**2. Sjögren's Syndrome**

The chronic inflammatory autoimmune disorder SS arises as primary SS (pSS) and, when linked with another underlying systemic autoimmune disorder, such as scleroderma, systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA), is defined as secondary SS [5]. The evolution to non-Hodgkin's lymphoma occurs in a larger percentage of SS patients than in the normal population [6,7]. The clinical hallmarks of SS, keratoconjunctivitis sicca and xerostomia [2], can be confirmed by various objective tests highlighting significant functional impairment of the SGs and lachrymal glands [8]. The involvement of these glands is characterized by focal infiltrating lymphocytes that surround the ducts and, in some patients, extend and replace the secretory functional units. Although infiltration of the SGs by lymphocytes is a hallmark of SS [9,10], multiple cytokines are upregulated, even in the absence of lymphocytic infiltrates, and have a direct effect on SGs epithelial cells (SGEC). Interestingly, substantial new evidence supports the role of epithelia in the production of constitutive or inducible mediators of the innate and acquired immune responses. The picture that emerges shows intrinsically activated SGEC that induce and promote chronic inflammatory reactions [11]. For this reason, on the basis of clinical observation, pSS was defined as an "autoimmune epithelitis" [12]. Indeed, SGEC are capable of releasing many cytokines that result overexpressed and thus act as key molecules in chronic inflammation, contributing to both systemic and exocrine manifestations of pSS [13–29]. A number of explanations has been offered for the dysregulated cytokine network in pSS and, in the past, the presence of anti-Ro/SSA and anti-La/SSB antibodies was shown to be related to increased glandular and extra-glandular manifestations. Important findings provided evidence for a pathogenic role of autoantibodies, demonstrating that anti-Ro/SSA autoantibodies stimulate the production of pro-inflammatory cytokines such as IL-6 and IL-8 by human SGEC from healthy donors, promoting chronic inflammatory reactions [25]. Furthermore, pSS autoantibodies can promote the activation of the NF-κB pathway, leading to the overexpression of multiple proangiogenic/pro-inflammatory factors. Indeed, inhibiting the NF-κB activity abrogated the release of these cytokines [25]. Starting from the initial studies carried out on autoantibodies, considerable progress has been made in identifying other possible molecular mechanisms implicated in the activation of NF-κB, which could explain the chronic inflammatory situation characteristic of SS. Accumulated data suggest that the multiple roles of NF-κB in pSS could be related to the dynamic context of dysregulated inflammatory factors observed in pSS.
