RESUMEN

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging.

Asunto(s)

Autofagia , Glándulas Salivales Menores , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/patología , Femenino , Glándulas Salivales Menores/patología , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Biopsia

RESUMEN

A 56-year-old female was referred to our service for management of a malignant salivary gland neoplasm with compromised margins that had been biopsied previously at another service. The patient reported a twenty-year history of a lesion in the oral cavity with progressive and exuberant growth over the past two years, associated with local pain and dyspnea. Physical examination revealed an erythematous, ulcerated, and hemorrhagic lesion measuring approximately 3 cm on the left soft palate and tonsillar pillar. Computed tomography revealed an expansile lesion in the topography of the left soft palate, growing predominantly toward the lumen of the nasopharynx and partially invading the left wall of this region. The patient underwent surgery and histopathologic examination revealed an infiltrative and aggressive epithelial neoplasia with large vacuolated and eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. The neoplastic cells were arranged in a solid, microcystic, tubular, and follicular pattern with eosinophilic luminal secretion. Mitotic figures were frequent and all margins were affected by the neoplasia. Morphologic and immunohistochemical features supported the diagnosis of secretory carcinoma, and the patient is currently being followed for further therapeutic intervention.

Asunto(s)

Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Glándulas Salivales Menores/patología , Carcinoma/patología , Tomografía Computarizada por Rayos X

RESUMEN

Mucoepidermoid carcinoma arising from minor salivary glands at the base of the tongue is rare. Surgical excision of the tumours remains the primary treatment of choice. The prognosis of this tumour depends on optimum clearance of the disease surgically, clinical staging and histopathological grading. Postoperatively, radiotherapy depends on the grading and histopathological features of the tumour. Long-term follow-up is a must to detect early recurrences of oropharyngeal tumours. In our case, the tumour was removed by the transoral route because it was a limited tumour and for better postoperative functional outcomes. Concurrent chemoradiotherapy was advised to address the perineural invasion and residual tumour of the base of the tongue region.

Asunto(s)

Carcinoma Mucoepidermoide , Neoplasias de la Lengua , Humanos , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/diagnóstico , Neoplasias de la Lengua/terapia , Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/cirugía , Masculino , Adolescente , Glándulas Salivales Menores/patología , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/terapia , Femenino

Asunto(s)

Adenocarcinoma , Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Glándulas Salivales Menores/patología , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/diagnóstico , Masculino , Femenino , Persona de Mediana Edad

RESUMEN

Pleomorphic adenomas (PA) are the most prevalent benign salivary gland neoplasms. They may occur at any age, with a peak incidence between 40 and 60 years of age. They are more commonly observed in females (60%). These tumors can arise in both the major and minor salivary glands. Approximately 80% of these tumors are diagnosed in the parotid gland, whereas 10% arise in the minor salivary glands, mainly affecting the palates, followed by the lips and cheeks. This report describes two cases of unusual lesions that were diagnosed as (PA) in the minor salivary glands in our department via a review of the relevant literature. The first case involved an 83-year-old man who presented with a slow-growing swelling on the right side of the upper lip, and the second case involved a 45-year-old woman who presented with a slow-growing lesion on the palate. The presence of PA was confirmed histopathologically after surgical resection. Although relatively rare, PA is a benign lesion, the diagnosis of which must be known for appropriate therapeutic management.

Asunto(s)

Adenoma Pleomórfico , Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Adenoma Pleomórfico/patología , Adenoma Pleomórfico/diagnóstico , Femenino , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Masculino , Glándulas Salivales Menores/patología , Anciano de 80 o más Años

