Search

Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

The study involved a gross anatomical description of the parotid gland, mandibular gland, monostomatic sublingual gland, polystomatic sublingual gland, and zygomatic gland in 12 adult Eurasian wolves (Canis lupus lupus) (wild free-ranging individuals and their zoo counterparts), including their morphometry and microscopic evaluation using hematoxylin & eosin, mucicarmine, azan trichrome, PAS, AB pH 1.0, AB pH 2.5; AB pH 2.5/PAS, and HDI stainings. Topographically, the salivary glands were located similarly to those of other terrestrial Carnivora. The parotid gland in all wolves had a shape similar to a trapezoid (four angles). The parotid duct opened onto the fourth upper premolar (P4). The parotid gland was a branched alveolar complex that produced serous secretion. In captive specimens, the mandibular gland was a complex branched tubular gland producing mucous secretion, while in free-ranging wolves it was a branched tubuloalveolar gland producing mucoserous secretion. The monostomatic sublingual gland in free-ranging wolves was a complex branched tubuloalveolar gland that produced seromucous secretion, while in captive wolves, it revealed a mucoserous secretion character. The polystomatic sublingual gland consisted of several independent packets (from 6-7 to 7-8) and was a complex branched tubuloalveolar gland with seromucous secretion. The zygomatic duct opened onto the last upper molar tooth (M3), and this gland was a complex branched tubular gland producing mucous secretion. The anatomical and histological similarities between the salivary glands of the oral cavity in captive and free-ranging wolves, compared to other terrestrial carnivores, provide valuable insights for veterinary treatments and understanding pathological conditions. These findings emphasize the need for further research on diverse populations of wolves and related species within the Canidae family to better understand the influence of diet on salivary gland morphology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Klećkowska-Nawrot et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to investigate the clinical and laboratory characteristics of salivary gland ultrasonography (SGUS)-positive patients with primary Sjögren's syndrome (pSS) compared to SGUS-negative patients and to analyse the diagnostic value of SGUS and labial salivary gland biopsy (LSGB) grading in pSS., Methods: A retrospective analysis of patients admitted to the Affiliated Hospital of Yangzhou University between May 2019 and November 2023 was conducted. According to the OMERACT scoring system, patients with pSS were divided into an SGUS-negative group (score <2) and an SGUS-positive group (score ≥2). The patient's age, gender, clinical symptoms, laboratory parameters and diagnostic examinations were compared and analysed, and Spearman correlation analysis was used to analyse the correlation between SGUS, LSGB and influencing factors., Results: There was no significant difference in dry mouth, dry eyes, tooth loss, fever, joint pain, fatigue, interstitial lung disease or renal tubular acidosis between the two groups, although there were more patients with salivary gland enlargement in the SGUS-positive group (p < 0.05). In terms of high levels of immunoglobulin G (IgG), high levels of rheumatoid factor (RF), anti-nuclear antibody ≥1:320, anti-Sjögren's syndrome A-52KD and anti-Sjögren's syndrome B, the number of cases in the SGUS-positive group was greater than that in the SGUS-negative group (p < 0.05). LSGB samples were graded per the Chisholm-Mason system with significant differences between multiple groups. SGUS score negatively correlated with age and positively correlated with LSGB grade., Conclusion: This study showed that the SGUS score positively correlated with LSGB grade in pSS patients and negatively correlated with patient age. Thus, SGUS and LSGB are consistent in the diagnosis of pSS to reflect the degree of salivary gland involvement, and patients who are SGUS positive have high RF and IgG levels, a variety of autoantibodies positive and a tendency toward salivary gland enlargement., (© 2024 Wiley Periodicals LLC.)

Objective: Patients with primary Sjögren's syndrome (pSS) have an increased risk of lymphoma, especially mucosa-associated lymphoid tissue (MALT) lymphoma of the salivary glands. Risk factors for lymphoma are well known, but there are no studies on screening by imaging. Therefore, we aimed to assess the usefulness and adverse effects of ultrasound of the major salivary glands and neck as lymphoma screening., Method: A retrospective, single-centre, analysis of imaging studies in pSS patients was conducted. Imaging studies were classified as either screening examinations (asymptomatic patients) or occasion-related (imaging due to signs of lymphoma or at least moderate systemic activity). Results were categorized as: not suspicious; requiring control; triggering tissue sampling with exclusion of lymphoma; or triggering tissue sampling with diagnosis of lymphoma., Results: The study included 134 patients and covered 1031 patient-years. Lymphoma was diagnosed in 15 patients (11.2%), all of whom had clinical signs of lymphoma at the time of diagnosis. During this period, 569 screening examinations and 179 occasion-related examinations were conducted. None of the screening examinations detected lymphoma, but follow-up imaging was recommended in 17.1% (95% CI 14.2-20.4%) and invasive exclusion of lymphoma was performed in 0.5% (95% CI 0.1-1.5%). In contrast, lymphoma was detected in 6.1% (95% CI 3.5-10.6%) of occasion-related examinations., Conclusion: pSS patients with neither signs of lymphoma nor increased systemic disease activity did not benefit from screening. In contrast, patients with symptoms of lymphoma or at least moderate systemic activity can benefit from imaging of the neck and major salivary glands.

Background: In Sjögren's syndrome (SS)-an autoimmune disease characterized by dry mouth and eyes-salivary gland epithelial cells (SGECs) undergo ferroptosis, which disrupts their integrity and impairs saliva secretion. Apigenin, a phytoestrogen, is known to activate estrogen signalling and alleviate xerostomia in ovariectomized mice; however, its effect on SGEC survival and function in SS remains unclear. We hypothesized that apigenin alleviates SS symptoms and progression by inhibiting ferroptosis in SGECs and aimed to elucidate the underlying mechanism., Methods: Apigenin (50 mg/kg) was orally gavaged to non-obese diabetic (NOD)/LtJ female mice (SS model); changes in SS functional indicators were analyzed using mRNA sequencing and bioinformatic analyses of submandibular glands. Interferon-gamma (IFN-γ)-stimulated SGECs were used to model SS in vitro; SGEC activity and aquaporin 5 (AQP5) expression were analyzed. Immunohistochemical staining, transmission electron microscopy, RT-qPCR, western blotting and other methods were used to verify the mechanisms., Results: Apigenin significantly increased salivary secretion and AQP5 expression while inhibiting ferroptosis and immune infiltration in NOD mouse submandibular glands. The oxidative stress gene ATF3 was upregulated and GPX4 was downregulated in NOD mice compared to that in control group (ICR mice); however, apigenin reversed this effect. IFN-γ treatment downregulated AQP5, SLC7A11, and GPX4 expression while promoting ATF3 expression and ferroptosis, which was mitigated by apigenin. ATF3 knockdown increased SLC7A11 and GPX4 expression, inhibiting SS and ferroptosis. Furthermore, apigenin inhibited ferroptosis in SGECs through ESR1 binding to ATF3., Conclusion: Apigenin alleviates SS by regulating SGEC ferroptosis via the ERα-regulated ATF3/SLC7A11 axis, highlighting its therapeutic potential in SS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sjögren'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., Methods: The 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, Fe 2+ , and mitochondrial changes were measured to evaluate ferroptosis of SGECs., Results: In 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., Conclusions: Genistein 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., Competing Interests: Declarations. Ethics approval and consent to participate: This study does not involve human participants, data, or tissue. Ethics approval for the use of NOD/LtJ mice was obtained from the Animal Care and Use Committee at the Institute of Laboratory, Guangzhou Medical University, with reference number G2023-147, 2/3/2023. Informed consent is not applicable. Competing interests: The authors declare no potential competing interests., (© 2024. The Author(s).)

