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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Otolaryngology".

Deadline for manuscript submissions: closed (10 December 2020) | Viewed by 83657

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Dr. Margherita Sisto

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Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy
Interests: pathophysiology and molecular immunology applied to immunological research lines; molecular processes underlying the interaction between receptors of the immune response, inflammation and characterization of new anti-inflammatory molecules; novel therapies for Sjögren’s syndrome autoimmune disease; evaluation of the molecular mechanisms linking chronic inflammation to fibrosis in Sjögren’s syndrome and others autoimmune diseases
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Dear Colleagues,

Salivary glands (SGs) fulfill important roles in oral biology and the loss of normal SG function results in widespread deterioration of oral health, greatly impacting the quality of patients’ life. To date, no definitive therapeutic approach compensates for the impairment of SGs, and treatment is purely symptomatic. SGs were affected by a variety of diseases, local and systemic, and the prevalence of SGs diseases depends on various etiological factors. The glands may suffer from viral, bacterial, rarely fungal infections, which may cause painful swelling or obstruction, affecting their functions. The SGs may also be affected by various benign and malignant tumors which consist of a heterogeneous group of lesions with complex clinical–pathological characteristics. Overall, some serious problems for patients with SG diseases are often due to autoimmune diseases such as Sjogren’s syndrome (SS), a complex systemic autoimmune inflammatory disorder. This Special Issue entitled “Diseases of Salivary Glands” is intended to provide an overview of recent advances in the field of SG disorders and understanding the cellular and molecular mechanisms involved in the pathogenesis of SG diseases.

We cordially invite researchers, involved in basic research as well as in translational studies, to submit their original research, systematic reviews, and short communications to this Special Issue.

Prof. Dr. Margherita Sisto
Guest Editor

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Keywords

Oral medicine
Oral disease
Salivary gland dysfunction
Potentially malignant oral disorders
Cellular and molecular pathway
Autoimmune diseases

Published Papers (14 papers)

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Editorial

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3 pages, 148 KiB

Open AccessEditorial

Special Issue—“Diseases of the Salivary Glands”

by Margherita Sisto

J. Clin. Med. 2020, 9(12), 3886; https://doi.org/10.3390/jcm9123886 - 30 Nov 2020

Cited by 1 | Viewed by 1292

Abstract

Salivary glands (SGs) are of the utmost importance for maintaining the health of the oral cavity and carrying out physiological functions such as mastication, protection of teeth, perception of food taste, and speech [...] Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

Research

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8 pages, 6212 KiB

Open AccessArticle

Primary Breast Extranodal Marginal Zone Lymphoma in Primary Sjögren Syndrome: Case Presentation and Relevant Literature

by Giuseppe Ingravallo, Eugenio Maiorano, Marco Moschetta, Luisa Limongelli, Mauro Giuseppe Mastropasqua, Gisella Franca Agazzino, Vincenzo De Ruvo, Paola Tarantino, Gianfranco Favia and Saverio Capodiferro

J. Clin. Med. 2020, 9(12), 3997; https://doi.org/10.3390/jcm9123997 - 10 Dec 2020

Cited by 4 | Viewed by 1936

Abstract

The association between autoimmune diseases, mostly rheumatoid arthritis, systemic lupus erythematosus, celiac disease and Sjögren syndrome, and lymphoma, has been widely demonstrated by several epidemiologic studies. By a mechanism which has not yet been entirely elucidated, chronic activation/stimulation of the immune system, along with the administration of specific treatments, may lead to the onset of different types of lymphoma in such patients. Specifically, patients affected by Sjögren syndrome may develop lymphomas many years after the original diagnosis. Several epidemiologic, hematologic, and histological features may anticipate the progression from Sjögren syndrome into lymphoma but, to the best of our knowledge, a definite pathogenetic mechanism for such progression is still missing. In fact, while the association between Sjögren syndrome and non-Hodgkin lymphoma, mostly extranodal marginal zone lymphomas and, less often, diffuse large B-cell, is well established, many other variables, such as time of onset, gender predilection, sites of occurrence, subtype of lymphoma, and predictive factors, still remain unclear. We report on a rare case of primary breast lymphoma occurring three years after the diagnosis of Sjögren syndrome in a 57-year-old patient. The diagnostic work-up, including radiograms, core needle biopsy, and histological examination, is discussed, along with emerging data from the recent literature, thus highlighting the usefulness of breast surveillance in Sjögren syndrome patients. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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24 pages, 9021 KiB

