3.1.1. Environmental Factors

According to the current physiopathogenic model of SS, environmental factors including viral infection lead to SGEC and Toll Like Receptors (TLRs) activation [12,13]. Primary viruses involved in SS induction include Epstein–Barr (EBV) viruses, Human T-lymphotropic virus type I (HTLVI), hepatitis virus C (HCV) and coxsackievirus [13].

EBV is a double stranded DNA virus appertaining to Herpesviridae family, with a strong tropism for B cells. EBV has often been associated with autoimmunity processes and diseases such as Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Multiple Sclerosis (MS) [14,15]. In addition, the high EBV load found in SG and lacrimal gland biopsies from SS patients as compared to controls [16,17] suggests its role in triggering the activation of the immune system. EBV is able to stimulate the production of proteins that mimic B cell receptor (BCR) and CD40 signalling and induce a strong B cell hyperactivity [18]. Recently, a correlation was established between past EBV infection and the presence of anti-Ro/SSA and anti-La/SSB autoantibodies in SS patients [19]. The RNA encoded by EBV binds TLR3 and induces the secretion of type I IFN and proinflammatory cytokines [20]. Another protein, the latent membrane protein 1 (LMP1) acting as a target for the EBV-induced cytotoxic T lymphocytes response may cause acini atrophy and SG lobule structure destruction observed in SS patients [21].

HTLV-1, a human endemic retrovirus in certain geographical areas such as Japan, has been reported to be present in SGEC [22]. In addition, epidemiologic studies revealed anti-HTLV-1 seropositivity in 23% of SS patients as compared to 3% in controls [23].

Coxsackie virus is a single stranded RNA virus belonging to the Picornaviridae family. A study has identified in SS patients a cross-reactivity between antibodies to the Ro60 epitope and 2B Coxsackie protein sharing 87% sequence homology [24]. However, these data remain controversial [25].

The role of HCV, a single stranded RNA small virus belonging to Flaviviridae family, has been examined in the initial triggering phase of SS. Clinical studies have shown that patients with HCV infection present sicca symptomatology, positive ocular tests, SG lymphocytic infiltration, and autoantibodies [26]. Therefore, HCV-associated SS (patients with HCV fulfilling SS 2002 classification criteria) is indistinguishable from pSS. On this basis, HCV chronic infection should be considered as an exclusion criterion for pSS as HCV infection could participate to SS development in a subset of patients.

Despite possible involvement of viral infection in SS, the most common antiviral drugs do not seem to show real benefit in the treatment of SS [26]. Indeed, as a viral infection may likely trigger onset of the disease, later antiviral treatment may manage a persistent infection but have no effect on the ongoing disease that may no longer be dependent on the presence of the initial viral infection.