Background: Although the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has improved the diagnosis and management of salivary gland lesions, determining the risk of malignancy (ROM) for AUS and SUMP categories remains challenging. We investigated the role of interventional cytopathologists in refining the differential diagnosis of these categories., Methods: We searched for salivary gland fine-needle aspirations (FNAs) performed at our Institution since the publication of the first edition of MSRSGC. In our Institution, salivary gland FNAs are performed by interventional cytopathologists only. We checked for the availability of histopathology reports to calculate the risk of neoplasm (RON) and ROM. Sensitivity, specificity, negative predictive value, and positive predictive values of our FNAs were assessed by focusing on the contribution of the AUS and SUMP categories to our diagnostic accuracy., Results: 929 salivary gland FNA diagnoses were retrieved. 37.02% FNAs had an available surgical follow-up. The ROM for each category was: 6% (ND); 0 (NN); 15.15% (AUS); 1.14% (NB); 24.4% (SUMP); 66.7% (SFM); and 94.74% (M). We observed a high level of concordance between our ROM data and the values proposed by the MSRSGC; higher accuracy (93.17%) and sensitivity (97%) were obtained when the AUS category was considered as a positive index for detecting salivary neoplasms; the best diagnostic accuracy (93.33%) was obtained when the SUMP category was considered as a negative index for malignancy., Conclusion: Interventional cytopathologists play an important role in salivary gland cytopathology, as demonstrated by the overt concordance between our ROM rates and those recommended by the MSRSGC., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

The pathogenesis of Sjögren's disease (SjD) is still elusive; however, the disease is widely recognised as a multistep disorder triggered by the interplay of environmental, hormonal and genetic factors. Innate immune system plays a crucial role in the initiation of the inflammatory process, but the amplification and the perpetuation of the autoimmune process require a continual interaction between the innate and adaptive immune systems. Several important contributions elucidating SjD pathogenesis have been recently published due to emerging technologies. This review provides an overview of the recent literature focusing, in the first part, on new insights into genetic and epigenetics studies. In the second part, we will discuss new findings related to salivary epithelial glandular cells and their interaction with other immune cells, type I interferon signature and innate immunity. Finally, as ectopic germinal centres like structures in the salivary glands of patients with SjD have been critically involved in autoreactive B cell activation and have been associated with progression towards B cell lymphomas, we will focus on new insights into their regulation in SjD and novel insights into the transition to lymphoma. Hopefully, a better comprehension of SjD complexity will pave the way to highly targeted therapeutic strategies.

This review discusses the clinical utility of salivary gland ultrasonography (SGUS) and lacrimal gland ultrasonography (LGUS) in primary Sjögren's syndrome (SjS). Several studies have shown that SGUS findings improve the diagnostic performance of the recent SjS classification criteria. Lacrimal gland ultrasonography findings can also aid in the diagnosis of SjS. However, SGUS and LGUS findings correlated with salivary or lacrimal gland function and minor salivary gland biopsy findings. A better treatment response to rituximab and salivary stimulants was observed in SjS patients with lower SGUS scores. In addition, the clinical implications of Doppler ultrasonography and ultrasound elastography of the salivary and lacrimal glands were investigated in patients with SjS.This review highlights the advantages of SGUS and LGUS in the diagnosis and prediction of salivary and lacrimal gland functions and treatment response in patients with SjS. Additionally, modalities other than B-mode ultrasonography, such as Doppler ultrasonography and ultrasound elastography, have been actively studied to demonstrate the clinical utility of SjS. Ultrasonography has great advantages such as immediate performance and interpretation, no harmful complications, and no discomfort to patients. Therefore, SGUS and LGUS are potentially useful diagnostic and predictive tools for SjS.

Sjögren's disease (SjD) is a chronic autoimmune disease, in which the immune system targets exocrine glands and leads to dryness symptoms. There is an increasing need to develop novel therapeutic approach as the treatment plan has not been changed in the past decade. However, findings in mouse model may not be directly applied in patients, given the substantial differences of immune system between human and mice. In the present study, using antigens derived from human salivary A-253 cells, we established experimental Sjögren's syndrome (ESS) in mice with human immune system (HIS). HIS-ESS mice exhibited key features of human disease, including salivary hypofunction, increased serum levels of autoantibodies and tissue destruction in the salivary glands. Phenotypic analysis revealed enhanced effector B and T cell subsets, including Th1, Th17 and T follicular helper (Tfh) cells in HIS-ESS mice, while multiplex imaging analysis suggested enlarged B cell follicles and expanded memory B cells. IL-17 neutralization therapy significantly ameliorated disease pathology at both acute and chronic stages, in which B cells were mainly affected, to the less extent Th1 and Tfh cells in HIS-ESS mice. Together, HIS-ESS mouse model highly recapitulated SjD features and immunopathogenesis, which may serve as a useful tool in drug screening and pre-clinical studies., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sjögren's disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background: Sjögren's syndrome (SS) is an autoimmune disease caused by infiltrating lymphocytes. FTY720 affects the S1P signaling pathway, which plays a role in T and B cell migration from secondary lymphoid tissues to target organs. In this study, we investigate the regulatory mechanism of FTY720 in the context of SS., Method: FTY720 was given orally every day to NOD mice. The salivary flow rate (SFR) and blood glucose level were assayed every 3 weeks. Histopathological features were investigated at the end of the study. In vitro, FTY720 was added to mouse splenocytes, and changes in the lymphocyte subsets were assessed., Results: In vivo, FTY720 increased the SFR and reduced the blood glucose level. The salivary gland histological score and infiltration of the salivary glands by B and T cells were dramatically decreased. Furthermore, STAT expression in the salivary gland was decreased. In vitro, FTY720 inhibited Th17 cells, while increasing regulatory T (Treg) cells, respectively. Also, FTY720 decreased and increased the numbers of germinal center (GC) B cells and regulatory B cells (Breg cells), respectively. FTY720 decreased the IgG level in culture supernatants. Also, STAT3 activation was decreased by FTY720., Conclusion: Our results show the therapeutic potential of FTY720 in the context of SS; FTY720 prevents lymphocyte migration from secondary lymphoid organs to target organs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Sjögren's disease is a chronic autoimmune disease characterized by symptoms of oral and ocular dryness and extraglandular manifestations. Mouth dryness is not only due to reduced saliva volume, but also to alterations in the quality of salivary mucins in patients with Sjögren's disease. Mucins play a leading role in mucosa hydration and protection, where sulfated and sialylated oligosaccharides retain water molecules at the epithelial surface. The correct localization of glycosyltransferases and sulfotransferases within the Golgi apparatus determines adequate O-glycosylation and sulfation of mucins, which depends on specific golgins that tether enzyme-bearing vesicles. Here, we show that a golgin called Giantin was mislocalized in salivary glands from patients with Sjögren's disease and formed protein complexes with Gal3-O-sulfotransferases (Gal3STs), which changed their localization in Giantin-knockout and -knockdown cells. Our results suggest that Giantin could tether Gal3ST-bearing vesicles and that its altered localization could affect Gal3ST activity, explaining the decreased sulfation of MUC5B observed in salivary glands from patients with Sjögren's disease.