Open AccessArticle

Immortalization of Salivary Gland Epithelial Cells of Xerostomic Patients: Establishment and Characterization of Novel Cell Lines

by Braxton D. Noll, Alexandre Grdzelishvili, Michael T. Brennan, Farah Bahrani Mougeot and Jean-Luc C. Mougeot

J. Clin. Med. 2020, 9(12), 3820; https://doi.org/10.3390/jcm9123820 - 25 Nov 2020

Cited by 3 | Viewed by 3683

Abstract

Primary Sjögren’s Syndrome (pSS) is an autoimmune disease mainly affecting salivary and lacrimal glands. Previous pSS studies have relied on primary cell culture models or cancer cell lines with limited relevance to the disease. Our objective was to generate and characterize immortalized salivary gland epithelial cells (iSGECs) derived from labial salivary gland (LSG) biopsies of pSS patients (focus score > 1) and non-Sjögren’s Syndrome (nSS) xerostomic (i.e., sicca) female patients. To characterize iSGECs (n = 3), mRNA expression of specific epithelial and acinar cell markers was quantified by qRT-PCR. Protein expression of characterization markers was determined by immunocytochemistry and Western blot. Secretion of α-amylase by iSGECs was confirmed through colorimetric activity assay. Spheroid formation and associated alterations in expression markers were determined using matrigel-coated cell culture plates. Consistent mRNA and protein expressions of both epithelial and pro-acinar cell markers were observed in all three iSGEC lines. When cultured on matrigel medium, iSGECs formed spheroids, secreted α-amylase after β-adrenergic stimulation, and expressed multiple acinar cell markers at late passages. One iSGEC line retained adequate cell morphology without a loss of SV40Lt expression and proliferation potential after over 100 passages. In conclusion, our established iSGEC lines represent a viable model for salivary research due to their passaging capacity and maintenance of pro-acinar cell characteristics. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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10 pages, 1604 KiB

Open AccessArticle

First Report of Sublingual Gland Ducts: Visualization by Dynamic MR Sialography and Its Clinical Application

by Tatsurou Tanaka, Masafumi Oda, Nao Wakasugi-Sato, Takaaki Joujima, Yuichi Miyamura, Manabu Habu, Masaaki Kodama, Osamu Takahashi, Teppei Sago, Shinobu Matsumoto-Takeda, Ikuko Nishida, Hiroki Tsurushima, Yasushi Otani, Daigo Yoshiga, Masaaki Sasaguri and Yasuhiro Morimoto

J. Clin. Med. 2020, 9(11), 3676; https://doi.org/10.3390/jcm9113676 - 16 Nov 2020

Cited by 4 | Viewed by 1959

Abstract

This study was done to determine whether the sublingual gland ducts could be visualized and/or their function assessed by MR sialography and dynamic MR sialography and to elucidate the clinical significance of the visualization and/or evaluation of the function of sublingual gland ducts by clinical application of these techniques. In 20 adult volunteers, 19 elderly volunteers, and 7 patients with sublingual gland disease, morphological and functional evaluations were done by MR sialography and dynamic MR sialography. Next, four parameters, including the time-dependent changes (change ratio) in the maximum area of the detectable sublingual gland ducts in dynamic MR sialographic images and data were analyzed. Sublingual gland ducts could be accurately visualized in 16 adult volunteers, 12 elderly volunteers, and 5 patients. No significant differences in the four parameters in detectable duct areas of sublingual glands were found among the three groups. In one patient with a ranula, the lesion could be correctly diagnosed as a ranula by MR sialography because the mass was clearly derived from sublingual gland ducts. This is the first report of successful visualization of sublingual gland ducts. In addition, the present study suggests that MR sialography can be more useful in the diagnosis of patients with lesions of sublingual gland ducts. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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20 pages, 2079 KiB

Open AccessArticle

Enhanced Salivary and General Oxidative Stress in Hashimoto’s Thyroiditis Women in Euthyreosis

by Katarzyna Morawska, Mateusz Maciejczyk, Łukasz Popławski, Anna Popławska-Kita, Adam Krętowski and Anna Zalewska

