Search Results (553)

Background and Objectives: Patients with Sjögren’s disease (SjD) do not experience any improvement in gastroesophageal reflux disease (GERD) symptoms after SjD treatment, and in some patients, reflux even worsens. It is important to note that GERD manifests itself through typical and atypical symptoms, the latter of which may include eye damage, as evidenced by a growing body of research. When SjD patients were prescribed medication to treat GERD, their condition improved at the same time. Therefore, we aim to investigate whether there is a link between ocular dryness and gastroesophageal reflux disease (GERD) in patients with Sjögren’s disease (SjD). Materials and Methods: Our study included 27 patients with SjD according to the 2016 American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) Sjögren’s syndrome Classification Criteria, and 28 patients with non-autoimmune sicca syndrome due to GERD (nonautoimmSicca). Results: The study involved 55 participants, 48 (87.3%) women and 7 (12.7%) men. The median age was 54 years (IQR 49–64). A total of 41 subjects (74.5%) had GERD, and 20 subjects (36.4%) tested positive for Helicobacter pylori: 13 (48.1%) and 1 (3.7%) in the SjD group, and 28 (100.0%) and 19 (67.9%) in the nonautoimmSicca group, respectively. A significant difference in asymmetric tear secretion (p < 0.001) was found between the nonautoimmSicca and SjD patients, with values of 5 (3–10) mm/5 min and 1 (0–2) mm/5 min, respectively. A low correlation was detected between sialometry results and tear secretion asymmetry (r = 0.48, p < 0.001). An increase of 1 mm/5 min in the tear secretion asymmetry between the eyes was associated with a 2.04-fold increase in the odds ratio for having GERD (95% CI 1.25–3.32, p = 0.004), and was associated with a 1.9-fold increase in the odds ratio for having GERD (95% CI 1.04–3.49, p = 0.038) in patients with SjD. The presence of Helicobacter pylori is associated with asymmetric tear secretion [95% CI 1.22 (1.05–1.41, p = 0.010)]. Conclusions: Asymmetric tear secretion between the eyes is associated with the odds of having GERD. Patients with non-autoimmune sicca syndrome due to GERD have significantly greater asymmetry in tear secretion compared to those diagnosed with Sjögren’s disease. Full article

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by inflammation and damage to salivary and lacrimal glands. Its etiology involves both genetic and environmental factors. Among susceptibility genes, IRF5 has been highlighted in European populations, but evidence in non-European groups remains limited. This study evaluated whether IRF5 variants rs2004640G/T, rs2070197T/C, rs10954213G/A, and rs59110799G/T are associated with pSS susceptibility, clinical manifestations, or the presence of autoantibodies in a Mexican population. The diagnosis was confirmed by rheumatologists using the 2016 ACR–EULAR classification criteria for pSS. Genotyping was performed using TaqMan probes in 231 controls and 132 pSS patients from central Mexico. Associations were analyzed through binary logistic regression under different genetic models, adjusting for age and geographic origin. Clinical correlations were examined with SNPStats, and haplotypes were constructed using Haploview. Results showed that all four IRF5 variants were significantly associated with pSS susceptibility. Moreover, rs2004640, rs2070197, and rs10954213 variants were associated with arthritis, a frequent clinical manifestation in pSS patients. This represents the first evidence in a Latin American population demonstrating that IRF5 variants contribute to increased risk of developing pSS. These findings suggest ethnicity-specific genetic influences and highlight the importance of expanding research beyond European cohorts. Replication in larger samples and functional analyses are needed to confirm these associations and clarify their biological relevance. Full article

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by the main clinical manifestation of oral and ocular dryness, predominantly affecting middle-aged and elderly women. As the most commonly affected target organs in SS, pathological changes in the salivary glands (SGs) and their underlying mechanisms are of great significance for understanding the disease progression. Recent studies have revealed that a dynamic imbalance of the extracellular matrix (ECM) in the SGs plays a crucial role in the pathogenesis of SS. Dysregulation of matrix metalloproteinases (MMPs) and the fibrotic processes they mediate constitute the core pathological changes. These alterations intertwine with local chronic inflammatory responses, cellular senescence, and hyperosmolarity, collectively leading to the destruction of the SG parenchymal structure and progressive loss of secretory function, significantly impairing the patients’ quality of life. However, research on the pathological mechanisms of the SG ECM remains insufficient, and there are currently no specific therapeutic interventions targeting ECM alterations in clinical practice. This review systematically elucidates the characteristics of pathological and physiological changes in the SG ECM in SS and thoroughly explores novel therapeutic strategies based on ECM regulation, as well as their clinical application prospects. Full article