Background/aim: Xerostomia following (chemo-) radiotherapy (CRT) is common in head and neck (HNC) patients. This prospective study focused on investigating the link between salivary gland function and the onset of malnutrition in HNC patients., Patients and Methods: Between 2018 and 2020, 61 HNC patients scheduled for curative CRT were prospectively recruited. Nutritional status was assessed by bioelectrical impedance analysis (BIA) and xerostomia was evaluated based on the Common Terminology Criteria for Adverse Events, (CTCAE). Patient-reported outcomes for xerostomia-related symptoms, such as "dry mouth" and "sticky saliva", were also collected. Data were assessed at the beginning of therapy, during treatment, at the end of treatment, and during follow-up. Organs at risk were contoured including the submandibular and parotid glands. Dose-volume parameters were extracted for the mean Dose (D mean ), V15 Gy, V30Gy and V45Gy., Results: No correlation was found between the dosimetric parameters [D mean , V15Gy (%), V30Gy (%) and V45Gy (%)] and the occurrence of malnutrition [defined by a fat-free mass index (FFMI) <15 kg/m 2 (♀) and <17 kg/m 2 (♂) kg/m 2 and/or body-mass index (BMI) <18.5 kg/m 2 ] at any of the three time points tested. However, the volume of the parotid glands prior to therapy appeared to be related to the development of malnutrition. This effect was not observed with the submandibular glands. A cumulative parotid gland volume of 55.3 cm 3 was identified as the threshold for malnutrition at the second follow-up examination., Conclusion: Although none of the dosimetric factors were associated with the development of malnutrition, the baseline parotid gland volume emerged as an independent predictor of malnutrition in head and neck cancer patients with xerostomia., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Salivary gland involvement is a common feature of rheumatologic disease. The authors review the anatomy of the major salivary glands and the uses of imaging modalities such as ultrasound, MRI, computed tomography, sialography, and scintigraphy in evaluating the major salivary glands in rheumatologic disease., Competing Interests: Disclosures Dr D. Mar has no disclosures or conflicts of interest to report. Dr R.M. Fairchild receives research funding from BeiGene, United States., (Published by Elsevier Inc.)

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., Competing Interests: 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., (Copyright © 2024 Ma, Feng and Lin.)

Introduction: Primary Sjögren's syndrome (pSS) is an autoimmune disorder primarily affecting salivary and lacrimal glands, although about 40% of patients experience systemic complications. In this setting, the identification of patient phenotypes characterized by increased risk of extra-glandular involvement still represents an unmet need., Areas Covered: The aim of this paper is to review the scientific evidence on the utility of salivary gland biopsies in pSS, emphasizing their role in defining prognosis. In latest years, research focused on disease-specific clinical, serological, or histological features able to categorize patient prognosis. Among histopathological features, focus score and ectopic germinal centers exhibit associations with glandular and extraglandular manifestations, including higher rates of lymphomagenesis., Expert Opinion: Pathological characterization of salivary glands provides information that go beyond a mere diagnostic or classification utility, providing insights for a stratification of disease severity and for predicting systemic manifestations. Thus, a salivary gland biopsy should be offered to all patients and included in routine practice, even when not strictly required for diagnostic purposes. More advanced analysis techniques of the tissue, including immunohistochemistry and 'omics' should be further explored in longitudinal studies to boost the ability to further stratify and predict disease evolution.

Context.—: Fine-needle aspiration (FNA) is a well-established procedure for the diagnosis and management of salivary gland lesions, despite challenges imposed by salivary gland tumor diversity, complexity, and cytomorphologic overlap. Until recently, the reporting of salivary gland FNA specimens was inconsistent among different institutions throughout the world, leading to diagnostic confusion among pathologists and clinicians. In 2015, an international group of pathologists initiated the development of an evidence-based tiered classification system for reporting salivary gland FNA specimens, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). The MSRSGC consists of 6 diagnostic categories, which incorporate the morphologic heterogeneity and overlap among various nonneoplastic, benign, and malignant lesions of the salivary glands. In addition, each MSRSGC diagnostic category is associated with a risk of malignancy and management recommendations., Objective.—: To review the current status of salivary gland FNA, core needle biopsies, ancillary studies, and the beneficial role of the MSRSGC in providing a framework for reporting salivary gland lesions and guiding clinical management., Data Sources.—: Literature review and personal institutional experience., Conclusions.—: The main goal of the MSRSGC is to improve communication between cytopathologists and treating clinicians, while also facilitating cytologic-histologic correlation, quality improvement, and research. Since its implementation, the MSRSGC has gained international acceptance as a tool to improve reporting standards and consistency in this complex diagnostic area, and it has been endorsed by the 2021 American Society of Clinical Oncology management guidelines for salivary gland cancer. The large amount of data from published studies using MSRSGC served as a basis for the recent update of the MSRSGC., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Sjӧgren's syndrome (SS), also known as Sjögren's disease, is a chronic autoimmune condition predominantly affecting the salivary and lacrimal glands. The disease is driven by autoimmune responses involving the activation and actions of major innate- and adaptive immune cell subsets. However, the specific characteristics and roles of regulatory T cells (Tregs) in SS remain elusive. This study seeks to clarify the main phenotypic and functional attributes of Tregs in the salivary glands and their draining lymph nodes in murine models of SS. Our flow cytometric analysis revealed that Tregs in the salivary gland-draining lymph nodes of female non-obese diabetic (NOD) mice, a spontaneous model of SS, exhibited a greater proportion of activated Tregs and fewer resting Tregs compared to Balb/c mice. Furthermore, Tregs from the salivary gland-draining lymph nodes of female C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mice, a model for primary SS, demonstrated significantly lower IL-10 production but markedly higher IFNγ- and IL-17 production than their C57BL/6 counterparts. Additionally, treatment of C57BL/6 Tregs with IL-7, a cytokine critical for SS pathogenesis, resulted in diminished IL-10 production and enhanced IFNγ and IL-17 production in these cells. Notably, the alterations in B6.NOD-Aec Tregs also included an increased expression of the immune-inhibitory molecule CTLA-4 compared to the C57BL/6 Tregs. Intriguingly, in vitro co-cultures of Tregs with conventional CD4 T cells and other key immune populations from lymph nodes indicated that Tregs from salivary gland-draining lymph nodes of both B6.NOD-Aec and C57BL/6 strains exhibited comparable and limited immunosuppressive effects on the proliferation and function of conventional CD4 T cells. The ability of B6.NOD-Aec Tregs to directly inflict damages to salivary gland epithelial tissues and contribute to SS pathologies through IFNγ and IL-17 that they produce warrants further investigations. In addition, enhancing the relatively weak immunosuppressive capacities of these Tregs may also serve as a viable strategy to alleviate the SS phenotype in the mouse models and potentially in patients., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Intermittent fasting exerts a profound beneficial influence on a spectrum of diseases through various mechanisms including regulation of immune responses, elimination of senescent- and pathogenic cells and improvement of stem cell-based tissue regeneration in a disease- and tissue-dependent manner. Our previous study demonstrated that alternate-day fasting (ADF) led to alleviation of xerostomia and sialadenitis in non-obese diabetic (NOD) mice, a well-defined model of Sjögren's syndrome (SS). This present study delved into the previously unexplored impacts of ADF in this disease setting and revealed that ADF increases the proportion of salivary gland stem cells (SGSCs), defined as the EpCAM hi cell population among the lineage marker negative submandibular gland (SMG) cells. Furthermore, ADF downregulated the expression of p16 INK4a , a cellular senescence marker, which was concomitant with increased apoptosis and decreased expression and activity of NLRP3 inflammasomes in the SMGs, particularly in the SGSC-residing ductal compartments. RNA-sequencing analysis of purified SGSCs from NOD mice revealed that the significantly downregulated genes by ADF were mainly associated with sugar metabolism, amino acid biosynthetic process and MAPK signaling pathway, whereas the significantly upregulated genes related to fatty acid metabolic processes, among others. Collectively, these findings indicate that ADF increases the SGSC proportion, accompanied by a modulation of the SGSC property and a switch from sugar- to fatty acid-based metabolism. These findings lay the foundation for further investigation into the functionality of SGSCs influenced by ADF and shed light on the cellular and molecular mechanisms by which ADF exerts beneficial actions on salivary gland restoration in SS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The complex nature of Sjögren's Disease (SjD) necessitates a comprehensive and patient-centered approach in both diagnosis and management. This narrative review emphasizes the need for a holistic understanding of the connection between salivary gland inflammation and oral symptoms in SjD., Areas Covered: The intricate relationship between salivary gland inflammation and dry mouth is explored, highlighting the variability in associations reported in studies. The association of the severity of xerostomia and degree of inflammation is also discussed. The frequent presence of recurrent sialadenitis in SjD further accentuates the connection of compromised salivary gland function and inflammation. The review additionally discusses local inflammatory factors assessed through salivary gland biopsies, which could potentially serve as predictors for lymphoma development in SjD. Insights into compromised quality of life and hypercoagulable state and their association with salivary gland inflammations are provided. Advancements in noninvasive imaging techniques, particularly salivary gland ultrasonography and color Doppler ultrasound, offer promising avenues for noninvasive assessment of inflammation., Expert Opinion: There is a need for longitudinal studies to unravel the connections between salivary gland inflammation and oral symptoms. This will enhance management strategies and optimize treatment outcomes for SjD patients.