J. Clin. Med. 2020, 9(7), 2102; https://doi.org/10.3390/jcm9072102 - 03 Jul 2020

Cited by 22 | Viewed by 2543

Abstract

Hashimoto’s thyroiditis (HT) is one of the most common autoimmune diseases. Although HT is inextricably linked to oxidative stress, there have been no studies assessing salivary redox homeostasis or salivary gland function in patients with HT. This study is the first to compare antioxidant defense and oxidative stress biomarkers in non-stimulated (NWS) and stimulated (SWS) whole saliva and plasma/erythrocytes of HT patients compared to controls. The study included 45 women with HT in the euthyreosis period as well as an age- and gender-matched control group. We showed that NWS secretion was significantly lower in HT patients compared to healthy controls, similar to salivary amylase activity in NWS and SWS. Catalase and peroxidase activities were considerably higher in NWS and SWS of HT patients, while the concentrations of reduced glutathione and uric acid were significantly lower in comparison with healthy subjects. Total antioxidant potential was significantly lower, while total oxidant status and the level of oxidation products of proteins (advanced glycation end products, advanced oxidation protein products) and lipids (malondialdehyde, lipid hydroperoxides) were significantly higher in NWS, SWS and plasma of HT patients. In conclusion, in both salivary glands of women with HT in euthyreosis, the ability to maintain redox homeostasis was hindered. In HT patients we observed oxidative damage to salivary proteins and lipids; thus, some biomarkers of oxidative stress may present a potential diagnostic value. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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18 pages, 2321 KiB

Open AccessArticle

Salivary Gland Dysfunction, Protein Glycooxidation and Nitrosative Stress in Children with Chronic Kidney Disease

by Mateusz Maciejczyk, Julita Szulimowska, Katarzyna Taranta-Janusz, Anna Wasilewska and Anna Zalewska

J. Clin. Med. 2020, 9(5), 1285; https://doi.org/10.3390/jcm9051285 - 29 Apr 2020

Cited by 29 | Viewed by 4003

Abstract

This study is the first to evaluate protein glycooxidation products, lipid oxidative damage and nitrosative stress in non-stimulated (NWS) and stimulated whole saliva (SWS) of children with chronic kidney disease (CKD) divided into two subgroups: normal salivary secretion (n = 18) and hyposalivation (NWS flow < 0.2 mL min⁻¹; n = 12). Hyposalivation was observed in all patients with severe renal failure (4–5 stage CKD), while saliva secretion > 0.2 mL/min in children with mild-moderate CKD (1–3 stage) and controls. Salivary amylase activity and total protein content were significantly lower in CKD children with hyposalivation compared to CKD patients with normal saliva secretion and control group. The fluorescence of protein glycooxidation products (kynurenine, N-formylkynurenine, advanced glycation end products), the content of oxidative damage to lipids (4-hydroxynonneal, 8-isoprostanes) and nitrosative stress (peroxynitrite, nitrotyrosine) were significantly higher in NWS, SWS, and plasma of CKD children with hyposalivation compared to patients with normal salivary secretion and healthy controls. In CKD group, salivary oxidation products correlated negatively with salivary flow rate, α-amylase activity and total protein content; however, salivary oxidation products do not reflect their plasma level. In conclusion, children with CKD suffer from salivary gland dysfunction. Oxidation of salivary proteins and lipids increases with CKD progression and deterioration of salivary gland function. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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9 pages, 1646 KiB

Open AccessArticle

Intra-Cystic (In Situ) Mucoepidermoid Carcinoma: A Clinico-Pathological Study of 14 Cases

by Saverio Capodiferro, Giuseppe Ingravallo, Luisa Limongelli, Mauro Giuseppe Mastropasqua, Angela Tempesta, Gianfranco Favia and Eugenio Maiorano

