Insights into the molecular mechanism of Sjogren's syndrome

Sjogren’s syndrome (SS) is a chronic autoimmune disease, that affects primarily salivary and lacrimal glands, leading to increased morbidity. Recent studies indicate that loss of salivary gland function is associated with defective cell polarity, lymphocytic infiltration and fibrosis. Our previous studies showed that deregulation of E-cadherin-mediated adhesion was associated with nuclear localization of YAP and suggested that the latter may be a key event in SS. In this study, our goal was to align altered morphological features in SS with cell polarity regulators. Specifically, we focused on the Par complex, known to play an important role in epithelial polarity, as well as components of tight junctions (TJs), ZO-1 and JAM-1, and compared them to changes in their expression and localization with markers of fibrosis, vimentin and α-smooth muscle actin (α-SMA). Using immunofluorescence staining and confocal microscopy we examined expression levels of YAP, Par3, ZO-1, JAM-1, vimentin, and α-SMA, and correlated them with a ductal differentiation marker K7 and a marker for lymphocytic infiltration, CD45+. Our results showed reduced levels of Par3, ZO-1 and JAM-1, in tissues from SS patients that were associated with increased nuclear localization of YAP. Collectively, these studies suggest that cell polarity cues are critical for normal function of salivary glands and that their deregulation is likely to be the underlying basis of at least a subset of SS patients. These findings will further contribute to a better understanding of the molecular basis of SS and will serve in improved diagnosis and future therapeutic intervention

An antigen-driven B-cell response within the salivary glands of patients with Sjögren’s syndrome

Infection with a bacterium or virus induces the production of antibodies, specialised protein molecules that bind to and eliminate the microorganism. These antibodies are produced by B-cells that are stimulated by antigen (any foreign protein or carbohydrate) in the lymph nodes and spleen. During this process, they diversify their variable region genes (V-genes), encoding the antigen-binding region of the antibody, by switching on machinery that mutates the V-genes at a very high rate (somatic hypermutation). In autoimmune diseases, B-cells produce autoantibodies against self-antigens present on the patient's own tissues. Clusters of B- and T-cells are frequently found in the target organs of autoimmune disease. The aim of the work described here was to determine whether these clusters of cells are responding to stimulation by antigen. For this purpose we investigated the B-cell response in patients with an autoimmune disease affecting the salivary and lachrymal glands. By cloning and sequencing the expressed V-genes from indvidual clusters of cells in the salivary glands, we were able to show that the B-cells in these clusters are undergoing clonal proliferation, somatic hypermutation and antigen selection. The presence of similar structures in the target tissues of other autoimmune diseases suggests that this is a widespread phenomenon

Sialendoscopic management of autoimmune sialadenitis: a review of literature

Autoimmune diseases of major salivary glands include Sjögren's syndrome and a complex of disorders classified as immunoglobulin G4-related diseases. These pathologies are characterised by an autoimmune reaction mediated by T-helper lymphocytes that targets the ducts of exocrine glands in Sjögren's syndrome and glandular parenchyma in immunoglobulin G4-related diseases. Immunoglobulin G4-related diseases represent recently introduced multi-organ diseases that also involve the salivary glands. However, the morbid conditions once known as Mikulicz's disease and Kuttner's tumour were recently considered as two variants of immunoglobulin G4-related diseases affecting the major salivary glands ( immunoglobulin G4-related sialadenitis). This review briefly summarises the pathogenesis and clinical features of autoimmune diseases of the major salivary glands, focusing on the diagnostic and therapeutic role of sialendoscopy

Mesenteric Panniculitis in Sjögren’s Syndrome: A New Systemic Manifestation to Consider?

The association between mesenteric panniculitis and Sjögren's syndrome, although rare, is starting to be recognized. Usually, mesenteric panniculitis is symptomatic, presenting with either general or gastrointestinal symptoms. Sjögren's syndrome is an autoimmune disease that typically affects secretory glands, but may have serious systemic involvement. We report the case of a 77-year-old patient in whom accidental discovery of asymptomatic mesenteric panniculitis on computed tomography led to the diagnosis of Sjögren's syndrome with several systemic manifestations

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

Coexisting primary Sjögren’s syndrome and sarcoidosis: coincidence, mutually exclusive conditions or syndrome?

