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Advances in understanding the pathogenesis of primary Sjögren's syndrome

Nature Reviews Rheumatology volume 9, pages 544–556 (2013)Cite this article

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Abstract

Primary Sjögren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.

Key Points

  • Environmental triggers promote activation of the innate immune system and the production of interferons (IFNs), which, in susceptible individuals, represent the first stages of primary Sjögren's syndrome (pSS) pathogenesis

  • B-cell-activating factor is induced by type I and type II IFNs and has a key role in activating autoreactive B cells; other cytokines such IL-21 could also be important for this process

  • Continuous B-cell activation as a result of the autoimmune response and subtle deficiencies in the control of nuclear factor κB activation might underlie increased lymphomagenesis associated with pSS

  • IL-12 is a central cytokine in pSS pathogenesis, promoting activation of the type II IFN system via both the innate (natural killer cells) and the adaptive (type 1 T-helper cells) immune systems

  • Epithelial cells are major players in pSS pathogenesis, not only as targets of disease, but also as drivers of the disease process that promote overactivation of the immune system

  • Many similarities exist between systemic lupus erythematosus and pSS pathogenesis; the main pathogenetic difference is the mucosa tropism of pSS, the basis for which remains unknown

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Figure 1: Schematic representation of the pathophysiology processes hypothesized to underlie pSS, based on our current understanding.

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  1. Service de Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud, Institut Pour la Santé et la Recherche Médicale (INSERM) U1012, 78 rue du Général Leclerc, Le Kremlin Bicêtre, 94275, France

    Gaëtane Nocturne & Xavier Mariette

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Nocturne, G., Mariette, X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol 9, 544–556 (2013). https://doi.org/10.1038/nrrheum.2013.110

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