Sjögren’s disease (SjD), which is also known as Sjögren’s syndrome (SS), is a chronic autoimmune disease characterized by dysfunction of exocrine glands, such as the salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Mice in which the SATB1 gene is conditionally deleted in hematopoietic cells (SATB1cKO mice) develop SS as early as 4 weeks of age; however, the etiology of the disease remains to be elucidated. Here, we found that the frequency of abnormally appearing CD4⁺CD8⁺ double positive (DP) T cells in the periphery of SATB1cKO mice was higher in the salivary glands than that in the spleen, suggesting a possible involvement of DP T cells in the pathogenesis of SS in SATB1cKO mice. To investigate the nature of DP T cells, we established DP T cell hybridomas by fusing T cells from the cervical lymph nodes of SATB1cKO mice with the BW5147 thymoma cell line. Among six DP hybridoma clones, the TCRβ gene from five clones exhibited a fetal or immature phenotype. In addition, four out of five clones exhibited upregulated transcription of IL-2 in the salivary glands of T/B cell-deficient RAG2^−/− mice, suggesting that autoreactive T cells were enriched in the DP T cell population of SATB1cKO mice. These results suggest that unusual DP T cells in SATB1cKO mice may be involved in autoimmune pathogenesis in SATB1cKO mice. Full article

Background/Objectives: The Notch–ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch receptor after the Notch receptor binds to a ligand. Crosstalk between Notch and ADAM17 is often altered in pathological situations. Alterations in Notch2 expression, in particular, appears to be correlated with the onset of various autoimmune diseases. In primary Sjögren’s disease (pSjD), an autoimmune disorder characterized by chronic inflammation, the role of ADAM17 has been extensively explored, but a correlation with Notch2 has not yet been evaluated. Methods: To analyze the gene and protein expression of Notch2 in pSjD and a possible correlation with ADAM17 expression and with the patient’s inflammatory grade, we employed an integrated co-detection protocol to analyze salivary gland tissue sections by combining in situ hybridization (ISH) with immunohistochemistry (IHC). Results: combined ISH/IHC allows us to demonstrate an increased expression of Notch2 mRNA and protein in pSjD salivary glands (SGs) biopsies, which appears correlated with an increased expression of ADAM17, both in acinar and duct cells and in infiltrating lymphocytes. Notch2/ADAM17 expression is higher in biopsies of pSjD SGs characterized by a high degree of inflammation. Conclusions: this work demonstrates the correlated expression in pSjD SGs of ADAM17, which plays multiple roles in the pathogenesis of SjD, and Notch2, widely considered a key player in various inflammatory mechanisms, offering a starting point for future therapeutic interventions to investigate. Full article

The sodium iodide symporter (NIS) is a key protein in thyroid function responsible for iodine uptake, and it may be involved in the pathogenesis of autoimmune thyroiditis. However, it is also expressed in the salivary glands, the primary target of autoreactive cells in Sjögren’s syndrome (SS). Given the common link between the two diseases, we computationally investigated whether the epitopes of NIS can trigger an immune response leading to SS in Hashimoto’s thyroiditis (HT) patients genetically predisposed to both diseases. The TepiTool 2016, ABCpred 2006, and DiscoTope 2.0 servers were used to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of NIS, thyroid peroxidase (TPO) and Ro60 Y RNA-binding protein (Ro60), which served as reference antigens for HT and SS, respectively. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) alleles associated with both SS and HT. We identified a total of 376 linear T-cell epitopes, 64 linear B-cell epitopes and 68 conformational B-cell epitopes of NIS. Compared to TPO, NIS T-cell epitopes showed significantly lower affinity for HLA alleles (p < 0.0001), while no significant difference was found compared to Ro60. While linear B-cell epitopes of NIS, TPO, and Ro60 showed similar binding affinity, conformational epitopes of NIS were predicted to have higher immunogenicity than Ro60 (p = 0.04), while no significant difference was found compared to TPO. These pivotal findings, discovered by the methods of computer modeling, suggest that NIS can potentially activate T cells and B cells in patients with genetic predisposition to SS and HT and need to be confirmed by further laboratory studies. Full article