Herein, we describe a 44-year-old female diagnosed with histologically proven coexistence of primary Sjögren's syndrome and sarcoidosis with pulmonary and muscular involvement. The differential diagnosis may be difficult, but this is not an exceptional case, which highlights the need to critically revise the consideration of sarcoidosis as an exclusion for primary Sjögren's syndrome, as established in current classification criteria

Is minor salivary gland biopsy more than a diagnostic tool in primary Sjorgren's syndrome? Association between clinical, histopathological, and molecular features: A retrospective study

Objectives: Several histological scoring systems, including the focus score, performed in minor salivary glands (MSGs) by hematoxylin-eosin (H&E) staining, have been employed in clinical practice to assess the inflammatory infiltrate and provide the diagnosis of primary Sjorgren's syndrome (pSS). Aims of this study were to integrate different scoring systems and identify potential differences in the molecular profile of lymphoid cytokines related to germinal center (GC) formation and clinical subsets in pSS. Methods: Overall, 104 pSS patients and 40 subjects with sicca non-pSS were retrospectively evaluated. MSG biopsies were evaluated by H&E and immunofluorescence to assess histological pattern, Chisholm and Mason grading system, Tarpley score, a grading for the severity of inflammatory infiltrate, T-/B-cell segregation, and the presence of GC. MSGs from 50 pSS patients and 30 sicca non-pSS patients were processed by real-time PCR to assess LTα, LTβ, BAFF, CXCR4, CXCL12, CXCR5, CXCL13, CCR7, CCL19, and CCL21. Results: GCs presence was associated with anti-Ro/SSA and anti-La/SSB antibodies, hypergammaglobulinemia, salivary gland swelling, higher Tarpley score and focus score, and extraglandular involvement but, at multivariate analysis, only extraglandular involvement was independently associated to GC. pSS patients displayed higher level of all cytokines compared to those with sicca symptoms. GC+ pSS patients displayed higher level of all cytokines compared to those GC-. Conclusions: Our study demonstrates that different histopathological patterns, including GC presence, reflect different cytokine expression and different clinical subsets. We believe that the combined immunofluorescence/molecular approach in MSGs would help to tailor diagnostic and therapeutic approach for different subsets of pSS patients

Conjunctival Inflammation in Thrombospondin-1 Deficient Mouse Model of Sjögren’s Syndrome

Lacrimal gland inflammation during autoimmune Sjögren’s syndrome (SS) leads to ocular surface inflammation – Keratoconjunctivitis sicca (KCS). This condition afflicts both the cornea and conjunctiva that form the ocular surface. Thrombospondin-1 (TSP-1) deficiency in mice results in lacrimal gland and corneal inflammation that resembles the human disease. In this study we report conjunctival pathology in this mouse model of SS. We found that TSP-1 null mice develop inflammation in the conjunctiva and associated loss of goblet cell function similar to that seen in patients with SS. Increased expression of Th1 (IFN-γ, TNF-α) and Th17 (IL-6, IL-17A) inflammatory cytokines and related transcription factors (Tbet and RORγt) were detected in TSP-1 null conjunctiva as well as their draining lymph nodes (LNs). The conjunctival inflammation was also accompanied by an increase in local lymphatic vessels. Interestingly, migration of antigen-bearing dendritic cells (DCs) from the ocular surface to the LNs was dependent on the TSP-1 available in the tissue. These results not only reveal potential immunopathogenic mechanisms underlying KCS in SS but also highlight the therapeutic potential of TSP-1

Severe dental caries as the first presenting clinical feature in primary sjÖgren's syndrome

Background: SjÖgren's syndrome is an autoimmune syndrome involving the exocrine glands specially the salivary and lacrimal glands leading to xerostomia and xerophtalmia. This paper presents a case with primary SjÖgren's syndrome that severe dental caries were the first clinical manifestation. Case Presentation: A 42-year-old man was referred to the School of Dentistry, Tehran University of Medical Sciences due to unexplained severe dental decays. After systematic evaluation and consultation with the rheumatologist and the ophthalmologist, the diagnosis of primary SjÖgren's syndrome was suggested and confirmed by serologic and histopathologic study. Conclusion: Primary SjÖgren's syndrome should be considered in the differential diagnosis of patients with early severe dental caries