RESUMEN

PURPOSE: There are a number of diagnostic criteria that can be used to support a diagnosis of Sjögren's syndrome (SS), a chronic autoimmune condition often characterised by xerostomia and xerophthalmia. Of the available investigations, the most invasive is the labial gland biopsy (LGB) for histopathology, which is associated with a risk of long-term altered sensation to the lip. A positive histological diagnosis is currently considered to be one of the most objective criteria, however there is debate about the interobserver agreement between pathologists, as well as the sensitivity and specificity of this test. We aim to determine if the diagnostic value of the LGB is significant enough to warrant the surgical procedure and its associated risks. METHODS: This study involved assessing the degree of agreement between members of a pathology team for a cohort of 50 LGBs taken for the purpose of confirming or excluding SS. The Tarpley system was used, which involves the allocation of a 'focus score'. Additionally, the histological diagnoses were compared to the relevant serological findings where available. RESULTS: All cases within the cohort had adequate tissue for assessment. 84% agreement (Cohen's Kappa = 0.585) was seen between the current team's consensus and the original reporting pathologist on whether the appearance was supportive of SS. However, only 58% agreement was seen for focus scores (Weighted Kappa = 0.496). The agreement between the serology result and whether the histology was supportive of SS was 79% (Cohen's Kappa = 0.493). CONCLUSION: The findings raise the possibility that undue emphasis is placed on the value of a histological SS diagnosis. The current system for assessing and grading these biopsies is ambiguous in nature, with a low threshold considered indicative of SS. Due to the risk of complications associated with a LGB, alternative minimally invasive investigations should always be considered. The histological findings in isolation, particularly when a low focus score is seen, may not be predictive of a diagnosis of SS.

Asunto(s)

Glándulas Salivales Menores , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/patología , Biopsia , Glándulas Salivales Menores/patología , Femenino , Persona de Mediana Edad , Anciano , Adulto , Masculino , Sensibilidad y Especificidad

RESUMEN

This study aimed to investigate the serum and expression levels of C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CXCL11, and CXC receptor 3 (CXCR3) in minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS), and to explore their correlations with clinical parameters. Serum samples from 49 patients diagnosed with pSS, 33 patients with rheumatoid arthritis (RA), and 30 healthy controls (HCs) were collected for measurements of CXCL9, CXCL10, CXCL11, and CXCR3. Additionally, CXCL levels in the MSG tissues were measured in 41 patients who underwent MSG biopsy. Correlations between CXCL and CXCL/CXCR levels in serum/MSG tissues and clinical factors/salivary scintigraphy parameters were analyzed. Serum CXCL11 and CXCR3 showed statistically significant differences among patients with pSS and RA and HCs (serum CXCL11, pSS:RA:HC = 235.6 ± 500.1 pg/mL:90.0 ± 200.3 pg/mL:45.9 ± 53.6 pg/mL; p = 0.041, serum CXCR3, pSS:RA:HC = 3.27 ± 1.32 ng/mL:3.29 ± 1.17 ng/mL:2.00 ± 1.12 ng/mL; p < 0.001). Serum CXCL10 showed a statistically significant difference between pSS (64.5 ± 54.2 pg/mL) and HCs (18.6 ± 18.1 pg/mL, p < 0.001), while serum CXCL9 did not exhibit a significant difference among the groups. Correlation analysis of clinical factors revealed that serum CXCL10 and CXCL11 levels positively correlated with erythrocyte sedimentation rate (r = 0.524, p < 0.001 and r = 0.707, p < 0.001, respectively), total protein (r = 0.375, p = 0.008 and r = 0.535, p < 0.001, respectively), globulin (r = 0.539, p < 0.001 and r = 0.639, p < 0.001, respectively), and European Alliance of Associations for Rheumatology SS Disease Activity Index (r = 0.305, p = 0.033 and r = 0.321, p = 0.025). Additionally, serum CXCL10 negatively correlated with the Schirmer test score (r = - 0.354, p = 0.05), while serum CXCL11 positively correlated with the biopsy focus score (r = 0.612, p = 0.02). In the MSG tissue, the percentage of infiltrating CXCL9-positive cells was highest (75.5%), followed by CXCL10 (29.1%) and CXCL11 (27.9%). In the correlation analysis, CXCL11-expressing cells were inversely related to the mean washout percentage on salivary gland scintigraphy (r = - 0.448, p = 0.007). Our study highlights distinct serum and tissue chemokine patterns in pSS, emphasizing CXCL9's potential for early diagnosis. This suggests that CXCL10 and CXCL11 are indicators of disease progression, warranting further investigation into their roles in autoimmune disorders beyond pSS.