J. Clin. Med. 2020, 9(4), 1157; https://doi.org/10.3390/jcm9041157 - 18 Apr 2020

Cited by 9 | Viewed by 9159

Abstract

Aims: To report on the clinico-pathological features of a series of 14 intra-oral mucoepidermoid carcinomas showing exclusive intra-cystic growth. Materials and methods: All mucoepidermoid carcinomas diagnosed in the period 1990–2012 were retrieved; the original histological preparations were reviewed to confirm the diagnosis and from selected cases, showing exclusive intra-cystic neoplastic components, additional sections were cut at three subsequent 200 m intervals and stained with Hematoxylin–Eosin, PAS, Mucicarmine and Alcian Blue, to possibly identify tumor invasion of the adjacent tissues, which could have been overlooked in the original histological preparations. Additionally, pertinent findings collected from the clinical charts and follow-up data were analyzed. Results: We identified 14 intraoral mucoepidermoid carcinomas treated by conservative surgery and with a minimum follow up of five years. The neoplasms were located in the hard palate (nine cases), the soft palate (two), the cheek (two) and the retromolar trigone (one). In all instances, histological examination revealed the presence of a single cystic space, containing clusters of columnar, intermediate, epidermoid, clear and mucous-producing cells, the latter exhibiting distinct intra-cytoplasmic mucin production, as confirmed by PAS, Mucicarmine and Alcian Blue stains. The cysts were entirely circumscribed by fibrous connective tissue, and no solid areas or infiltrating tumor cell clusters were detected. Conservative surgical resection was performed in all cases, and no recurrences or nodal metastases were observed during follow up. Conclusions: Mucoepidermoid carcinomas showing prominent (>20%) intra-cystic proliferation currently are considered low-grade tumors. In addition, we also unveil the possibility that mucoepidermoid carcinomas, at least in their early growth phase, may display an exclusive intra-cystic component and might be considered as in situ carcinomas, unable to infiltrate adjacent tissues and metastasize. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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Review

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18 pages, 3479 KiB

Open AccessReview

Candida Infection Associated with Salivary Gland—A Narrative Review

by Soo-Min Ok, Donald Ho, Tyler Lynd, Yong-Woo Ahn, Hye-Min Ju, Sung-Hee Jeong and Kyounga Cheon

J. Clin. Med. 2021, 10(1), 97; https://doi.org/10.3390/jcm10010097 - 30 Dec 2020

Cited by 10 | Viewed by 14616

Abstract

Candida species are common global opportunistic pathogens that could repeatedly and chronically cause oral mucosa infection and create an inflammatory environment, leading to organ dysfunction. Oral Candida infections may cause temporary or permanent damage to salivary glands, resulting in the destruction of acinar cells and the formation of scar tissue. Restricted function of the salivary glands leads to discomfort and diseases of the oral mucosa, such as dry mouth and associated infection. This narrative review attempts to summarize the anatomy and function of salivary glands, the associations between Candida and saliva, the effects of Candida infection on salivary glands, and the treatment strategies. Overall, clinicians should proactively manage Candida infections by educating patients on oral hygiene management for vulnerable populations, conducting frequent checks for a timely diagnosis, and providing an effective treatment plan. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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37 pages, 1868 KiB

Open AccessReview

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

by Kimberly J. Jasmer, Kristy E. Gilman, Kevin Muñoz Forti, Gary A. Weisman and Kirsten H. Limesand

J. Clin. Med. 2020, 9(12), 4095; https://doi.org/10.3390/jcm9124095 - 18 Dec 2020

Cited by 68 | Viewed by 7193

Abstract

Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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26 pages, 924 KiB

Open AccessReview

Contributions of Major Cell Populations to Sjögren’s Syndrome

by Richard Witas, Shivai Gupta and Cuong Q. Nguyen

J. Clin. Med. 2020, 9(9), 3057; https://doi.org/10.3390/jcm9093057 - 22 Sep 2020

Cited by 24 | Viewed by 4654

Abstract

Sjögren’s syndrome (SS) is a female dominated autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands and subsequent exocrine glandular dysfunction. SS also may exhibit a broad array of extraglandular manifestations including an elevated incidence of non-Hodgkin’s B cell lymphoma. The etiology of SS remains poorly understood, yet progress has been made in identifying progressive stages of disease using preclinical mouse models. The roles played by immune cell subtypes within these stages of disease are becoming increasingly well understood, though significant gaps in knowledge still remain. There is evidence for distinct involvement from both innate and adaptive immune cells, where cells of the innate immune system establish a proinflammatory environment characterized by a type I interferon (IFN) signature that facilitates propagation of the disease by further activating T and B cell subsets to generate autoantibodies and participate in glandular destruction. This review will discuss the evidence for participation in disease pathogenesis by various classes of immune cells and glandular epithelial cells based upon data from both preclinical mouse models and human patients. Further examination of the contributions of glandular and immune cell subtypes to SS will be necessary to identify additional therapeutic targets that may lead to better management of the disease. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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18 pages, 2257 KiB

Open AccessReview

Understanding the Complexity of Sjögren’s Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

