Sjögren’s Syndrome and Environmental Factors

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Introduction

Sjögren’s syndrome (SS) is a systemic, chronic, autoimmune, inflammatory condition involving the exocrine glands. First defined as “autoimmune epithelitis” by Moutsopoulos, SS is characterized by the presence of lymphocyte infiltrates in glandular tissue that might lead, over time, to a progressive glandular dysfunction. The type I interferon (IFN) pathway is highly expressed and there is evidence of the so-called “IFN signature” in peripheral blood mononuclear cells and minor salivary gland biopsies coming from patients with SS. Expression of Toll-like receptors (TLRs) and major histocompatibility complex class I and II molecules by salivary gland epithelial cells is essential for autoantigen presentation and thus production of proinflammatory cytokines. B lymphocytes play a central role in the development of disease and the production of B-cell activating factor (BAFF) by epithelial cells together with autoantigen presentation greatly contributes to the stimulation of the adaptive immune system and the potential development of lymphoma.

Both genetic and environmental factors have been suggested to be responsible for SS development ( Fig. 10.1 ).

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Sjögren’s Syndrome and Infections

Among the environmental agents, infections seem to be the most important trigger of disease. Several infections may mimic SS, including tuberculosis; leprosy; spirochetes; hepatitis A, B, or C; parvovirus B19; dengue fever; malaria; subacute bacterial endocarditis; and HIV. In such conditions, viruses play a key role in activating the immune response; this is referred in particular to viruses expressing a specific tropism for salivary and lachrymal glandular tissue: cytomegalovirus, Epstein-Barr virus (EBV), and human herpes virus types 6, 7, and 8. These viruses are able to induce an activation of the innate immune system via TLR pathways, which consequently stimulates the production of chemokines/cytokines such as type I IFN, whose expression is up-regulated in labial salivary glands, plasma, and peripheral blood cells of SS patients. Over the last few years, an increasing body of evidence has confirmed the crucial role of type I IFNs in the multifactorial etiology of SS. The critical question that arises is what drives the production of a classical antiviral protein in the setting of autoimmunity.

It seems that one of the key targets of SS autoantibodies, Ro52, plays an essential role in the regulation of IFN production. Indeed, murine models with deficient expression of Ro52 overexpress type I IFN. After type I IFN stimulation, Ro52, which is normally located in cytoplasm, migrates to the nucleus with subsequent increase of Ro52 transcription and negative regulation of IFN production. To the same extent the phosphoprotein La seems to play a pleiotropic role. Actually, La is able to associate to small cytoplasmic RNAs as well as to viral RNA. Specifically, it interacts with the leader RNA sequence of respiratory syncytial virus, exercising a protective effect on the virus itself. As result of such interaction, IFN activation is prevented and viral growth is favored. Moreover, cells infected by EBV are able to release a small RNA–La complex that seems to bind TLR3, inducing IFN I and tumor necrosis factor (TNF) production.

In light of such considerations, we could hypothesize that after a viral infection, an increased expression of both Ro and La antigens is driven in salivary gland epithelial cells. On one hand, such overexpression might be the result of the prolonged IFN I activation and, on the other hand, of a viral strategy to escape from the immune response. In this context the inflammation pushes an increased cellular lysis and apoptosis, determining the external exposition of autoantigens and the production of autoantibodies. In addition, a certain sequence homology between the protein Ro60 and the B2 protein of Coxsackie virus has been demonstrated to be able to activate CD4+ cells by molecular mimicry. In patients with systemic lupus erythematosus, a molecular mimicry has been also discovered between Ro60 and the nuclear antigen 1 of EBV, and for this reason it has been proposed as a mechanism responsible for the epitope spreading. Oral feeding with Ro60 proved to be able to prevent the epitope from spreading and the development of sicca symptoms in an experimental model of SS.

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