The purpose was to identify transactivation DNA-binding protein-related genes in salivary gland injury in primary Sjögren syndrome (pSS) in southwest China. We downloaded the datasets of GSE7451, GSE23117, and GSE40611. In order to screen the candidate genes, 2 kinds of machine learning algorithms were used. We collected blood from 28 patients and 20 controls to verify the expression of candidate genes using quantitative real-time polymerase chain reaction. The receiver operating characteristic curve was used to evaluate the diagnostic efficiency. Correlations between candidate genes and immune cells were examined. A total of 31 differentially expressed genes were obtained. Through different algorithms, 6 genes including IFIT1, CSF2RB, TRIM22, PPM1H, VAMP7, and C21orf2 were getted. Validation results suggested that the expression of CSF2RB, VAMP7, IFIT1, C21orf2, and TRIM22 was significantly increased in pSS. The area under the curve of CSF2RB was 0.937 and that of TRIM22 was 0.915. Immune infiltration analysis showed that the percentage of activated mast cells was lower than the controls (P = .025). Correlation analysis suggested that CSF2RB was associated with immune cell infiltration. The expression of CSF2RB was significantly upregulated, which could be related to the increase of γδ T cells. We revealed that CSF2RB could be the candidate gene of pSS. CSF2RB was involved by regulating various immune cells. The expression of CSF2RB was significantly upregulated, which was related to the increase of γδ T cells., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aimed to compare the salivary gland ultrasonography(SGUS) findings in patients with primary Sjögren's Syndrome (pSS) and diabetes mellitus(DM) patients with sicca symptoms and to examine the relationship between salivary gland ultrasonography (SGUS) findings with clinical and laboratory parameters., Methods: In this study, 34 patients with pSS and 34 DM patients with sicca symptoms were included. In all patients, bilateral parotid, and submandibular gland ultrasonography (totally 272 glands) was performed by blinded rheumatologist, using the Hocevar and the Outcome Measures in Rheumatology (OMERACT) scoring system. Clinic and ultrasonographic variables were compared between groups. The association between SGUS score and disease duration was analyzed by correlation analysis., Results: Patients with pSS presented significantly higher SGUS scores than patients with DM (the Hocevar score; 20.93(± 9.65) vs. 3.82(± 3.71); p < 0.05, the OMERACT score; 5.96(± 2.30) vs. 2.07(± 1.65); p < 0.05, respectively). In patients with pSS, the submandibular gland scores were significantly higher than the parotid gland scores (right; p < 0.05 vs. left; p < 0.01) while DM patients showed significantly higher parotid gland scores (right; p < 0.05 vs. left; p < 0.05). In pSS patients, the SGUS scores were associated with disease duration (r = 0.57; r = 0.50; p < 0.05), symptom duration (r = 50; r = 0.47; p < 0.05), and the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index (ESSPRI)-dryness score (r = 0.35, r = 0.36; p < 0.05). However, in DM patients, the SGUS scores are highly correlated with the ESSPRI-dryness (r = 0.74, r = 0.72; p < 0.05) and HbA1C level (r = 0.91, r = 0.86; p < 0.05)., Conclusions: This study demonstrated that major salivary gland involvement was more severe and correlated with disease duration, and submandibular gland was dominantly affected in pSS. Contrarily, in DM patients, salivary gland involvement was milder, parotid dominant and related to level of dryness and HbA1C, rather than disease duration when compared to pSS., (© 2024. The Author(s).)

In the pathogenesis and progression of Sjögren's syndrome (SS), hematopoietic cells in the peripheral circulation, tissue-resident immune cells, and parenchymal cells of salivary gland tissues (such as epithelial cells, endothelial cells, fibroblasts, etc.) all play crucial roles. These diverse cells form intricate networks and interact with each other, leading to tissue destruction and persistent chronic inflammation, ultimately causing irreversible damage in glandular function. Among these, salivary gland epithelial cells (SGECs) consistently hold a key position, characterized by their functions in expressing co-stimulatory and antigen-presenting molecules and secreting pro-inflammatory cytokines and chemokines. Moreover, SGECs actively engage in and facilitate the development of specific pathological structures within the salivary gland, such as lymphoepithelial lesions (LELs) and tertiary lymphoid structures (TLSs), thereby substantially elevating the risk of mucosa-associated lymphoid tissue (MALT) lymphoma. Overall, SGECs are recognized for their essential and irreplaceable contributions to the pathogenesis of SS. This review article initially delves into the anatomical composition of salivary gland epithelial cells, subsequently focusing on elucidating the different cytokines derived from SGECs, encompassing chemokines, pro-inflammatory cytokines, anti-inflammatory cytokines, pro-survival cytokines, and damage-associated molecular patterns (DAMPs), to explore their key roles in the pathogenesis of SS., Competing Interests: 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., (Copyright © 2024 Dong, Wang and Wu.)

Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

Objective: The role of Helicobacter pylori (Hp) in the pathological processes of the gastric mucosa is well understood. Decreasing trend in successful eradication of HP from the stomach was observed in last years. This lack of succes is mainly caused by increasing ATB resistance. Nevertheless other possible causes of this phenomenon are being explored. Thus, many studies have focused on the search for extragastric reservoirs as potential sources of persistence or reinfection after successful Hp eradication. The pathological potential of Hp at these localities has also been studied., Methods: Our study aimed to determine the presence of Hp inside the salivary glands ductal system through its detection from sialolites. Subsequently, we tried to prove the possible ability of Hp to penetrate the salivary gland parenchyma by detecting Hp from the tissue of salivary tumors. Concrements and salivary tumor tissue samples were collected using sialendoscopy or standard surgery, and Hp detection and genotyping were performed through PCR., Results: Hp was detected in 68.3% of the sialopathy samples. VacA S1AM1 was the most common genotype. CagA-positive genotype represented only 34% of the total number of positive samples., Conclusion: Our findings of Hp positivity in concrements provide compelling evidence of Hp presence in the ductal system of salivary glands. Confirmation of Hp presence in tumor tissue suggests its potential ability to infiltrate the gland's parenchyma. Further research is needed to confirm Hp's ability to cause local infection, as well as the possible causal association between Hp presence in the studied region, sialolithiasis, and salivary gland tumors., Competing Interests: The authors report no conflicts of interest in this work.

Sjӧgren's syndrome is a systemic autoimmune disease primarily targeting the salivary and lacrimal glands. Our previous investigations have shown that administration of interleukin-22 (IL-22), an IL-10 family cytokine known for its complex and context-dependent effects on tissues, either protective- or detrimental, to salivary glands leads to hypofunction and pathological changes of salivary glands in C57BL/6 mice and in non-obese diabetic (NOD) mice, the latter being a commonly used model of Sjӧgren's syndrome. This study aims to delineate the pathophysiological roles of endogenously produced IL-22 in the development of salivary gland pathologies and dysfunction associated with Sjӧgren's disease in the NOD mouse model. Our results reveal that neutralizing IL-22 offered a protective effect on salivary gland function without significantly affecting the immune cell infiltration of salivary glands or the autoantibody production. Blockade of IL-22 reduced the levels of phosphorylated STAT3 in salivary gland tissues of NOD mice, while its administration to salivary glands had the opposite effect. Correspondingly, the detrimental impact of exogenously applied IL-22 on salivary glands was almost completely abrogated by a specific STAT3 inhibitor. Moreover, IL-22 blockade led to a downregulation of protein amounts of Ten-Eleven-Translocation 2, a methylcytosine dioxygenase critical for mediating interferon-induced responses, in salivary gland epithelial cells. IL-22 neutralization also exerted a protective effect on the salivary gland epithelial cells that express high levels of surface EpCAM and bear the stem cell potential, and IL-22 treatment in vitro hampered the survival/expansion of these salivary gland stem cells, indicating a direct negative impact of IL-22 on these cells. In summary, this study has uncovered a critical pathogenic role of the endogenous IL-22 in the pathogenesis of Sjögren's disease-characteristic salivary gland dysfunction and provided initial evidence that this effect is dependent on STAT3 activation and potentially achieved through fostering Tet2-mediated interferon responses in salivary gland epithelial cells and negatively affecting the EpCAM high salivary gland stem cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fine-needle aspiration represents a valid tool for the diagnosis/management of salivary gland lesions. The past years assessed the lack of uniform diagnostic reports for salivary cytopathology leading to interpretative issues. In 2015, an international group of cytopathologists developed an evidence-based tiered classification system for reporting salivary gland fine-needle aspiration (FNA) specimens, the "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC). The present landscape of salivary cytology is represented by the growing adoption of the MSRSGC and the assessment of its diagnostic role. The future landscape is characterized by the increasing role of ancillary techniques for diagnostic and prognostic purposes., Competing Interests: Disclosure The authors have nothing to disclose. This research did not receive any specific grant from any funding agency in the public, commercial, or not-profit sectors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: We aimed to evaluate the histopathological alterations in human salivary glands after radioactive iodine (RAI) treatment for thyroid diseases., Study Design: We retrospectively selected patients with a history of RAI treatment for thyroid diseases from a database of patients who underwent surgery for oral and maxillofacial diseases and had specimens of salivary glands at Peking University School of Stomatology between December 2012 and July 2023. The patients' clinical records and histopathological slides of the salivary glands were carefully reviewed., Results: Sixteen patients were included. Three symptomatic patients showed duct cell cytoplasmic vacuolization and increased numbers of disordered duct cell layers (3/3), severe duct stenosis and dilation (2/3), and exfoliated epithelial cells in the duct lumen (1/3). The glandular parenchyma showed severe acinar atrophy (2/2), fat content enhancement (2/2), and severe periductal fibrosis (3/3). Thirteen asymptomatic patients showed duct cell cytoplasmic vacuolization (5/13), acinar atrophy and increased fat content in the parenchyma (5/13), and periductal fibrosis (5/13)., Conclusion: Main histopathologic changes in the salivary glands after RAI treatment for thyroid diseases are cytoplasmic vacuolization of duct cells, acinar atrophy, fat content enhancement, and periductal fibrosis. These changes were evident in symptomatic cases, and were also seen in some asymptomatic patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To investigate the potential molecular mechanism of miR-34a in Sjögren's syndrome (SS). Transmission electron microscopy was used to observe the salivary gland tissues of mild and severe SS patients. SS mouse model was constructed and injected with miR-34a antagonist. HSGE cells were transfected with miR-34a mimic. Starbase predicted miR-34a binding sites and validated them with dual-luciferase reporter assays. Immunohistochemistry, HE staining, CCK-8, TUNEL assay, flow cytometry, immunofluorescence and Western Blot were used to investigate the effects of miR-34a on NF-κB signaling and mitochondrial pathway of apoptosis in HSGE cells. Severe SS patients showed obvious mitochondrial damage and apoptosis in salivary glands. MiR-34a was overexpressed and NF-κB signaling is activated in salivary glands of severe SS patients. Inhibition of miR-34a alleviated salivary gland injury in SS mice, as well as inhibited the activation of NF-κB signaling and mitochondrial pathway of apoptosis. In conclusion, miR-34a promoted NF-κB signaling by targeting IκBα, thereby causing mitochondrial pathway apoptosis and aggravating SS-induced salivary gland damage., (Copyright © 2024. Published by Elsevier Inc.)

