These results do not provide support for a common TLR pathway hypothesis between NSCLC and IPF.

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Section: Discussionmentioning

confidence: 99%

Expression profiles of Toll-like receptors in non-small cell lung cancer and idiopathic pulmonary fibrosis

et al. 2012

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“…Concurrent with the movement of DNA in cells, TLR9 redistributes from the ER to endosomes [4]. Endosomal TLRs have been implicated in autoimmune disease pathologies, such as those of rheumatoid arthritis and systemic lupus erythematosus [5,6]. Dysregulation of TLR7/TLR9 signaling has been found to promote autoimmune disease [6].…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of a novel anti-TLR9 intrabody

Reimer

Somplatzki

Zegenhagen

et al. 2013

Cellular and Molecular Biology Letters

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Toll-like receptor 9 (TLR9) is a component of the innate immune system, which recognizes the DNA of both pathogens and hosts. Thus, it can drive autoimmune diseases. Intracellular antibodies expressed inside the ER block transitory protein functions by inhibiting the translocation of the protein from the ER to its subcellular destination. Here, we describe the construction and characterization of an anti-TLR9 ER intrabody (αT9ib). The respective single-chain Fv comprises the variable domains of the heavy and light chain of a monoclonal antibody (mAb; 5G5) towards human and murine TLR9. Co-expression of αT9ib and mouse TLR9 in HEK293 cells resulted in co-localization of both molecules with the ER marker calnexin. Co-immunoprecipitation of mouse TLR9 with αT9ib indicated that αT9ib interacts with its cognate antigen. The expression of αT9ib inhibited NF-κB-driven reporter gene activation upon CpG DNA challenge but not the activation of TLR3 or TLR4. Consequently, TLR9-driven TNFα production was inhibited in RAW264.7 macrophages upon transfection with the αT9ib expression plasmid. The αT9ib-encoding open reading frame was integrated into an adenoviral cosmid vector to produce the recombinant adenovirus (AdV)-αT9ib. Transduction with AdVαT9ib specifically inhibited TLR9-driven cellular TNFα release. These data strongly indicate that αT9ib is a very promising experimental tool to block TLR9 signaling.

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“…Different inflammatory diseases of the posterior ocular segment show predilection for particular vascular beds, for example, punctate inner choroidopathy (PIC) and multiple evanescent white dot syndrome (MEWDS) appear to preferentially affect the inner choroid (Machida et al, 2008). Other diseases, for example, systemic lupus erythematosus (SLE) may affect both retinal and choroidal vasculature to different extents (Nag and Wadhwa, 2006;Trivedi and Greidinger, 2009). …”

Section: Introductionmentioning

confidence: 99%

Expression of Toll-like receptors in human retinal and choroidal vascular endothelial cells

Stewart

Wei

Branch

et al. 2015

Experimental Eye Research

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Endosomal Toll-like receptors in autoimmunity: mechanisms for clinical diversity

Cited by 34 publications

References 75 publications

Expression profiles of Toll-like receptors in non-small cell lung cancer and idiopathic pulmonary fibrosis

Expression profiles of Toll-like receptors in non-small cell lung cancer and idiopathic pulmonary fibrosis

Molecular cloning and characterization of a novel anti-TLR9 intrabody

Expression of Toll-like receptors in human retinal and choroidal vascular endothelial cells

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