Asunto(s)

Quimiocina CXCL10 , Quimiocina CXCL11 , Receptores CXCR3 , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/patología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/metabolismo , Femenino , Persona de Mediana Edad , Masculino , Receptores CXCR3/metabolismo , Adulto , Quimiocina CXCL11/sangre , Quimiocina CXCL10/sangre , Anciano , Glándulas Salivales Menores/patología , Glándulas Salivales Menores/metabolismo , Quimiocina CXCL9/sangre , Suero/química , Suero/metabolismo

RESUMEN

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

Asunto(s)

Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Carcinoma Adenoide Quístico/terapia , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/diagnóstico , Neoplasias de las Glándulas Salivales/terapia , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Glándulas Salivales Menores/patología , Grupo de Atención al Paciente/organización & administración , Guías de Práctica Clínica como Asunto

RESUMEN

OBJECTIVES: Adenoid cystic carcinoma (ACC) of the salivary glands has poor long-term prognosis and a high metastatic rate. Toll-like receptors (TLRs), first-line immune activators, have been associated with both tumor progression and suppression. We aimed to study TLR3 and TLR7 behavior in ACC. MATERIALS AND METHODS: We studied TLR3 and TLR7 immunoexpression of 46 minor salivary gland ACCs diagnosed at the Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland over the period 1974-2012. The associations of TLR3 and TLR7 immunoexpression with clinicopathological factors were evaluated by χ2-test and Fisher's exact test. RESULTS: In the majority of samples, both TLR3 and TLR7 were immunoexpressed in cytoplasm. The immunoexpression was heterogeneous between individual tumors. Stronger TLR7 immunoexpression associated with recurrence rate and poorer disease-specific survival (DSS). TLR3 did not associate significantly with survival although we found an inverse correlation between TLR3 and TLR7 immunopositivity. Hence, when TLR3 immunoexpression was negative or mild, TLR7 immunoexpression was moderate to strong, and vice versa. CONCLUSIONS: TLR3 and TLR7 are immunoexpressed in minor salivary gland ACC. TLR7 is potentially an independent prognostic marker for recurrence rate and DSS.

Asunto(s)

Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Receptor Toll-Like 3 , Receptor Toll-Like 7 , Humanos , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 3/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/mortalidad , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/inmunología , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/inmunología , Femenino , Pronóstico , Masculino , Persona de Mediana Edad , Glándulas Salivales Menores/patología , Glándulas Salivales Menores/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/metabolismo , Anciano de 80 o más Años

RESUMEN

OBJECTIVES: Sjögren disease (SjD) diagnosis often requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of patients with SjD lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose 'seronegative' SjD. METHODS: IgG binding to a high-density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca-controls without autoimmunity (n=75) and autoimmune-feature controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for binding abundance and controlled false discovery rate in group comparisons. For predictive modelling, we used logistic regression, model selection methods and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity. RESULTS: IgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) bound more in SSA- SjD than sicca-controls (p=0.004) and combined controls (sicca-controls and autoimmune-feature controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 and DTD2 were bound more in FS-positive than FS-negative participants (p=0.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (area under the curve (AUC) 74%) and between FS-positive versus FS-negative (AUC 72%). CONCLUSION: We present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS positivity.

Asunto(s)

Autoanticuerpos , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/diagnóstico , Femenino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Persona de Mediana Edad , Masculino , Adulto , Estudios de Casos y Controles , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Glándulas Salivales Menores/inmunología , Glándulas Salivales Menores/patología , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangre , Anciano , Teorema de Bayes

RESUMEN

Secretory carcinoma is a malignant salivary gland tumor, which typically presents as an indolent painless mass within the parotid gland. Involvement of the minor gland is reported but less common. Secretory carcinoma was often misclassified as other salivary gland mimics, particularly acinic cell carcinoma, prior to 2010. It was first recognized as a molecularly distinct salivary gland tumor harboring the same fusion gene as well as histologic and cytogenetic features seen in juvenile breast cancer. Secretory carcinoma is generally managed in the same way as other low-grade salivary gland neoplasms and has a favorable prognosis; however, high-grade transformation requiring aggressive therapeutic interventions have been documented. Recent studies of biologic agents targeting products of this fusion gene offer the promise of a novel therapeutic option for treatment of this malignancy. Due to the limited number of reported cases, the spectrum of clinical behavior, best practices for management, and long-term treatment outcomes for secretory carcinoma remain unclear. A long-standing secretory carcinoma involving minor salivary glands of the mucobuccal fold, which was detected years after it was first noted by the patient, is reported. This case brings to light the importance of a thorough clinical exam during dental visits and reviews diagnostic differentiation of this malignancy from other mimics and discusses decision making for its management.