Middle-ear salivary gland choristoma (SGCh) is a rare, benign tumor that causes conductive hearing loss owing to middle-ear morphological abnormalities. Early diagnosis is challenging, and surgical resection is indispensable for a definitive diagnosis. We report the case of a 3-year-old boy diagnosed with middle-ear SGCh during the follow-up period for left-sided hearing loss discovered at newborn hearing screening (NHS). Long-term follow-up after the NHS result, subsequent computed tomography/magnetic resonance imaging, and surgical resection led to its relatively early diagnosis and treatment., Competing Interests: No potential conflict of interest relevant to this article was reported.

The salivary glands are often damaged during head and neck cancer radiotherapy. This results in chronic dry mouth, which adversely affects quality of life and for which there is no long-term cure. Mouse models of salivary gland injury are routinely used in regenerative research. However, there is no clear consensus on the radiation regime required to cause injury. Here, we analysed three regimes of γ-irradiation of the submandibular salivary gland. Transcriptional analysis, immunofluorescence and flow cytometry was used to profile DNA damage, gland architecture and immune cell changes 3 days after single doses of 10 or 15 Gy or three doses of 5 Gy. Irrespective of the regime, radiation induced comparable levels of DNA damage, cell cycle arrest, loss of glandular architecture, increased pro-inflammatory cytokines and a reduction in tissue-resident macrophages, relative to those observed in non-irradiated submandibular glands. Given these data, coupled with the fact that repeated anaesthetic can negatively affect animal welfare and interfere with saliva secretion, we conclude that a single dose of 10 Gy irradiation is the most refined method of inducing acute salivary gland injury in a mouse model., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Sjögren syndrome (SS) is an autoimmune disease characterized by chronic inflammatory infiltrates in the salivary and lacrimal glands. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T-cells, predominantly found in mucosal tissues with crucial role in epithelial homeostasis. Thus, MAIT cells may be implicated in mucosal alterations of SS patients. Activation markers, inflammatory and cytotoxic cytokines were examined in 23 SS patients and compared to 23 healthy controls (HC). Tissular MAIT cells in salivary gland (SG) biopsies were also analyzed. Circulating MAIT cells were decreased in SS patients with a higher expression of CD69 and a higher CD4/CD8 ratio of MAIT cells. MAIT cells showed a higher production of IFNγ, TNFα and GzB in SS compare to HC. Tissular MAIT cells were present within inflamed SG of SS patients, while they were absent in SG of HC. Overall, circulating MAIT cells are decreased in the peripheral blood of SS albeit producing higher amounts of IFNγ, TNFα, and GzB. Tissular MAIT cells are detected in salivary glands from SS with a proinflammatory tissular cytokine environment. MAIT cells with abnormal phenotype, functions and tissular homeostasis may contribute to epithelial damage in SS., (© 2024. The Author(s).)

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease primarily affecting exocrine glands such as the salivary glands, leading to impaired secretion and sicca symptoms. As the mainstay of salivation, salivary gland epithelial cells (SGECs) have an important role in the pathology of pSS. Emerging evidence suggests that the interplay between immunological factors and SGECs may not be the initial trigger or the sole mechanism responsible for xerostomia in pSS, challenging conventional perceptions. To deepen our understanding, current research regarding SGECs in pSS was reviewed. Among the extensive aberrations in cellular architecture and function, this review highlighted certain alterations of SGECs that were identified to occur independently of or in absence of lymphocytic infiltration. In particular, some of these alterations may serve as upstream factors of immuno-inflammatory responses. These findings underscore the significance of introspecting the pathogenesis of pSS and developing interventions targeting SGECs in the early stages of the disease., (© 2024. The Author(s).)

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., Competing Interests: 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., (Copyright © 2024 Qi, Tian, Wang, Yan, Wang, Wei, Wang, Zhang, Zhang and Wang.)

Salivary glands' neoplasms are hard to diagnose and present a complex etiology. However, several viruses have been detected in these neoplasms, such as HCMV, which can play a role in certain cancers through oncomodulation. The co-infections between HCMV with betaherpesviruses (HHV-6 and HHV-7) and polyomaviruses (JCV and BKV) has been investigated. The aim of the current study is to describe the frequency of HCMV and co-infections in patients presenting neoplastic and non-neoplastic lesions, including in the salivary gland. Multiplex quantitative polymerase chain reaction was used for betaherpesvirus and polyomavirus quantification purposes after DNA extraction. In total, 50.7% of the 67 analyzed samples were mucocele, 40.3% were adenoma pleomorphic, and 8.9% were mucoepidermoid carcinoma. Overall, 20.9% of samples presented triple-infections with HCMV/HHV-6/HHV-7, whereas 9.0% were co-infections with HCMV/HHV-6 and HCMV/HHV-7. The largest number of co-infections was detected in pleomorphic adenoma cases. All samples tested negative for polyomaviruses, such as BKV and JCV. It was possible to conclude that HCMV can be abundant in salivary gland lesions. A high viral load can be useful to help better understand the etiological role played by viruses in these lesions. A lack of JCV and BKV in the samples analyzed herein does not rule out the involvement of these viruses in one or more salivary gland lesion subtypes.

The association between different viruses and cancer is well acknowledged in human pathology. However, the precise understanding of how oncogenic viruses intervene in the development of cancer of salivary glands (SGs) remains incomplete. Our review aimed to explore the current literature regarding SGs cancer to evaluate the potential involvement of human papillomaviruses (HPVs) in their development. Our work hypothesis suggests that viruses may be involved in these tumors' immunogenicity. The literature analysis showed HPV-positive detection in different head and neck malignancies, added to variable risk factors and a constant increasing incidence rate. HPV tumorigenesis mechanism is complex, involving E6 and E7 HPV oncoproteins. Additionally, the reported findings generally support the relationship between SGs cancer and high oncogenic subtypes 16 and 18. However, the pathogenic contribution of HPV subtypes 11, 33, 45, 52, 56, and 59 is controversial and further research may clarify their potential involvement in the SG tumor's development. This literature review may enhance the understanding of the role of viral contribution as an etiopathogenic co-factor in SG carcinogenesis. Thus, these data may add value to innovative concepts and treatment strategies development, given that virus-induced tumors can be prevented by targeted immunization, added to oncolytic or viral therapy., Competing Interests: The authors declare that they have no conflict of interests.

