**1. Introduction**

The pathogenesis of Sjögren's syndrome (SS), which affects salivary glands (SGs) as well as lacrimal glands (LGs), involves multiple factors including genetic elements [1–3] and subsequent environmental factors [4]. The clinical characteristics of individuals with SS are exocrine dysfunction (e.g., xerostomia and xerophthalmia) with the appearance of autoantibodies (including anti-Ro/SS-A and La/SS-B antibodies) [5]. With respect to genetic elements of SS, human leukocyte antigen (HLA) alleles have shown the strongest association with SS, and significant variations in HLA alleles by ethnicity have been revealed. Environmental factors that affect gender differences or the production of various autoantibodies may exert estrogen deficiency-mediated immunological effects [6] or alterations of the oral microbiome [7].

In addition, viral infections are profoundly associated with the activation of innate immunity, followed by an acquired immune response. Recognition of single-stranded ribonucleic acid (RNA) by toll-like captor 7/9 was a representative sensor of innate immunity in SS [8,9]. With the activation of an innate immunity signal with an interferon-gamma (IFN-γ) signature in viruses, the subsequent function of antigen presentation through the induction of major histocompatibility complex (MHC) is followed by an expansion of antigen-specific autoreactive T cells. In contrast, some viruses have a unique characteristic, i.e., a so-called in vivo 'reactivation' by various stimuli up to years after the

initial infection [10]. In this review, we provide a comprehensive explanation of the roles of viruses that cause a breakdown of immune tolerance or modulation of the immune system in the pathogenesis of SS, and we describe the various detection analyses that have been used for these viruses. We focus on the actions of Epstein-Barr virus (EBV) and retroviruses by comparing the effects of these viruses in salivary glands of individuals with Sjögren's syndrome, as well as on the epidemiological and immunological findings.
