**3.1 Environmental factors**

#### **3.1.1 Viral infections**

Ebstein-barr, Human T Lymphotropic Virus-1 and hepatitis C have been proposed to be associated with SS. However, the link between these viral infections and SS remains weak (Pflugfelder et al., 1993; Green et al., 1989, Haddad et al., 1992; Iwakiri et al., 2009). Coxsackie virus was found to be increased in SS salivary glands, but these findings have been the subject of some controversies (Triantafyllopoulou et al., 2004, Gottenberg et al., 2006a). Innate immunity is classically stimulated by infectious agents, which results in type I interferon production. Upon viral infection, the activation of the interferon pathway can be perpetuated by the formation of immune complexes containing viral RNA, thereby leading to plasmacytoid dendritic cell activation and production of interferon-.

### **3.1.2 Stress**

Stress has been advocated as being a forerunner of SS, since pSS patients experienced a high degree of stress prior to the onset of disease (Karaiskos et al., 2009).

#### **3.2 Endocrine factors**

#### **3.2.1 Sexual hormones**

The high female to male predominance of SS clearly delineates the role of hormones in the pathogenesis of SS. Estrogenic action is largely imputed in the high female predominance in several autoimmune diseases, including SS (Whitacre, 2001). Estrogens and androgens are thought to respectively contribute or protect to autoimmunity. Onset of SS generally occurs around menopause, when modification of the androgen-estrogen ratio occurs. Patients with SS have been shown to possess lower systemic concentrations of dehydroepiandrosterone (DHEA) than matched aged-controls (Valtysdottir et al., 2001). Furthermore, decreased salivary DHEA levels, reduced cystein-rich secretory protein (CRISP-3, a protein upregulated by DHEA) expression, alteration of CRISP-3 polarized expression in acini, altered and decreased conversion of DHEA, and abnormal expression of steroidogenesis enzymes were detected in SS patients (Laine et al., 2007, Porola et al., 2008; Spaan et al., 2009). Women's local salivary gland dihydrotestosterone production is totally dependent on DHEA conversion, rendering them highly vulnerable to local androgen deficiency.

Estrogens play a cardinal role in targeting salivary epithelial cell and stimulating apoptosis through a Fas-mediated mechanism (Ishimaru et al., 1999). Retinoblastomaassociated protein 48 (RbAp48) induces tissue specific apoptosis in salivary glands depending on the level of estrogen deficiency (Ishimaru et al., 2008). More recently, the presence of functional estrogen receptors has been observed in salivary epithelial cells (Tsinti et al., 2009). In the latter study, estrogen was shown to block expression of ICAM-1, an adhesion molecule displaying increased expression in salivary glands of SS patients. It may therefore be speculate that estrogen deficiency might lead to increased innate immunity.

Prolactin, a pro-inflammatory hormone, stimulates estrogen activity and inhibits estrogen production, high level T cell proliferation, IL2 receptor expression, IFN- production and stimulation of antibody production (Taiym et al., 2004). Higher levels of prolactin are detected in SS patients, and may be involved with the production of autoantibodies involved in SS (Taiym et al., 2004).
