*2.1. Possible Mechanism Triggered by Viral Infection in AIDs*

An acute or chronic viral infection is thought to play a crucial role as a triggering phase of the immunological instability that is required for the formulation of the chronic inflammatory condition in AIDs. As an initial step of innate immunity that involves several functions of cytotoxic T lymphocytes or natural killer T cells, the recognition of mobilized pathogens by receptors of innate immunity is required. Pathogen-associated molecular patterns (PAMPs) are common structures detected in pathogenic microbes that contribute to the initiation of innate immunity [11]. In concert with the detection of PAMPs, the concept of pattern recognition receptors (PRRs) was defined; PRRs have several molecules including toll-like receptors (TLRs), C-type lectin receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) [12–14]. Toll-like receptor 7 (TLR7) in particular is known to recognize single-stranded RNA viruses in exosomes of plasmatoid dendritic cells (pDCs) followed by a MyD88-dependent activation of the nuclear factor kappa B pathway after the assembly of tumor necrosis factor (TNF)-receptor associated factor-6 or interferon (IFN)-regulatory factor-7 (IRF-7) [15], which are associated with the induction of type I IFNs.

In our previous study, the expression of downstream signal transduction after stimulation with the TLR7 ligand was confirmed in the salivary glands of patients with SS and in an in vitro investigation using cultured epithelial cells obtained from SS patients [8], and pDCs appeared to be a source of type I IFN (including IFN-α and IFN-β). Regarding the close association between retinoic acid-inducible gene I (RIG-I)-like family signaling and SS, Maria et al. [16] demonstrated that RIG-I and melanoma differentiation associated gene-5 (MDA-5) were strongly expressed in mononuclear cells (MNCs) of salivary glands from SS patients. They also demonstrated that TLR7 stimulation had the potential to activate the signaling pathway of RIG-I-like family members in vitro. These observations suggested that TLRs and RLRs that were stimulated in salivary gland pDCs or monocytes are closely associated with RNA-sensing receptor-mediated innate immunity with the presentation of the type I IFN signature.
