*3.4. Salivary Gland Epithelial Cells (SGECs)*

SGECs are one of the targets of autoimmune attack in SS as exhibited by the aberrant apoptosis that occurs in the SG. However, further scrutiny into the role of SGECs has revealed that this class of cells is not merely the bystander target, but rather an active participant in the autoimmune response [84,85]. SGECs expressed high levels of HLA-DR, costimulatory molecules CD80 and CD86, and adhesion molecules, allowing them to perform as non-professional antigen presenting cells [86]. Additionally, SGECs have been identified to be sources of multiple chemokines and proinflammatory cytokines including CXCL12, CXCL13, IL-6, IL-7, IL-22, ICOSL, and BAFF [74,87–93]. Local expression of certain chemokines by SGEGs, including CXCL12 and CXCL13 is believed to contribute to the formation of ectopic GCs in the glands [89]. Furthermore, the Ro52 antigen has been detected in SGECs of pSS at higher levels than control patients, and is positively associated with the severity of inflammation [94]. Enhanced endoplasmic reticulum (ER) stress detected in the SGECs of pSS patients has been hypothesized to contribute to the production of proinflammatory cytokines from SGECs [95]. Co-culture experiments discovered that SGEC expression of ICOSL and IL-6 can differentiate naïve T cells into follicular T cells, demonstrating the ability of SGECs to influence lymphocytic organization in the SGs [91].

TLR 1, 2, 3, 4, and 7 are known to be expressed by SGECs [96–98]. Furthermore, TLR3 stimulation of the SG of New Zealand Black X New Zealand White (NZB/W) F1 mice was shown to reduce salivary flow in mice [99]. Separate studies observed that TLR3 stimulation induced apoptosis in SGECs, and SGECs from pSS patients were more susceptible to anoikis induced by TLR3 stimulation [100,101]. Additionally, pSS patients were found to overexpress the costimulatory molecule B7-H3 which was determined to be able to induce apoptosis of SGECs [102]. Stimulation of patient SGECs with TLR agonists dsRNA virus and poly I:C resulted in increased BAFF expression, further demonstrating the role of SGECs as regulators of the immune response [92]. The anti-inflammatory activity of peroxisome-proliferator-activated receptor-γ (PPARγ) was found to be reduced in SS patient derived SGECs, allowing for overactive NF-κB and IL-1β pathways [103]. TLR stimulation of the SGECs, presumably from a viral infection, represents a possible initiating event in the autoimmune cascade where increased cell death, and the release of inflammatory cytokines drive an escalating cycle of inflammation [84,85,104]. Overall, like macrophages and DCs, SGECs possess the ability to both produce various chemokines, inflammatory cytokines, and act as APCs, allowing them to exert a powerful influence guiding the behavior of lymphocytes within the SGs.
