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Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome

Abstract

Sjögren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. The involvement of these glands is characterized by focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Immunologically-activated or apoptotic glandular epithelial cells that expose autoantigens in genetically predisposed individuals might drive autoimmune-mediated tissue injury. Alterations in several immune mediators, such as upregulation of type I interferon-regulated genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23–type 17 T-helper cell pathway, have been reported. Extension of the pathological process that affects the exocrine glands into periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic findings that involve the lungs, liver or kidneys. These manifestations develop as a result of lymphocytic invasion or an immune-complex-mediated process, or both, and present as skin vasculitis coupled with peripheral neuropathy or glomerulonephritis (or both). Patients with systemic extraepithelial manifestations display low serum levels of the complement component C4 and mixed type II cryoglobulins, and show an increased risk of developing non-Hodgkin lymphoma, thereby reflecting an overall worse prognosis with higher mortality rates than those without extraepithelial manifestations.

Key Points

  • At the molecular and cellular levels, epithelial cells have an important role in the initiation and perpetuation of autoimmune lesions in Sjögren's syndrome (SS)

  • Antigen presentation, apoptosis, chemokine production or germinal center formation lie at the center of SS pathogenesis; epithelial cells have a key role in all these processes

  • Alterations in a number of immune mediators contribute to chronic immune dysregulation

  • These changes include: upregulation of type I-interferon-regulated genes; abnormal expression of B-cell-activating factor; and activation of the interleukin-23–T-helper type 17 cell pathway

  • Among autoimmune diseases, SS displays the highest incidence of malignant lymphoproliferative disorders

  • Severe involvement of exocrine glands, vasculitis, low C4 levels and cryoglobulinemia at diagnosis identify specific SS patients with a high risk of lymphoma development and therefore high mortality rates

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Figure 1: Lesions in the salivary glands of patients with Sjögren's syndrome.
Figure 2: Cellular and molecular pathways implicated in the pathogenesis of Sjögren's syndrome.
Figure 3: B-cell hyperactivity, monoclonality and lymphomagenesis.

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Acknowledgements

We would like to thank Professor H. M. Moutsopoulos for his inspiration and guidance.

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M. Voulgarelis researched the data for the article, provided a substantial contribution to the discussion of content and wrote the article. A. G. Tzioufas reviewed and edited the manuscript before submission.

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Correspondence to Michael Voulgarelis.

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Voulgarelis, M., Tzioufas, A. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome. Nat Rev Rheumatol 6, 529–537 (2010). https://doi.org/10.1038/nrrheum.2010.118

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