The expression of immune-modulatory molecules outlined above suggests that salivary gland epithelial cell are suitably equipped to mediate the recruitment, activation, amplification, differentiation, and maturation of inflammatory cells. These data strongly implicate these cells in the regulation of local autoimmune responses in salivary glands and justify the term “autoimmune epithelitis” [1] in relationship to SjS.

3.4Tissue Injury and Repair

3.4.1Functional Impairment of Glands and Autonomic Nervous System Involvement

Exocrine secretion is controlled by the peripheral autonomic system. Salivary glands are enriched with neuroendocrine-related molecules. Besides the muscarinic and cholinergic receptors, several other molecules including the vasointestinal peptide (VIP) or neuropeptide Y (NPY) are located in the exocrine glands. Unmyelinated afferent nerve fibers provide signals from the lacrimatory and salivatory nuclei of the midbrain to the exocrine glands. These nuclei are under the influence of higher cortical centers, as indicated by the common and reversible side effect of centrally acting medications (e.g., tricyclic antidepressants, clonidine) that cause oral and ocular dryness [70].

In the salivary glands, the neuronal signals from CNS affect the epithelial and stromal tissues via the interaction of the neurotransmitters with their receptors and other neurotransmitters located on the surface of these cells. The main signaling neurotransmitters that have been described so far are acetylcholine and VIP. Cholinergic nerves stimulate mucous saliva secretion through the interaction of the released acetylcholine with muscarinic receptors of the epithelial cells (mainly types M1 and M3) [71]. VIP acts through specific receptors, helping to achieve a maximal degree of secretion [72].

In the peripheral tissue, it is still unknown how the autoimmune lesion and the locally produced inflammatory molecules interact with the neuroendocrine molecules. Although biopsies of salivary and lacrimal glands from patients with SjS have focal lymphocytic infiltrates and partial destruction of glandular secretory units, in some patients, the degree of dryness is higher than that anticipated for the level of glandular destruction. This suggests that additional mechanisms leading to dryness are operating. The impairment of the secretory function in these cases may be explained by either the destruction of neural innervations of the residual glandular elements and the relative density of acetylcholine receptors on the glandular cells, or by the action of cytokines (e.g., TNF-alpha and IL-1), autoantibodies, and other inflammatory mediators (e.g., metalloproteinases) produced locally. These substances may lead to an impaired release of neurotransmitters, a decreased response of the residual glandular cells to available neurotransmitters, or even blockade of their receptors.

Studies of animal models of SjS gave some insights on the complex interaction between innate and adaptive immunity and salivary gland dysfunction. These studies revealed that, as in human disease, inflammation and dysfunction are discordant in some animals. In New Zealand white (NZB/W) F1 mice, incomplete Freund’s adjuvant, a nonspecific inflammatory stimulus, accelerates glandular hypofunction by a manner that was not associated with a strong adaptive autoimmune

suggest an important role of epithelial cell apoptosis in the pathogenesis of SjS [57, 59, 79]. Elevated levels of epithelial apoptotic cell death have been detected in the minor salivary gland tissues of SjS patients [57]. Several apoptotic mechanisms have been implicated in the apoptosis of the glandular epithelia in SjS. These include the classical Fas/Fas-Ligand (FasL) apoptotic pathway, as well as the cytotoxic effect of proteases, such as perforin and granzymes, and/or cytokines, such as IFNg, that are produced in SjS autoimmune lesions [57, 59, 79, 80]. Long-term cultured salivary gland epithelial cells obtained from patients with SjS display significantly higher surface constitutive expression of Fas and FasL molecules than those derived from controls [59]. However, salivary gland epithelial cells are resistant to anti-Fas- mediated apoptosis and become sensitive after protein or RNA synthesis inhibition. These facts suggest the importance of anti-apoptotic mechanisms operative within salivary gland epithelial cells. Such mechanisms include the anti-apoptotic proteins cFLIP and Bcl-2, which are expresses constitutively by these cells [59].

Treatment with IFNg, a cytokine that is abundant within SjS autoimmune lesions, overcomes the resistance of salivary gland epithelial cells and promotes their apoptotic death via the Fas/FasL pathway and anoikia [59], providing thus a mechanism for the elevated epithelial apoptotic cell death observed in the minor salivary glands of SjS patients [57]. In addition, recent data suggest that the overexpression of Ro52 autoantigens in the epithelia may contribute in the reduced epithelial proliferation and increased apoptotic cell death observed in SjS [81].

Cell–matrix interactions are important for cellular functions of the epithelial cell, including response to growth factor signals, proliferation, and ability for cellular regeneration. In lacrimal gland cells grown in vitro, cell–matrix interactions are necessary for secretory responses to muscarinic M3 agonists and are further augmented by novel non-matrix proteins such as BM180 [82, 83]. Proteases such as matrix metalloproteinases and lysosomal cysteine proteinases (cathepsins) play important roles during normal embryonic development of glandular tissue [84]. They mediate cellular migration and differentiation, via the controlled degradation of extracellular matrix (ECM) [84]. Numerous studies have demonstrated a close association of proteases with various diseases, such as rheumatoid arthritis and osteoarthritis [85].

Increased levels of matrix metalloproteinases are also implicated in the progression of SjS [86]. Persisting action of matrix metalloproteinases may lead to destruction and atrophy of exocrine tissues, resulting in sicca symptoms [87]. The epithelial cells express a family of specific receptors including integrins to these matrix proteins, the expression of which is elevated in SjS patients [88]. Moreover, the extracellular matrix in the affected glands may be modified by collagenases and other metalloproteinases [86, 88].

Cytokines such as IL-1, IL-6, IL-8, and TNF-alpha are transcribed in increased amounts by conjunctival epithelial cells of SjS patients [89]. The local production of cytokines by mononuclear cells and also epithelial cells might contribute to the immune-mediated destruction of exocrine glands in primary SjS. Tissue damage appears to start very early during the disease process. Studies of lacrimal glands in the nonobese diabetic (NOD) mice revealed that the initial infiltrating cells at