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Role of innate immune system in systemic sclerosis

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Abstract

Recognition of microbial or viral compounds is crucial to elicit an immune response and pattern recognition receptors (PRRs) form the first line of defence. An important family of PRRs are the Toll-like receptors (TLRs) with numerous evidences indicating their crucial role in identifying microbial or viral compounds. However, the danger theory, where the innate immune system responds to danger signals such as proteins released during damage or necrosis rather than only non-self is gaining ground. Indeed, TLRs are able to recognise endogenous molecules and have been implicated as key players in numerous autoimmune diseases including systemic sclerosis (SSc). TLR2 is known to be upregulated in SSc and has been shown to respond to the endogenous ligand amyloid A resulting in increased IL-6 secretion. TLR4 is now known to respond to a variety of endogenous ligands including fibronectin, containing alternatively spliced exons encoding type III repeat extra domain (EDA). EDA is only expressed upon tissue damage, and elevated levels can be found in SSc patients, idiopathic pulmonary fibrosis and cardiac allograft fibrosis, while deletion of EDA or TLR4 in mice reduces their fibrotic response. Further, stimulation of TLR8 with single-stranded RNA leads to increased expression of TIMP-1. This has been shown to require both IRAK4 and NF-κB with evidence suggesting autoantibodies bind to RNA to stimulate TIMP-1 production in monocytes. Therefore, TLR-mediated signalling provides numerous potential therapeutic targets for development of therapies for the treatment of multi-systemic autoimmune diseases.

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  1. School of Biological and Biomedical Sciences, Durham University, South Road, Durham, DH3, UK

    Nicola Fullard & Steven O’Reilly

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  1. Nicola Fullard
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  2. Steven O’Reilly
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Correspondence to Steven O’Reilly.

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This article is a contribution to the Special Issue on Immunopathology of Systemic Sclerosis - Guest Editors: Jacob M. van Laar and John Varga

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Fullard, N., O’Reilly, S. Role of innate immune system in systemic sclerosis. Semin Immunopathol 37, 511–517 (2015). https://doi.org/10.1007/s00281-015-0503-7

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