West Nile virus (WNV) is an arthropod-borne flavivirus first identified in 1937. Over time, WNV has spread globally and is now endemic in Italy. Although most human WNV infections are asymptomatic (80%), less than 1% progress to a neuroinvasive disease with high mortality rates. This case involves a 45-year-old woman with post-surgical hypoparathyroidism and Sjögren’s syndrome who developed severe encephalomyelitis linked to WNV, leading to ventilator-associated pneumonia and death. Neuropathological findings revealed a bilaterally cribriform thalamus and reddish punctate lesions near the dentate nucleus of the cerebellum. The trachea and bronchial hilum branches contained whitish foamy liquid. The left lung showed multiple brownish-violet areas, with whitish regions at dissection. The heart appeared unremarkable. A detailed neuropathological examination focused on areas involved in motor control pathways. Tissue samples were stained with hematoxylin and eosin and trichrome techniques, and immunohistochemistry was performed using CD68, CD3, and CD20. A significant damage was observed in the lenticular nucleus and motor thalamus, with prominent concentric vascular calcifications. The cerebellar cortex showed near-total depletion of Purkinje cells. In the spinal cord, CD68 and CD3 positivity was noted in the lateral funiculi, anterior horns, and Clarke’s column. Lung findings showed pulmonary edema, chronic emphysema, and bronchopneumonia. The observed CD3 and CD68 positivity confirms that WNV spreads trans-synaptically along motor control pathways. We speculate on the potential molecular mechanisms by which hypoparathyroidism and Sjögren’s syndrome may have played a role in the neuroinvasive progression of the disease. Full article

The relationship between the oral microbiome and autoimmune diseases (ADs) has attracted considerable research interest. This study employed two-sample Mendelian randomization (MR) to investigate causal relationships between oral microbiota and six ADs, including rheumatoid arthritis (RA), type 1 diabetes (T1D), inflammatory bowel disease (IBD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). Using genome-wide association study data from oral microbiome features and ADs, we applied inverse-variance weighted estimation complemented by sensitivity analyses and reverse MR to assess robustness and reverse causation. Analysis of 309 tongue dorsum and 285 salivary microbial features identified four tongue dorsum and five salivary taxa with genome-wide significant causal effects. Specific microbial taxa from both oral niches demonstrated protective or risk-enhancing effects for RA, T1D, IBD, and MS, while no causal associations were found for SLE or SS. These findings establish the causal role of specific oral microbiota in autoimmune pathogenesis and highlight priority candidates for further investigation as potential microbial biomarkers. Full article

Background and Objectives: Sjögren’s syndrome (SS) causes destructive salivary gland dysfunction with substantial oral morbidity. To synthesize practical, evidence-based approaches for early recognition, initial oral management, and timely referral to dental care. Materials and Methods: Narrative review of English-language literature from the Web of Science Core Collection and PubMed, prioritizing systematic reviews, randomized trials, and consensus guidelines. Results: Early oral signs include rapid multifocal root and cervical caries, burning sensations, and rising dental treatment needs. Unstimulated whole saliva ≤ 0.1 mL/min supports significant hypofunction and complements the 2016 ACR/EULAR criteria. Preventive care should combine dietary counseling, salivary stimulation, and topical remineralization. Adjuncts include high-fluoride toothpaste, biomimetic hydroxyapatite dentifrices, and casein phosphopeptide–amorphous calcium phosphate (CPP-ACP). However, evidence for fluoride varnish in SS remains mixed. Pharmacologic sialogogues require screening for contraindications. Conclusions: Embedding oral screening, simple salivary metrics, and a structured referral pathway into rheumatology visits can reduce preventable tooth loss and improve comfort, function, and treatment adherence. Full article

