**3. The toll-like receptors**

TLRs are a highly conserved family of PRRs. With the most recent addition of murine TLR13 (Shi et al., 2011), 14 mammalian TLRs have been reported to date, with 10 human subtypes. All TLRs are type I transmembrane proteins comprising an extracellular domain of multiple leucine rich repeats (LRRs), a single membrane spanning -helix and a cytoplasmic Toll/IL-1 receptor (TIR) homology signalling domain.

TLRs can be classified according to their subcellular localization: the endosomal TLRs 3, 7, 8 and 9 reside in intracellular compartments, whilst the others are found at the plasma membrane. This distribution also reflects the ligand specificity of TLRs; the cell surface receptors predominantly recognize pathogenic and self surface elements, whereas endosomal receptors primarily sense nucleic acids. Recognition of ligand triggers receptor dimerization which in turn triggers a multitude of signalling cascades leading to the expression of pro-inflammatory mediators such as cytokines and chemokines, which are designed to combat the perceived danger. In this way the body mounts an effective immune response (reviewed in (Piccinini et al., 2010). The TLR ligands that induce such a response include both PAMPs and DAMPs, and a more detailed list of them, with particular reference to those found in RA, can be found in Table 2. Thus, TLRs are critical for both the response to invading pathogens and the response to 'sterile' tissue damage.
