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Review
. 2024 Jul 10:15:1405126.
doi: 10.3389/fimmu.2024.1405126. eCollection 2024.

Advances in cellular and molecular pathways of salivary gland damage in Sjögren's syndrome

Wenxia Qi  1 , Jiexiang Tian  2 , Gang Wang  2 , Yanfeng Yan  3 , Tao Wang  2 , Yong Wei  1   2 , Zhandong Wang  1 , Guohua Zhang  1 , Yuanyuan Zhang  1   2 , Jia Wang  1
Affiliations
Review

Advances in cellular and molecular pathways of salivary gland damage in Sjögren's syndrome

Wenxia Qi et al. Front Immunol. .

Abstract

Sjögren's Syndrome (SS) is an autoimmune disorder characterized by dysfunction of exocrine glands. Primarily affected are the salivary glands, which exhibit the most frequent pathological changes. The pathogenesis involves susceptibility genes, non-genetic factors such as infections, immune cells-including T and B cells, macrophage, dendritic cells, and salivary gland epithelial cells. Inflammatory mediators such as autoantibodies, cytokines, and chemokines also play a critical role. Key signaling pathways activated include IFN, TLR, BAFF/BAFF-R, PI3K/Akt/mTOR, among others. Comprehensive understanding of these mechanisms is crucial for developing targeted therapeutic interventions. Thus, this study explores the cellular and molecular mechanisms underlying SS-related salivary gland damage, aiming to propose novel targeted therapeutic approaches.

Keywords: Sjögren’s syndrome; cellular; molecular biology; pathomechanisms; salivary gland damage.

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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
Pathologic mechanisms of salivary gland damage in Sjögren’s syndrome. Viral infection, hormonal imbalance, genetic susceptibility, and apoptosis lead to activation of SGECs, resulting in the release of the intracellular antigens Ro/La onto the surface of SGECs. Ro and La proteins activate immune cells on the extramembrane surface via TLR, and CD4+ T lymphocytes are activated via MHC-II molecules, which are expressed on the surface of SGECs.Activated CD4+T cells differentiate into Th17, Th1, and Tfh cells in response to inflammatory cytokines.SGECs interact with CD4+ T cells through inflammatory cytokines, repressors, leading to the production of pro-inflammatory cytokines (IL-21, IL-17, IFN-γ, TNF-α).With the involvement of BAFF, CD4+ T cells activate B lymphocytes, ultimately leading to the formation of autoantibodies and germinal centers. Abnormal upregulation of TGF-β1 in SGECs leads to morphological and functional mesenchymal changes in SGECs through activation of the TGF-β1/SMAD/Snail signaling pathway, which contributes to the process of SG fibrosis. Prolonged inflammatory stimulation results in a marked elevation of ATP, which activates P2X7R, and activated P2X7R allows NLRP3 to enter the cytoplasm thereby activating the NLRP3 inflammatory vesicles. activation of NLRP3 generates activated Caspase-1, which in turn cleaves the GSDMD, which punches holes in the cytosol at the N-terminal end, releasing mature IL-1β, IL-18, and thus activating the initial T cells, the differentiate into Th1 and Th17, which further secrete inflammatory cytokines.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The research was supported by two National Natural Science Foundation of China (81960832, 81860858) and the Natural Science Foundation of Gansu Province for 2 projects (21JRI1RA158, 22JR11RA131).

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