Aging is associated with chronic low-grade inflammation of exocrine glands, such as the lacrimal glands. Histamine, synthesized by histidine decarboxylase (HDC), is implicated in immune modulation; however, its role in age-related lacrimal gland inflammation remains unclear. To explore the role of histamine in age-related lacrimal gland inflammation, we compared wild-type and histidine decarboxylase knockout (HDC-KO) C57BL/6 mice at 6 weeks and 12 months of age (10 males and 10 females in each group). Histological and immunohistochemical analyses were performed to assess lymphocytic infiltration, mast cells, and the expression of cytokines and adhesion molecules. Gene expression levels were quantified using reverse transcriptase quantitative PCR (RT-qPCR). Aged wild-type mice showed significant upregulation of mRNA transcription of HDC and histamine H1 receptor, along with increased infiltration of B220-positive B cells and CD3-positive T cells in the lacrimal gland. The mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and ICAM-1 were elevated with age, whereas these changes were attenuated in HDC-KO mice. The mRNA expression of PPARγ, an anti-inflammatory factor, was upregulated in the aged HDC-KO mice. Mast cell numbers increased with age but did not differ according to sex. These findings suggest that histamine, via HDC and H1 receptor signaling, contributes to age-associated lacrimal gland inflammation by enhancing cytokine and ICAM-1 expression. HDC deficiency suppresses this inflammatory response, potentially through the upregulation of PPARγ. Thus, histamine may be a key mediator of age-related inflammation in the lacrimal gland and a potential therapeutic target. Full article

Polyneuropathy is a common condition that limits the quality of life among patients with primary Sjögren disease (pSjD). Somatic sensory fiber neuropathy involving small myelinated (A-δ) and unmyelinated C fibers may precede the development of sicca syndrome. The cutaneous silent period (CSP) is an inhibitory spinal reflex that can be used as a tool for evaluating the dysfunction of A-δ fibers. This study sought to examine CSP parameters, and their correlates, in patients with pSjD vs. healthy controls. We recruited 134 consecutive patients with a diagnosis of pSjD, of whom 109 subjects were included in the analysis. Electrodiagnostic tests comprised a nerve conduction study (NCS) and CSP analysis, alongside laboratory tests and questionnaires (the ESSPRI and SF-36). The examination of the healthy control (HC) group consisted of 113 NCSs and CSP studies. NCS tests of the median nerve in both groups were within the normal range. Statistical analysis revealed a significant difference in CSP duration (p < 0.001), S1 latency (p < 0.001) and S2 latency (p < 0.001) between the pSjD and HC groups. We observed prolonged CSP duration in approximately 38% of patients with pSjD and prolonged S2 latency in 18.35%. Small A-delta fiber neuropathy was diagnosed in 38% (41 subjects) patients. A regression analysis of CSP parameters indicated an association between the age of patients and PM Scl-75 antibodies (ab) levels in the pSjD cohort. As a new, noninvasive method of assessing A-δ nerve fibers, CSP was found to have a relation to the age and PM Scl-75 antibodies in patients with pSjD. The utility and sensitivity of CSP as a test for screening A-δ fiber function require further investigation in large cohorts of the pSjD population. Full article

Background: Complete fetal atrioventricular block (CAVB) is a rare but life-threatening condition, occurring in approximately 1–2% of pregnancies associated with maternal anti-Ro/SSA antibodies. The transplacental migration of anti-Ro/SSA and anti-La/SSB antibodies damages the fetal cardiac system, leading to sustained bradycardia, cardiomyopathy, fetal hydrops, and intrauterine fetal demise. Despite the use of fluorinated corticosteroids or β-agonists, therapeutic efficacy remains limited once a complete block is established. Case Presentation: We present the case of a 35-year-old primigravida with a pregnancy achieved through in vitro fertilization (IVF). At 20 weeks of gestation, she was referred to our emergency unit due to persistent fetal bradycardia. Fetal echocardiography confirmed CAVB with a ventricular rate of 64 bpm. Maternal serologic testing was positive for anti-Ro/SSA and anti-La/SSB antibodies, suggesting an autoimmune etiology. Treatment with oral dexamethasone and salbutamol was initiated, but follow-up echocardiography at 24 weeks showed worsening cardiac status, including reduced ventricular rate of 59 bpm, cardiomegaly, and pericardial effusion. Intrauterine fetal death occurred at 25 weeks of gestation. Management and Outcome: Four months postpartum, the patient underwent a minor salivary gland biopsy. Histopathological evaluation confirmed the diagnosis of primary Sjögren’s syndrome. Conclusions: This case illustrates the severe consequences of autoimmune-mediated CAVB and the limited effectiveness of available treatments once a complete block has developed. It underscores the importance of early fetal rhythm surveillance and targeted maternal autoimmune screening—particularly before assisted reproduction, where structured preconception evaluation offers an opportunity for earlier recognition and risk stratification. Earlier detection may improve counseling and management strategies in future pregnancies. Full article