J. Clin. Med. 2020, 9(9), 2821; https://doi.org/10.3390/jcm9092821 - 31 Aug 2020

Cited by 8 | Viewed by 4046

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune inflammatory disease with a poorly defined aetiology, which targets exocrine glands (particularly salivary and lachrymal glands), affecting the secretory function. Patients suffering from SS exhibit persistent xerostomia and keratoconjunctivitis sicca. It is now widely acknowledged that a chronic grade of inflammation plays a central role in the initiation, progression, and development of SS. Consistent with its key role in organizing inflammatory responses, numerous recent studies have shown involvement of the transcription factor nuclear factor κ (kappa)-light-chain-enhancer of activated B cells (NF-κB) in the development of this disease. Therefore, chronic inflammation is considered as a critical factor in the disease aetiology, offering hope for the development of new drugs for treatment. The purpose of this review is to describe the current knowledge about the NF-κB-mediated molecular events implicated in the pathogenesis of SS. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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21 pages, 2733 KiB

Open AccessReview

Imaging in Primary Sjögren’s Syndrome

by Martha S. van Ginkel, Andor W.J.M. Glaudemans, Bert van der Vegt, Esther Mossel, Frans G.M. Kroese, Hendrika Bootsma and Arjan Vissink

J. Clin. Med. 2020, 9(8), 2492; https://doi.org/10.3390/jcm9082492 - 03 Aug 2020

Cited by 43 | Viewed by 8873

Abstract

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dysfunction and lymphocytic infiltration of the salivary and lacrimal glands. Besides the characteristic sicca complaints, pSS patients can present a spectrum of signs and symptoms, which challenges the diagnostic process. Various imaging techniques can be used to assist in the diagnostic work-up and follow-up of pSS patients. Developments in imaging techniques provide new opportunities and perspectives. In this descriptive review, we discuss imaging techniques that are used in pSS with a focus on the salivary glands. The emphasis is on the contribution of these techniques to the diagnosis of pSS, their potential in assessing disease activity and disease progression in pSS, and their contribution to diagnosing and staging of pSS-associated lymphomas. Imaging findings of the salivary glands will be linked to histopathological changes in the salivary glands of pSS patients. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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63 pages, 2516 KiB

Open AccessReview

Current State of Knowledge on Primary Sjögren’s Syndrome, an Autoimmune Exocrinopathy

by Dorian Parisis, Clara Chivasso, Jason Perret, Muhammad Shahnawaz Soyfoo and Christine Delporte

J. Clin. Med. 2020, 9(7), 2299; https://doi.org/10.3390/jcm9072299 - 20 Jul 2020

Cited by 73 | Viewed by 14136

Abstract

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3–3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the “autoimmune epithelitis” still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin’s lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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26 pages, 1330 KiB

Open AccessReview

Role of Viral Infections in the Pathogenesis of Sjögren’s Syndrome: Different Characteristics of Epstein-Barr Virus and HTLV-1

by Hideki Nakamura, Toshimasa Shimizu and Atsushi Kawakami

J. Clin. Med. 2020, 9(5), 1459; https://doi.org/10.3390/jcm9051459 - 13 May 2020

Cited by 27 | Viewed by 3852

Abstract

Viruses are possible pathogenic agents in several autoimmune diseases. Sjögren’s syndrome (SS), which involves exocrine dysfunction and the appearance of autoantibodies, shows salivary gland- and lacrimal gland-oriented clinical features. Epstein-Barr virus (EBV) is the most investigated pathogen as a candidate that directly induces the phenotype found in SS. The reactivation of the virus with various stimuli induced a dysregulated form of EBV that has the potential to infect SS-specific B cells and plasma cells that are closely associated with the function of an ectopic lymphoid structure that contains a germinal center (GC) in the salivary glands of individuals with SS. The involvement of human T-cell leukemia virus type 1 (HTLV-1) in SS has been epidemiologically established, but the disease concept of HTLV-1-associated SS remains unexplained due to limited evidence from basic research. Unlike the cell-to-cell contact between lymphocytes, biofilm-like structures are candidates as the mode of HTLV-1 infection of salivary gland epithelial cells (SGECs). HTLV-1 can infect SGECs with enhanced levels of inflammatory cytokines and chemokines that are secreted from SGECs. Regardless of the different targets that viruses have with respect to affinitive lymphocytes, viruses are involved in the formation of pathological alterations with immunological modifications in SS. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands)

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