The Involvement of Alarmins in the Pathogenesis of Sjögren's Syndrome

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS.

Keywords: Sjögren’s syndrome; alarmins; autoimmunity; cytokines; damage associated molecular pattern; innate immunity.

Figure 1

Hypothesis of the contribution of nuclear alarmins to the pathogenesis of Sjögren’s syndrome. Apoptotic and necrotic SGEC are a potent source of nuclear alarmins. Once in the extracellular milieu, they bind to their receptor, leading to the secretion of pro-inflammatory cytokines following the activation of intracellular pathways such as NF-κB. IL-33 works in concert with IL-12 to activate NK and NKT cells, thus promoting the release of IFN-γ. IFN-γ in turn acts on SGEC to further release IL-33 in the extracellular milieu, thereby constituting a vicious auto-inflammatory loop.

Figure 2

Hypothesis of the contribution of extracellular alarmins to the pathogenesis of Sjögren’s syndrome. Apoptotic and necrotic SGEC are a potent source of extracellular alarmins. Once in the extracellular milieu, they bind to their receptor, leading to the secretion of pro-inflammatory cytokines through the activation of intracellular pathways such as NF-κB or via the activation of NLRP3 inflammasome. DC are activated and are a potent source of IFN-γ. IFN-γ in turn acts on SGEC to further release alarmins in the extracellular milieu, thereby constituting a vicious auto-inflammatory loop. HSP can also be captured by surrounding APC, allowing cross-presentation of the pept i confirm ides by MHC I that further contribute to progression toward autoimmunity by activating CD8+ and CD4+ T cells.

Figure 3

Hypothesis of the contribution of granule-derived, plasma membrane and extra-cellular matrix alarmins to the pathogenesis of Sjögren’s syndrome. Apoptotic and necrotic SGEC are a potent source of granule-derived, plasma membrane and extra-cellular matrix alarmins. Neutrophils contribute to the release of α-defensin. Once in the extracellular milieu, they bind to their receptor, leading to the secretion of pro-inflammatory cytokines through the activation of intracellular pathways such as NF-κB. DC are recruited and activated by α and β-defensin, leading in type I IFN secretion. IFN-γ acts on SGEC to further release alarmins in the extracellular milieu, thereby constituting a vicious auto-inflammatory loop. DC activation further contributes to the progression toward autoimmunity by activating the adaptive immune system.