Objective: This systematic review was performed to examine the usefulness of salivary gland ultrasound elastography (USE) as a diagnostic tool for Sjögren's syndrome (SjS)., Methods: Electronic databases (MEDLINE, EMBASE, the Cochrane Library, and Web of Science: Science Citation Index) were searched to identify studies using USE to diagnose SjS from database inception to 15 July 2022. The primary outcome was improved diagnostic accuracy for SjS with the use of USE. Risk of bias and applicability concerns were assessed using the GRADE system, which is continuously developed by the GRADE Working Group., Results: Among 4550 screened studies, 24 full-text articles describing the applications of USE to diagnose SjS were reviewed. The overall risk of bias was determined to be low for 17 of the 24 articles, medium for 5, and high for 2. Articles comparing patients with SjS and healthy subjects reported high diagnostic accuracy of USE, with most results showed statistically significant differences (parotid glands: 15 of the 16 articles, submandibular glands: 11 of the 14 articles)., Conclusions: This systematic review suggests that the assessment of salivary glands using USE is a useful diagnostic tool for SjS., (© 2024. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

Introduction: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was proposed by American Society of Cytopathology and International Academy of Cytology to standardize reporting system ensuring uniformity and better communication between clinicians and cytopathologists., Aims and Objectives: 1. To categorize salivary lesions as per MSRSGC. 2. To establish diagnostic accuracy of MSRSGC and calculate risk of malignancy for each diagnostic category., Materials and Methods: An ambispective study was conducted over 5 years including 45 FNAC cases of salivary lesions. The cases were categorized according to Milan System, and diagnostic accuracy of MSRSGC was established. Risk of malignancy for each category was calculated., Results: The patients' age ranged from 13 to 77 years with maximum swellings in parotid (53.3%) followed by submandibular (15.6%) and submental (2.2%). Histopathological follow-up was done in all cases. The number of cases in each category was as follows: category I: 03 (6.7%), category II: 06 (13.3%), category III: 4 (8.9%), category IVA: 25 (55.6%), category IVB: 04 (8.9%), category V: 02 (4.4%), and category VI: 01 (2.2%). The calculated ROM was as follows: category I: 0%, category II: 0%, category III: 0% category IVA: 8.0%, category IVB: 25%, category V: 50%, and category VI: 100%. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy with (without) indeterminate categories for malignancy were 88.9%(96.9), 66.7%(50.0), 94.1%(94.1), 50.0%(66.7), and 85.7%(91.9), respectively., Conclusion: MSRSGC is an effective and standardized reporting system for categorization and risk stratification of salivary swellings which helps in enhancing patient care., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Background: Fine-needle aspiration cytology (FNAC) for salivary gland tumors can be challenging to due to the diversity of lesions and cytomorphological convergence between the tumors. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was hence developed and introduced to provide enhanced communication in salivary gland cytopathology. To evaluate the diagnostic utility and validity of MSRSGC in combination with ancillary radiological investigations, we aim to find correlation between Milan system and the radiological impression comparing with final histopathological diagnosis., Aims and Objective: Correlate the Milan category with the radiological and final histopathological diagnosis of salivary gland lesions. Review the FNAC diagnosis of salivary gland lesions and identify cytomorphological predictors of malignancy. Correlate the FNAC and the radiological diagnosis with final diagnosis in histopathology., Material and Methods: A five year retrospective study, comprising fifty four cases of salivary gland FNAC were included in the study., Results: Majority of the cases belong to Milan VI-Malignant followed by Milan IVa-Benign and rest of cases were among other categories. The sensitivity, specificity, positive predictive value, and negative predictive value of adjuvant radiological diagnosis in differentiating benign and malignant salivary gland lesions was found to be 80%, 62.5%, 72.7%, and 71.4%, respectively. We could observe that the concurrent radiological assessment along with Milan system of reporting in salivary gland FNAC especially under suspicious categories (Milan Category IVb as well as Milan Category V) is a useful and sensitive predictor of malignancy., Conclusion: A correlation with any form of ancillary radiological assessment is a helpful adjuvant with Milan system to derive a relatable diagnosis in salivary gland neoplasm especially those in categories describing the suspicious entities., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Necrotising sialometaplasia (NSM) is a non-neoplastic lesion mainly arising in the minor salivary glands of the oral cavity. In the clinical features, NSM shows swelling with or without ulceration, and can mimic a malignant disease such as squamous cell carcinoma. Histopathologically, NSM usually shows the lobular architecture that is observed in the salivary glands. Additionally, acinar infarction and squamous metaplasia of salivary ducts and acini are observable. The aetiology of this lesion remains unknown, although it has a characteristic feature that sometimes requires clinical and histopathological differentiation from malignancy. In this study, we investigated upregulated genes in NSM compared with normal salivary glands, and focused on the TGF-β3 (TGFB3) gene. The results of the histopathological studies clarified that fibroblasts surrounding the lesion express TGF-β3. Moreover, in vitro studies using mouse salivary gland organoids revealed that TGF-β3 suppressed salivary gland cell proliferation and induced squamous metaplasia. We demonstrated a possible aetiology of NSM by concluding that increased TGF-β3 expression during wound healing or tissue regeneration played a critical role in cell proliferation and metaplasia. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is widely accepted and endorsed by professional societies. Although several studies focusing on the MSRSGC have been published, few have been prospective studies. The objective of this study was to evaluate the effectiveness of the MSRSGC in cytopathology practice., Methods: A comprehensive literature search was conducted to identify all prospective studies on the MSRSGC. The risk of malignancy (ROM), risk of neoplasm, and diagnostic accuracy for each diagnostic category were calculated. Data were tabulated in Microsoft Excel, and analyses were performed with the Open Meta-Analyst program., Results: Seven prospective and seven retrospective studies were identified. The total number of fine-needle aspirations (FNAs) was 1587 in the prospective studies and 1764 in the retrospective studies. The ROM values for the nondiagnostic, nonneoplastic, atypia of undetermined significance, benign neoplasm, salivary gland neoplasm of uncertain malignant potential, suspicious for malignancy, and malignant categories in prospective versus retrospective studies were 21.0% versus 26.6%, 9.4% versus 8.1%, 34.9% versus 39.6%, 2.4% versus 2.1%, 36.6% versus 31.2%, 86.0% versus 66.0%, and 97.0% versus 96.7%, respectively. Sensitivities, specificities, and diagnostic odds ratios were 83.1% (95% confidence interval [CI], 71.1%-90.8%) versus 89.1% (95% CI, 83.6%-92.9%), 98.4% (95% CI, 96.6%-99.3%) versus 94.9% (95% CI, 91.9%-96.9%), and 310.7 (95% CI, 121.2-796.6) versus 218.8 (95% CI, 107.3-438.1)., Conclusions: This meta-analysis indicated that the MSRSGC works well in FNA cytopathology practice and improves diagnostic accuracy in all diagnostic categories. The ROMs of prospective studies were in concordance with the MSRSGC reference values., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Interstitial lung disease is a common complication of anti-synthetase syndrome (ASS), and lymphocytic infiltration is often observed in the lesion. We have recently reported that disease-specific autoantibodies are produced by infiltrating lymphocytes in some autoimmune diseases. Here, we investigate the antigen specificity of B cells in the lung lesions of ASS patients. A total of 177 antibodies were produced from antibody-secreting cells in bronchoalveolar fluid (BALF) of three each of serum anti-Jo-1 and serum anti-EJ antibody-positive patients. Twelve to 30% and 50 to 62% of these antibodies were disease-specific autoantibodies, respectively. These autoantibodies recognized conformational epitopes of the whole self-antigen and had affinity maturations, indicating that self-antigens themselves are the target of humoral immunity. In addition, 100 antibodies were produced from two salivary gland tissues, obtained by chance, of ASS patients. Salivary glands are not generally recognized as lesions of ASS, but unexpectedly, ASS-related autoantibody production was also observed similar to that of BALF. Immunostaining confirmed the presence of ASS-related autoantibody-producing cells in salivary glands. Our results suggest that disease-specific autoantibody production at lesion sites is a common pathogenesis of autoimmune diseases, and that tissue-specific production of autoantibodies can provide insights regarding the distribution of organ manifestations in autoimmune diseases., Competing Interests: 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., (Copyright © 2024 Takeshita, Suzuki, Nakazawa, Kamata, Ishii, Oyamada, Oshima, Usuda, Tsunoda and Takeuchi.)