Asunto(s)

Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/terapia , Glándulas Salivales Menores/patología , Diagnóstico Diferencial , Carcinoma/patología , Carcinoma/genética , Carcinoma/terapia , Femenino , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVE: To investigate the expression and secretion of epidermal growth factor (EGF) in major and minor salivary gland tissues of human subjects and to examine the potential influence of sex and age on EGF expression and secretion. DESIGN: Saliva samples from the oral cavity at rest and after citric acid stimulation, as well as serum samples, were collected from 150 healthy subjects, and the concentrations of EGF were measured with enzyme-linked immunosorbent assay (ELISA) and compared. The expression of EGF mRNA and protein in normal salivary gland tissues was measured by real-time polymerase chain reaction (RT-PCR), Western blot (WB), and immunohistochemistry (IHC). RESULTS: The EGF concentration in acid-stimulated saliva was significantly higher than that in resting saliva (P < 0.001), and significantly higher than that in serum (P < 0.001). No sex difference was observed in EGF levels of whole saliva and serum, whereas the EGF levels in saliva and serum were decreased with age (P < 0.001 and P < 0.001, respectively). The EGF concentration and compound secretion rate (CSR) in resting submandibular glands saliva were significantly higher than those in resting parotid glands saliva (P = 0.002 and P < 0.001, respectively). The EGF was expressed in all major and minor salivary glands and ranked in order of submandibular, parotid, sublingual, and labial glands. CONCLUSION: All salivary glands have the function of secreting EGF, and the submandibular gland is the main source of salivary EGF. Aging is a factor influencing the expression and secretion of EGF.

Asunto(s)

Western Blotting , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento Epidérmico , Inmunohistoquímica , Reacción en Cadena en Tiempo Real de la Polimerasa , Saliva , Glándulas Salivales , Humanos , Femenino , Masculino , Factor de Crecimiento Epidérmico/metabolismo , Adulto , Saliva/metabolismo , Saliva/química , Persona de Mediana Edad , Glándulas Salivales/metabolismo , Factores Sexuales , Anciano , Factores de Edad , ARN Mensajero/metabolismo , Adolescente , Glándula Submandibular/metabolismo , Glándulas Salivales Menores/metabolismo , Ácido Cítrico/metabolismo

RESUMEN

INTRODUCTION: Tumors of minor salivary gland origin are uncommon lesions, representing 2-3 % of all malignant neoplasms of the upper aerodigestive tract and 9-23 % of all salivary gland tumors. The aim of this study is to report the demographic features, sites, histological types and the management and outcomes of oral and oropharyngeal minor salivary gland tumors diagnosed and treated in a University Hospital with a multidisciplinary head and neck team. MATERIALS AND METHODS: A single-center retrospective observational study was conducted in a cohort of patients who received diagnosis of minor salivary gland carcinoma of oropharynx and oral cavity between July 30th 2000 and 30th September 2021. The following data of the included patients were collected: age, gender, smoke history, alcohol consumption, past medical history, comorbidities, anatomic location of the tumor, histopathology, staging, management, and outcomes. RESULTS: A total of 30 cases (16 females, 14 males) of oral and oropharyngeal minor salivary gland tumors were reviewed. The most frequent histotype was polymorphous adenocarcinoma (12 patients). The majority of patients presented with low stage at diagnosis, with 66,66 % of the population classified as stage I or II at diagnosis. On the whole, 29 patients out of 30 benefitted from a surgical approach as first treatment. In 11 patients, adjuvant radiotherapy was performed and in 6 cases it was associated with chemotherapy. Brachytherapy with different timing was performed in 5 cases. The recurrence rate was 26.66 %. Overall disease specific survival at five and ten years was found to be approximately 81 % and 33 % respectively. CONCLUSIONS: Surgery is still considered to be the gold standard of the treatment of minor salivary gland tumors. Radiation therapy, in spite of not being considered as a curative primary treatment for salivary malignancies, is extensively used as an adjuvant treatment.