PANoptosis is an integrated form of regulated cell death that combines pyroptosis, apoptosis, and necroptosis through a coordinated molecular platform known as the PANoptosome. Autophagy, in parallel, maintains immune homeostasis by controlling cellular stress responses. Although both pathways are essential for innate and adaptive immunity, their functional interplay has only recently been explored. This review summarizes current knowledge on the bidirectional relationship between PANoptosis and autophagy, with emphasis on how autophagy can restrain PANoptotic signaling or, under certain conditions, promote inflammatory cell death. We discuss cell-type-specific aspects of this crosstalk in macrophages, dendritic cells, monocytes, neutrophils, T cells, and B cells, focusing on key PANoptosis mediators and autophagy-related proteins. We then examine how dysregulated autophagy and exaggerated PANoptotic signaling contribute to chronic inflammation and tissue damage in immune-mediated inflammatory disease, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, psoriasis, and inflammatory bowel disease. Finally, we outline shared molecular principles that position the autophagy–PANoptosis axis as a fundamental immunoregulatory mechanism and a promising source of therapeutic targets in chronic inflammatory and autoimmune disorders. Full article

Even though primary Sjögren disease (pSjD) is mainly associated with sicca symptoms, there are extraglandular manifestations of the disease which affect the quality of life of patients the most and may even be life-threatening. Among the most severe, polyneuropathy and myopathy are worth mentioning. Additionally, clinical observations suggest a higher prevalence of fibromyalgia (FM) in this group of patients, clouding physicians’ assessment and potentially leading to unsuccessful therapeutic decisions. The aim of our study was to evaluate the frequency of pSjD and FM co-occurrence as well as to find the most effective screening tools and markers of such overlap. A total of 97 consecutive patients with diagnosed pSjD were incorporated in the study after obtaining their informed consent. Participants completed a set of broadly available questionnaires, including Fibromyalgia Survey Questionnaire, SF-36 and EULAR Sjögren’s Syndrome Patient-Reported Index (ESSPRI). Data on their laboratory results was collected in the dedicated database. Moreover, patients underwent electroneurographic (ENG) and electromyographic (EMG) testing. Central nervous system (CNS) abnormalities were detected using MRI. Objective disease activity was evaluated based on EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). The mean age was 55.3 (range 19.0–78.0 years, SD = 13.9). The disease duration ranged from 2 to 42 years (M = 9.03 years, SD = 7.1 years). Nearly half of the participants (n = 44, 45%) met diagnostic criteria of FM. Interestingly, the diagnosis of FM correlated with CNS involvement. There was no significant correlation between FM and either polyneuropathy/myopathy nor laboratory findings (however, C3c and folic acid concentrations were near the level of significance—mean 1.2 vs. 1.29; p = 0.075 and mean 11.35 vs. 9.21; p = 0.071, respectively). Within the subcategories of SF-36 and ESSPRI scales, significant positive correlation was noted with ESSPRI total score and ESSPRI pain score (neuropathic subcategory), while a negative correlation was found with SF-36 vitality score, physical functioning score, and the SF-36 total score. FM is common among pSjD patients and should be considered rather a comorbidity requiring different therapeutic approaches. At the fast-paced clinical environment, a concise ESSPRI assessment may be helpful in the initial screening of patients at risk of FM. Even though the origin of this phenomenon is unknown, the concepts of central sensitization and microglia polarization may be potential explanations and more molecular research in this direction could benefit the pSjD patients. Full article

Saliva specimens are widely used for coronavirus disease 2019 (COVID-19) testing using RT-qPCR due to their advantages over nasopharyngeal swabs of being non-invasive and self-collectable. However, saliva collection can be time-consuming in individuals with reduced saliva secretion, including those with diabetes, diseases involving salivary glands such as Sjögren’s syndrome, and older adults. In this study, we evaluated the diagnostic performance of mouth rinse specimens, which can be easily collected even from individuals with reduced saliva secretion, as an alternative to saliva for RT-qPCR COVID-19 testing. Among the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive specimens analyzed, 88.2% were derived from patients possessing risk factors associated with reduced salivary secretion, including diabetes, use of medications such as anticholinergics or antihistamines, smoking, and older age. The analysis results of mouth rinse specimens demonstrated 96.7% overall agreement with those of saliva specimens, with a sensitivity of 94.1% and specificity of 100%; however, the viral load in the mouth rinse specimens was lower than that in saliva because of sample dilution. These findings suggest that mouth rinse specimens are a practical, versatile, and reliable alternative specimen for RT-qPCR COVID-19 testing. Full article