EBV and other viruses as triggers of tertiary lymphoid structures in primary Sjögren’s syndrome

Abstract

Sjögren's syndrome (SS) is an autoimmune disease that targets salivary (SG) and lachrymal glands, leading to exocrine dysfunction. Several viruses have been associated with SS, although the role of persistent viral infections in triggering and/or perpetuating the disease is still a matter of controversy. Together with exocrine dysfunction, SS is characterised by the production of autoantibodies and the presence of lymphomonocytic periductal aggregates in the SG, which in 30/40% of the patients display features of tertiary lymphoid structures (TLS) supporting an ectopic germinal centre response. Here we first review i) the relevance of TLS in SS and ii) the evidence in support of a role for viruses in SS insurgence and/or persistence; next, iii) we review recent data which links viral infection with TLS formation in the SG and suggests that viral-host interactions within TLS favour breach of tolerance and development of autoimmunity in SS.

Keywords::

• autoimmunity
• EBV
• ectopic germinal centers
• Sjögren’s syndrome
• tertiary lymphoid structures
• viruses

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Viral infection has long been associated with the development of autoimmunity and Sjögren’s syndrome (SS), but the involvement of one or more viral pathogens in SS is still controversial.

• Activation of the type-I interferon signature, critical for immune surveillance against viruses, is a typical feature of SS patients and genetic variability in critical genes regulating the type-I interferon pathway has been discovered in SS patients.

• Tertiary lymphoid structures (TLS) are lymphoid aggregates forming in non-lymphoid tissues in chronic inflammatory diseases and acquiring features normally restricted to secondary lymphoid organs.

• TLS in SS salivary glands (SG) support functional germinal centers that promote autoreactive B-cell activation, autoantibody production and progression toward B-cell lymphoma.

• In response to viral infections at mucosal site, that is, influenza virus, TLS formation is a physiological process that is required to mount a protective antiviral immune response.

• In animal models of sialoadenitis, an SS-like disease, associated with the development of TLS, autoimmunity and exocrine dysfunction can be driven by viral infection of murine SG.

• TLS in the SG of SS patients are preferential sites for Epstein–Barr virus (EBV) latency and reactivation.

• EBV reactivation is frequently observed among in situ differentiated autoreactive plasma cells, suggesting a critical role for EBV in breach of tolerance and autoimmunity within TLS.