Asunto(s)

Neoplasias Orofaríngeas , Neoplasias de las Glándulas Salivales , Glándulas Salivales Menores , Humanos , Masculino , Estudios Retrospectivos , Femenino , Neoplasias de las Glándulas Salivales/terapia , Neoplasias de las Glándulas Salivales/epidemiología , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Persona de Mediana Edad , Glándulas Salivales Menores/patología , Anciano , Adulto , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/epidemiología , Anciano de 80 o más Años , Neoplasias de la Boca/terapia , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/epidemiología , Estadificación de Neoplasias

RESUMEN

To identify the value of salivary gland ultrasound (SGUS) combined with magnetic resonance imaging (MRI) and magnetic resonance sialography (MRS) in predicting the results of labial salivary gland biopsy (LSGB) in patients with suspected primary Sjögren syndrome (pSS), and construct a nomogram model to predict LSGB results. A total of 181 patients who were admitted with suspected pSS from December 2018 to April 2023 were examined and divided into a training set (n = 120) and a validation set (n = 61). Baseline data of the two groups were examined, and the value of SGUS, MRI, and MRS in predicting LSGB was analyzed. Multivariate logistic analysis was used to screen for risk factors, and nomogram prediction models were constructed using these results. In the training set, the SGUS, MRI, and MRS scores of patients in the LSGB + group were higher than those in the LSGB - group (all P < 0.001). The positive prediction value (PPV) was 91% for an SGUS score of 3, and 82% for MRI and MRS scores of 2 or more. We developed a nomogram prediction model based on SGUS, MRI, and MRS data, and it had a concordance index (C-index) of 0.94. The Hosmer-Lemeshow test (χ2 = 3.17, P = 0.92) also indicated the nomogram prediction model had good accuracy and calibration for prediction of LSGB results. A nomogram model based on SGUS, MRI, and MRS results can help rheumatologists decide whether LSGB should be performed in patients with suspected pSS.

Asunto(s)

Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico por imagen , Síndrome de Sjögren/patología , Glándulas Salivales/diagnóstico por imagen , Glándulas Salivales/patología , Biopsia , Glándulas Salivales Menores/diagnóstico por imagen , Glándulas Salivales Menores/patología , Ultrasonografía/métodos

RESUMEN

Introduction: This was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren's syndrome (SS). Methods: The inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted. Results: A total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers. Discussion: Patients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

Asunto(s)

Guanidinas , Glándulas Salivales Menores , Síndrome de Sjögren , Humanos , Glándulas Salivales Menores/patología , Estudios de Seguimiento , Pronóstico , Estudios de Cohortes , Brote de los Síntomas , Linfocitos B/patología , Biopsia , Inflamación/patología

RESUMEN

A 3-year-old boy presented with repeated episodes of corneal erosions and ulceration and absence of tear secretion since birth. Examination under anesthesia revealed a dry ocular surface, with corneal scarring and vascularization. Computed tomography of the orbit showed complete absence of lacrimal glands bilaterally. Minor salivary gland transplantation was performed in the right eye, which was more severely affected. This procedure has been used to manage severe dry eyes but not previously for congenital alacrimia. On long-term follow-up, 5 years after surgery, we observed considerable improvement in the photophobia, corneal transparency, and neovascularization.

Asunto(s)

Glándulas Salivales Menores , Humanos , Masculino , Preescolar , Glándulas Salivales Menores/trasplante , Tomografía Computarizada por Rayos X , Estudios de Seguimiento , Aparato Lagrimal/cirugía

RESUMEN

OBJECTIVES: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated. METHODS: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi. RESULTS: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-ß, which were normalised by JAKi without cytotoxicity. CONCLUSIONS: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.

Asunto(s)

Inhibidores de las Cinasas Janus , Quinasas Janus , Leucocitos Mononucleares , Factores de Transcripción STAT , Glándulas Salivales Menores , Transducción de Señal , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/inmunología , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Transducción de Señal/efectos de los fármacos , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Glándulas Salivales Menores/inmunología , Femenino , Interferones , Piperidinas/farmacología , Piperidinas/uso terapéutico , Persona de Mediana Edad , Masculino , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Adulto , Inflamación , Pirroles/farmacología , Pirroles/uso terapéutico , Células Epiteliales/efectos de los fármacos