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of radiotherapy (ranging from 14-18 Gy) or a fractionated dose of 8 Gy × 3 of F-PRT (128 Gy/second) or S-PRT (0.95 Gy/second). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathologic examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT-treated mice showed improvement in their salivary flow. S-PRT-irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared with the S-PRT-treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of patients with head and neck cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Sjogren's syndrome (SS) is an autoimmune disease characterized by dysfunction of exocrine glands, such as salivary glands. However, the molecular mechanism of salivary secretion dysfunction in SS is still unclear. Given the significance of glutathione peroxidase 4 (GPX4) in cellular redox homeostasis, we hypothesized that dysregulation of GPX4 may play a pivotal role in the pathogenesis of salivary secretion dysfunction observed in SS. The salivary gland of SS patients and the SS mouse model exhibited reduced expression of the ferroptosis inhibitor GPX4 and the important protein aquaporin 5 (AQP5), which is involved in salivary secretion. GPX4 overexpression upregulated and GPX4 knockdown downregulated AQP5 expression in salivary gland epithelial cells (SGECs) and salivary secretion. Bioinformatics analysis of GSE databases from SS patients' salivary glands revealed STAT4 as a key intermediary regulator between GPX4 and AQP5. A higher level of nuclear pSTAT4 was observed in the salivary gland of the SS mouse model. GPX4 overexpression inhibited and GPX4 knockdown promoted STAT4 phosphorylation and nuclear translocation in SGECs. CHIP assay confirmed the binding of pSTAT4 within the promoter of AQP5 inhibiting AQP5 transcription. GPX4 downregulation accumulates intracellular lipid ROS in SGECs. Lipid ROS inhibitor ferrostatin-1 treatment during in vitro and in vivo studies confirmed that lipid ROS activates STAT4 phosphorylation and nuclear translocation in SGECs. In summary, the downregulated GPX4 in SGECs contributes to salivary secretion dysfunction in SS via the lipid ROS/pSTAT4/AQP5 axis. This study unraveled novel targets to revitalize the salivary secretion function in SS patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Paclitaxel is a highly effective chemotherapeutic agent used to treat breast, ovarian, and other cancers. At the same time, paclitaxel causes peripheral neuropathy as a side effect in 45%-70% of patients., Aim: The aim of the study was to investigate the effect of paclitaxel-induced peripheral neuropathy on the development of pathological changes in the salivary glands of animals and to explore the possibility of correction of the identified changes with vitamin B/ATP complex., Materials and Methods: To simulate toxic neuropathy, animals were injected i/p with paclitaxel 2 mg/kg for 4 days. In order to correct the identified changes, rats were injected i/m with vitamin B/ATP complex (1 mg/ kg) for 9 days. In the homogenate of the submandibular salivary glands, α-amylase activity, total proteolytic activity, total antitryptic activity, the content of medium mass molecules, thiobarbituric acid reactive substances (TBARS), oxidatively modified proteins, and catalase activity were determined., Results: A significant increase in the content of oxidatively modified proteins, medium mass molecules, and the content of TBARS and significant decrease in the activity of catalase and amylase were determined in the salivary glands of animals with toxic neuropathy compared to these parameters in intact animals. Administration of vitamin B/ATP complex for 9 days against the background of paclitaxel-induced neuropathy led to normalization of antitryptic activity and amylase activity, a significant decrease in the content of oxidatively modified proteins, medium mass molecules, and TBARS along with a significant increase in catalase activity in the salivary glands of animals compared to the untreated rats with neuropathy., Conclusion: Paclitaxel-induced neuropathy caused the development of pathological changes in the salivary glands of rats, which was evidenced by a carbonyl- oxidative stress and impaired protein synthetic function. The correction with vitamin B/ATP complex restored the protein-synthetic function and the proteinase-inhibitor balance, suppressed the oxidative stress and normalized free radical processes in the salivary glands of rats.

Elevated oxidative stress can play a pivotal role in autoimmune diseases by exacerbating inflammatory responses and tissue damage. In Sjögren's disease (SjD), the contribution of oxidative stress in the disease pathogenesis remains unclear. To address this question, we created mice with a tamoxifen-inducible conditional knockout (KO) of a critical antioxidant enzyme, superoxide dismutase 2 ( Sod2) , in the salivary glands (i-sg- Sod2 KO mice). Following tamoxifen treatment, Sod2 deletion occurred primarily in the ductal epithelium, and the salivary glands showed a significant downregulation of Sod2 expression. At twelve weeks post-treatment, salivary glands from the i-sg- Sod2 KO mice exhibited increased 3-Nitrotyrosine staining. Bulk RNA-seq revealed alterations in gene expression pathways related to ribosome biogenesis, mitochondrial function, and oxidative phosphorylation. Significant changes were noted in genes characteristic of salivary gland ionocytes. The i-sg- Sod2 KO mice developed reversible glandular hypofunction. However, this functional loss was not accompanied by glandular lymphocytic foci or circulating anti-nuclear antibodies. These data demonstrate that although localized oxidative stress in salivary gland ductal cells was insufficient for SjD development, it induced glandular dysfunction. The i-sg- Sod2 KO mouse resembles patients classified as non-Sjögren's sicca and will be a valuable model for deciphering oxidative-stress-mediated glandular dysfunction and recovery mechanisms.

Sjögren's Disease (SjD) is an autoimmune disease of the exocrine tissues. Etiological events result in the loss of epithelial homeostasis alongside extracellular matrix (ECM) destruction within the salivary and lacrimal glands, followed by immune cell infiltration. In this review, we have assessed the current understanding of epithelial-mesenchymal transition (EMT)-associated changes within the salivary epithelium potentially involved in salivary dysfunction and SjD pathogenesis. We performed a PubMed literature review pertaining to the determination of pathogenic events that lead to EMT-related epithelial dysfunction and signaling in SjD. Molecular patterns of epithelial dysfunction in SjD salivary glands share commonalities with EMT mediating wound healing. Pathological changes altering salivary gland integrity and function may precede direct immune involvement while perpetuating MMP9-mediated ECM destruction, inflammatory mediator expression, and eventual immune cell infiltration. Dysregulation of EMT-associated factors is present in the salivary epithelium of SjD and may be significant in initiating and perpetuating the disease. In this review, we further highlight the gap regarding mechanisms that drive epithelial dysfunction in salivary glands in the early or subclinical pre-lymphocytic infiltration stages of SjD.