**6. Toll-Like Receptor-Mediated NF-**κ**B Activation in pSS**

A large volume of recent evidence underlines the finding that the SGs epithelium is the major actor in the promotion and progression of the chronic inflammatory reactions observed in pSS, through the induction of pro-inflammatory cytokines and chemokines [8,71]. The innate immune system uses a diverse set of recognition receptors to activate the intracellular signalling pathway, such as Toll-like receptors (TLRs) molecules. Indeed, TLRs activation lead to the recruitment of adaptor proteins within the cytosol, that culminates in signal transduction resulting in the transcription of genes involved in chronic inflammation [72,73]. TLRs were initially identified as receptors important only in host defences, but it is now clear that the TLRs, for example TLR2 and TLR4, are crucial in autoimmunity development [74–76], as demonstrated in RA [74], SLE [77], multiple sclerosis [78], and inflammatory bowel diseases [79]. Studies comparing mice and humans revealed that numerous types of epithelial cells express TLRs, supporting the hypothesis that the epithelium represents the first line of defence of the innate immune system [80,81]. These observations were confirmed also in pSS; the induction of TLRs signalling in SGEC leads to the release of inflammatory mediators, including IL-6, IL-8, and TNF-α [72], which are critical mediators of the inflammatory processes of pSS. In addition, recent works have evidenced the important contribution of TLRs activation to the initiation and progression of the pSS pathogenesis. In particular, TLR2, TLR3, and TLR4 are expressed on the SGEC membrane [82], and in addition, immunohistochemical analyses of TLR2, 3 and 4 on labial SG tissue from pSS patients confirmed a significantly higher constitutive expression of these receptors, found in SG-infiltrating mononuclear cells as well as acinar cells and ductal SGEC, supporting the intrinsic epithelial activation in pSS [40]. TLR4, in particular, resulted highly expressed specifically in infiltrating mononuclear cells and in ductal and acinar cells [83,84] of pSS SGs, and receptor levels were correlated with the degree of glandular inflammation [83,84]. At the same time, investigations conducted on pSS peripheral blood mononuclear cell (PBMC) confirmed a dysregulation of TLR7, 8 and 9 molecules compared to controls, where TLR7 and 8 recognize single-stranded RNA [85], while TLR9 is activated by un-methylated CpG DNA [86]. This led to an altered recognition of DNA and RNA, eventually resulting in the development of pSS. [87].