RESUMEN

OBJECTIVE: Lysosome-associated membrane protein 3 (LAMP3) misexpression in salivary gland epithelial cells plays a causal role in the development of salivary gland dysfunction and autoimmunity associated with Sjögren's disease (SjD). This study aimed to clarify how epithelial LAMP3 misexpression is induced in SjD. METHODS: To explore upstream signaling pathways associated with LAMP3 expression, we conducted multiple RNA sequencing analyses of minor salivary glands from patients with SjD, submandibular glands from a mouse model of SjD, and salivary gland epithelial cell lines. A hypothesis generated by the RNA sequencing analyses was further tested by in vitro and in vivo assays with gene manipulation. RESULTS: Transcriptome analysis suggested LAMP3 expression was associated with enhanced type I interferon (IFN) and IFNγ signaling pathways in patients with SjD. In vitro studies showed that type I IFN but not IFNγ stimulation could induce LAMP3 expression in salivary gland epithelial cells. Moreover, we discovered that LAMP3 overexpression could induce ectopic Toll-like receptor 7 (TLR-7) expression and type I IFN production in salivary gland epithelial cells both in vitro and in vivo. TLR-7 knockout mice did not develop any SjD-related symptoms following LAMP3 induction. CONCLUSION: Epithelial LAMP3 misexpression can be induced through enhanced type I IFN response in salivary glands. In addition, LAMP3 can promote type I IFN production via ectopic TLR-7 expression in salivary gland epithelial cells. This positive feedback loop can contribute to maintaining LAMP3 misexpression and amplifying type I IFN production in salivary glands, which plays an essential role in the pathophysiology of SjD.

Asunto(s)

Células Epiteliales , Interferón Tipo I , Proteínas de Membrana de los Lisosomas , Glándulas Salivales , Síndrome de Sjögren , Receptor Toll-Like 7 , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/genética , Síndrome de Sjögren/metabolismo , Animales , Ratones , Interferón Tipo I/metabolismo , Humanos , Células Epiteliales/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Glándulas Salivales/metabolismo , Glándulas Salivales/inmunología , Proteínas de Membrana de los Lisosomas/genética , Proteínas de Membrana de los Lisosomas/metabolismo , Transducción de Señal , Femenino , Interferón gamma/metabolismo , Línea Celular , Glándulas Salivales Menores/inmunología , Glándulas Salivales Menores/metabolismo , Proteínas de Neoplasias , Proteína 3 de la Membrana Asociada a Lisosoma

RESUMEN

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

Asunto(s)

Linfoma no Hodgkin , MicroARNs , Síndrome de Sjögren , Humanos , Glándulas Salivales/metabolismo , Síndrome de Sjögren/diagnóstico , Glándulas Salivales Menores/patología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/complicaciones , Biomarcadores/metabolismo , MicroARNs/genética , MicroARNs/metabolismo

RESUMEN

BACKGROUND: Primary Sjogren's syndrome (pSS) is a complex autoimmune disease featuring damage to salivary and lacrimal glands, with the possibility of manifestations across multiple organs. Antibody-producing B cells have long been appreciated to play a significant role in pSS pathogenesis, with a number of autoreactive antibody species having been identified to be elevated in pSS patients. While several studies have attempted to characterize the BCR repertoires of peripheral blood B cells in pSS patients, much remains unknown about the repertoire characteristics of gland-infiltrating B cells. METHODS: Through paired scRNAseq and scBCRseq, we profiled the BCR repertoires of both infiltrating and circulating B cells in a small cohort of patients. We further utilize receptor reconstruction analyses to further investigate repertoire characteristics in a wider cohort of pSS patients previously profiled through RNAseq. RESULTS: Via integrated BCR and transcriptome analysis of B cell clones, we generate a trajectory progression pattern for infiltrated memory B cells in pSS. We observe significant differences in BCR repertoires between the peripheral blood and labial gland B cells of pSS patients in terms of relative expansion, isotype usage, and BCR clustering. We further observe significant decreases in IgA2 isotype usage among pSS patient labial and parotid gland B cells these analyses relative to controls as well as a positive correlation between kappa/lambda light chain usage and clinical disease activity. CONCLUSIONS: Through BCR repertoire analysis of pSS patient salivary glands, we identify a number of novel repertoire characteristics that may serve as useful indicators of clinical disease and disease activity. By collecting these BCR repertoires into an accessible database, we hope to also enable comparative analysis of patient repertoires in pSS and potentially other autoimmune disorders.

Asunto(s)

Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/genética , Glándulas Salivales/patología , Glándulas Salivales Menores/patología , Linfocitos B , Receptores de Antígenos de Linfocitos B/genética