6 weeks of age, consisting mainly of T-lymphocytes, are responsible for the increased MMP and cathepsin-H expression, initiating the ECM degradation [90].

3.5Pathogenetic Factors

3.5.1Genetic Predisposition

The role of genetics in SjS is addressed in detail in Chap. 2. However, a genetic predisposition for the development of SjS is indicated by several clinical and molecular associations. Family members of SjS patients have a higher incidence of SjS and a higher prevalence of serological autoimmune abnormalities than do ageand sex-matched controls. SjS is associated with increased frequencies of HLA-B8, HLA-Dw3, and HLA-DR3 [91, 92]. Molecular immunogenetics have shown that the majority of primary SjS patients carry the DQA1*0501 allele independent of racial and ethnic differences, suggesting that this allele may be a determining factor in the predisposition of certain individuals to primary SjS [93].

The limited number of genome-wide association studies performed in SjS to date have revealed significant genetic associations [94]. Associations of gene polymorphisms outside the HLA-locus with SjS are noteworthy, particularly those that influence the type-I IFN response. In this regard, the genetic association of IRF5 rs2004640 T allele with predisposition to SjS has been confirmed [95]. Another study has found a correlation between IRF5 (CGGGG indel, SNP rs10488631) and STAT4 (SNP rs7582694) polymorphisms and SjS development in a Swedish and Norwegian cohort [96]. The odds ratio in subjects with the risk alleles from both genes was 6.78-fold larger than that found in SLE. These findings indicate that a genetic susceptibility favoring a higher IFN response to different stimuli could be a key event in the onset or perpetuation of the disease.

3.5.2Environmental Factors

As for many autoimmune diseases, environmental factors and particularly viral infections have been also considered as the main triggering agents for SjS. Viral implication is suggested by three observations. First, the aberrant immune response in SjS cannot be explained solely by activation factors, attributed to the inflammatory microenvironment. Thus, the majority of the infiltrating lymphocytes are CD4+/ CD45RO+/Bcl-2+ [7, 57] memory T cells whose antigenic specificity, self or nonself, remains unknown. In addition, in chronic lesions, B cells undergo oligoclonal expansion and organize with T cells and dendritic cells (DCs) to form ectopic follicles. The factor(s) of the ectopic germinal center formation is(are) unknown. Furthermore, epithelial cells produce proinflammatory cytokines in the relative absence of professional antigen-presenting cells implying an activated phenotype that is not directly explained by an autoimmune process against epithelial cell antigens [97].

Table 3.4 List of viruses that have been implicated in SjS pathogenesis

Type of virus References

Cytomegalovirus (CMV)

Epstein–Barr (EBV)

Retroviruses

Human herpes virus type 6 (HHV6)

Human T lymphotropic virus type I (HTLV-1)

Human herpes virus type 8 (HHV-8)

Coxsackievirus

Finally, studies with the use of complementary DNA (cDNA) microarray in salivary gland biopsies have shown overexpression of type I IFN-inducible genes, including IFN-stimulated transcription factor 3g (ISGF3G), and IFN-induced transmembrane proteins such as IFITM1 [98, 99]. Increased production of type I IFNs can be initiated in response to “pathogen-associated molecular patterns” (PAMPs) detected by cell surface or endosomal Toll-like receptors (TLRs). TLRs 3, 4, 8, and 9, as well as the receptor CD91 (involved in antigen presentation to MHC class I and II molecules, via cross priming mechanisms) are functionally expressed in epithelial cells [63–65]. TLR8 and TLR9 sense nucleic acids (single-stranded RNA and prokaryotic unmethylated CpG-DNA, respectively) on endosomal membranes.

The identity of the IFN-inducing nucleic acids in the affected salivary glands remains elusive, and their role in the induction of IFN response genes is still unidentified. Taken all together, it is still unclear whether the syndrome is initiated or perpetuated by an exogenous pathogen such as a persisting single-stranded RNA or DNA virus (activating TLR8 or TLR9 PAMP receptors, respectively) or an endogenous small nuclear or cytoplasmic RNA, associated with the Ro or La autoantigens [100].

Second, certain known viruses, such as the hepatitis C virus (HCV), have often been detected in salivary gland epithelial cells of patients with chronic sialadenitis. This provides evidence that a single-stranded epitheliotropic RNA virus has the capacity of establishing a persistent epithelial cell infection of the salivary glands associated with lymphocytic periductal infiltrates that are often indistinguishable from primary SjS when examining salivary gland biopsies. The difference with primary SjS is mainly clinical, since HCV patients present with different systemic manifestations as well as an increased risk of lymphoma development arising from the salivary glands. These patients do not have circulating anti-Ro/SS-A and anti- La/SS-B autoantibodies.

Third, several studies have shown that certain viruses harbor the salivary glands of SjS patients (Table 3.4). Epstein–Barr virus genes and reactivation antigens, endogenous retroviral particles, and coxsackieviral sequences and capsid proteins