Role of Viral Infections in the Pathogenesis of Sjögren's Syndrome: Different Characteristics of Epstein-Barr Virus and HTLV-1

Abstract

Viruses are possible pathogenic agents in several autoimmune diseases. Sjögren's syndrome (SS), which involves exocrine dysfunction and the appearance of autoantibodies, shows salivary gland- and lacrimal gland-oriented clinical features. Epstein-Barr virus (EBV) is the most investigated pathogen as a candidate that directly induces the phenotype found in SS. The reactivation of the virus with various stimuli induced a dysregulated form of EBV that has the potential to infect SS-specific B cells and plasma cells that are closely associated with the function of an ectopic lymphoid structure that contains a germinal center (GC) in the salivary glands of individuals with SS. The involvement of human T-cell leukemia virus type 1 (HTLV-1) in SS has been epidemiologically established, but the disease concept of HTLV-1-associated SS remains unexplained due to limited evidence from basic research. Unlike the cell-to-cell contact between lymphocytes, biofilm-like structures are candidates as the mode of HTLV-1 infection of salivary gland epithelial cells (SGECs). HTLV-1 can infect SGECs with enhanced levels of inflammatory cytokines and chemokines that are secreted from SGECs. Regardless of the different targets that viruses have with respect to affinitive lymphocytes, viruses are involved in the formation of pathological alterations with immunological modifications in SS.

Keywords: Epstein-Barr virus; HTLV-1; salivary gland epithelial cell; viral infection.

Figure 1

The expression of tax/HBZ and HTLV-1 virions in salivary glands (SGs) of patients with Sjögren’s syndrome (SS). (A) Massive lymphocytic infiltration was by hematoxylin-eosin staining in a labial salivary gland from a patient with sicca symptoms and adult T-cell leukemia (ATL). The expression of tax/HTLV-1 bZIP factor (HBZ) in SGs from a patient with ATL (B) and patients with HTLV-1-associated myelopathy complicated with SS (C), examined by in situ hybridization. A dominant expression of HBZ (green) was observed in the ATL SGs in both infiltrating mononuclear cells (MNCs) and ducts (B). In contrast, a dominant expression of tax (red) was observed in MNCs of salivary glands from patients with HAM-SS (C). Electron microscopy (D) revealed the existence of HTLV-1 virions (arrowheads) at the contact face between HCT-5 cells (an HTLV-1-infected cell line) and salivary gland epithelial cells (SGECs).

Figure 2

A hypothetical scheme of the initial transmission of HTLV-1 virions. HTLV-1 virions exist with extracellular matrix proteins or linker proteins including galectin-3, agrin, and tetherin. After the initial contact of HCT-5 cells with SGECs, HTLV-1 virions are Table 1. virions by the extension of a long structure that is stretched from the surface of HCT-5 cells.

Figure 3

The different roles of EBV and HTLV-1 in the pathogenesis of SS. EBV exists in B cells and/or B cells that expresses LMP2A in ectopic lymphoid structures (ELSs) as a latent phase. Once the reactivation of EBV is induced by environmental factors (including dioxin), EBV changes to the lytic phase. Lytic EBV can infect SGECs and perifollicular EBRF⁺ plasma cells (PCs) that can react with Ro52. In contrast, HTLV-1 that bears tax and HTLV-1 bZIP factor (HBZ) infects salivary glands of patients with SS. An in vitro study showed that after the HTLV-1 infection of salivary glands, SGECs express inflammatory cytokines or chemokines including soluble ICAM-1, IP-10, and RANTES. Inhibitory effects of HTLV-1 toward ELS components (including B cells), PCs that produce anti-Ro/SS-A, La/SS-B antibodies, follicular dendritic cells (FDCs), and follicular helper T cells (Tfh) have been considered.