Salivary Glands

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.

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.

BackgroundSjögren's syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein-estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS.MethodsThe effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin-eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα-XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe2+, and mitochondrial changes were measured to evaluate ferroptosis of SGECs.ResultsIn NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing.ConclusionsGenistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes.

Parallel to and after publication of the WHO 2024 classification of head and neck tumors, several developments concerning known existing salivary gland tumor entities, but also proposing new evolving tumor entities have been published. This review article describes the most important new developments in salivary gland pathology published through 2022-2025, that were not included in the 5th edition of the WHO Classification of Head and Neck Tumours 2024. This review summarizes these recent developments in both the benign and the malignant tumor categories. Among the recently proposed entities are palisading adenocarcinoma, microcribriform adenocarcinoma, fenestrating adenocarcinoma and skin-analogue poroid carcinoma. Developments in existing carcinoma entities include recognition of mucoacinar carcinoma as subtype of mucoepidermoid carcinoma (MAML2-fused), mucoepidermoid carcinoma without squamous cell differentiation, metatypical adenoid cystic carcinoma, and adenoid cystic carcinoma with prominent tubular hypereosinophilia. In the benign tumor category, recognition of pleomorphic adenoma with canalicular/trabecular phenotype driven by HMGA2 fusions, triphasic basal cell adenoma with S100 protein-positive "stroma", characterized by CTNNB1 mutations, metaplastic Warthin tumor with KRAS mutations and delineation of thymus-like phenotype in non-sebaceous lymphadenoma with recurrent CYLD mutations are the main highlights. Emerging concepts include benign tumor with ductal and papillary morphology (sialadenopapillary ductal tumor). Finally, new grading schemes have been developed/ proposed for acinic cell carcinoma and secretory carcinoma.