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Review
. 2024 Oct 14:15:1421436.
doi: 10.3389/fimmu.2024.1421436. eCollection 2024.

Immune and non-immune mediators in the fibrosis pathogenesis of salivary gland in Sjögren's syndrome

Danbao Ma  1 , Yun Feng  2 , Xiang Lin  1   3
Affiliations
Review

Immune and non-immune mediators in the fibrosis pathogenesis of salivary gland in Sjögren's syndrome

Danbao Ma et al. Front Immunol. .

Abstract

Sjögren's syndrome (SS) or Sjögren's disease (SjD) is a systemic autoimmune disease clinically manifested as sicca symptoms. This disease primarily impacts the functionality of exocrine glands, specifically the lacrimal and salivary glands (SG). SG fibrosis, an irreversible morphological change, is a severe consequence that occurs in the later stages of the disease due to sustained inflammation. However, the mechanism underlying SG fibrosis in SS remains under-investigated. Glandular fibrosis may arise from chronic sialadenitis, in which the interactions between infiltrating lymphocytes and epithelial cells potentially contributes to fibrotic pathogenesis. Thus, both immune and non-immune cells are closely involved in this process, while their interplays are not fully understood. The molecular mechanism of tissue fibrosis is partly associated with an imbalance of immune responses, in which the transforming growth factor-beta (TGF-β)-dependent epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling are recently investigated. In addition, viral infection has been implicated in the pathogenesis of SS. Viral-specific innate immune response could exacerbate the autoimmune progression, resulting in overt inflammation in SG. Notably, post-COVID patients exhibit typical SS symptoms and severe inflammatory sialadenitis, which are positively correlated with SG damage. In this review, we discuss the immune and non-immune risk factors in SG fibrosis and summarize the evidence to understand the mechanisms upon autoimmune progression in SS.

Keywords: Sjögren’s disease (SjD); Sjögren’s syndrome; epithelial-mesenchymal transition; extracellular matrix remodeling; fibrosis; infection; salivary gland.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic Illustration of Immune Mediators Involved in Modulation of Fibrosis Pathogenesis in Salivary Glands. Chronic inflammation, caused by various types of immune cells, plays a crucial role in the process of salivary gland (SG) fibrosis, driving the epithelial-mesenchymal transition (EMT) program, myofibroblast differentiation, and extracellular matrix (ECM) remodeling. In patients with Sjögren’s Syndrome, the salivary epithelium is often damaged, and numerous epithelial cells undergo apoptosis. The autoimmune reaction in situ is initiated by autoantigens released by apoptotic salivary gland epithelial cells (SGECs). The chronic inflammation in the SG is primarily caused by pro-inflammatory cytokines from effector T cells, such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-21 (IL-21), and interleukin-6 (IL-6). Transforming growth factor-beta (TGF-β), secreted by regulatory T cells (Treg cells), is the key regulator of EMT-driven fibrosis. CD8+ T cells can exacerbate tissue damage by inducing SGECs apoptosis in contact manner, via the Fas/Fas ligand (FasL) pathway and other effector molecules e.g granzyme B, perforin, IFN-γ, and TNF-α. B cells could differentiate into plasma cells and participate in the formation of ectopic germinal centers via the C-X-C motif chemokine receptor 3/chemokine ligand 10 (CXCR3/CXCL10) axis. Macrophages contribute to fibrosis by producing matrix metalloproteinases (MMPs), associated with enhanced the expression of the reactive oxygen species (ROS)-related gene hypoxia-inducible factor 1-alpha (Hif-1α). Created by BioRender.com.
Figure 2
Figure 2
Schematic Illustration of Non-Immune Mediators Associated to the Fibrotic Pathogenesis of Sjögren’s Syndrome. In terms of non-immune factors, the EMT and apoptosis of SGECs are critical processes in the development of salivary gland fibrosis. The transformation of fibroblasts into myofibroblasts is an important step in the development of SG fibrosis. This process involves the deposition of ECM, the formation of TLS, and the accumulation of inflammatory cytokines. The equilibrium between matrix MMPs, such as MMP-2 and -9, and tissue inhibitors of metalloproteinases (TIMPs), including TIMP-1 and -2, influences the degradation of ECM and facilitates the accumulation of fibronectin. The mis-localization of the aquaporin 5 (AQP5) water channel protein in SGECs may result in increased saliva osmolarity, which in turn impairs water transport, while simultaneously enhancing the production of pro-inflammatory cytokines. Viral infection represents a significant etiological factor in SS, with the SARS-CoV-2 virus, Epstein-Barr virus (EBV), human T-lymphotropic virus (HTLV-1), and human immunodeficiency virus (HIV) serving as prominent examples. Additionally, the process of SG fibrosis is influenced by other mechanisms, including oxidative stress and mitochondrial dysfunction. The diagram was created using BioRender.com.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was funded by grants through National Key Research and Development Program of China (2023YFE0203100), Mainland-Hong Kong Joint Funding Scheme (MHP/104/22), General Research Fund, Hong Kong Research Grants Council (17116521, 27111820 and 17109123), Health and Medical Research Fund (19201121 and 20212601).

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