Primary Sj?gren’s syndrome accompanied by pleural effusion: a case report and literature review

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by the infiltration of lymphocytes in exocrine glands, specifically the salivary and lacrimal glands, resulting in the typical symptoms of xerophthalmia and xerostomia. SS may be accompanied by pleural effusion when the lung is involved, but this occurrence has been reported in only 10 cases in the literature. We report the case of a 42 year-old woman with severe bilateral pleural effusion for eight years. Primary Sjögren’s Syndrome was finally diagnosed based on the presence of xerophthalmia and xerostomia, biopsy of the minor salivary glands, and positive anti-SS-A antibody in the serum and pleural effusion. Biopsy of the parietal pleura through video-assisted thoracoscopy revealed infiltration of lymphocytes. The patient had a long history of pleural effusion without clear etiology. Malignant disease was first suspected because of abnormal density lesion on the left lung and malignant cells found on cytology, but PET-CT revealed no malignant lesion. Examinations did not support infection, malignant tumor, pulmonary sarcoidosis, or other connective tissue diseases. This data could be useful for the future study of pleural effusion in SS.     

Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren's syndrome‐related antigen A (SSA) and La/SSB in salivary gland epithelial cells

The aim of this study was to examine the levels of endoplasmic reticulum (ER) stress in minor salivary glands, to investigate the interplay between ER stress-induced autophagy and apoptosis in human salivary gland (HSG) cells and to test the effect of ER stress-induced apoptosis on the cellular redistribution of the two major Sjögren’s syndrome (SS) autoantigens Ro/Sjögren’s syndrome-related antigen A (SSA) and La/Sjögren’s syndrome-related antigen B (SSB). Minor salivary gland biopsies from SS patients and sicca controls were examined by immunohistochemistry for the expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) as an indicator of unfolded protein response (UPR). HSG cells were treated with thapsigargin (TG) and cell viability, autophagy and apoptosis were assessed. Immunoblot was applied to detect the conversion of LC3I to LC3II and the protein levels of GRP78/BiP and X-box binding protein-1 (XBP-1). Apoptosis was evaluated by a single-stranded DNA enzyme-linked immunosorbent assay (ELISA). Ro/SSA and La/SSB localization was visualized using immunofluorescence. GRP78/BiP was expressed by acinar and ductal epithelial cells in salivary glands of patients and sicca controls. TG treatment induced autophagy, as indicated by enhanced protein expression of LC3II. The protein levels of UPR marker XBP-1 were increased after TG treatment, while GRP78/BiP levels were decreased. TG treatment resulted in induction of HSG apoptosis. Ro/SSA and La/SSB autoantigens were localized predominantly to the cytoplasm in resting cells, while they were redistributed to cell membrane and blebs in the apoptotic cells. In conclusion, ER stress is activated in minor salivary gland epithelial cells from SS patients and controls. ER stress-induced apoptosis in HSG cells leads to cell surface and apoptotic blebs relocalization of Ro/SSA and La/SSB autoantigens.     

The Significance of Ectopic Germinal Centers in the Minor Salivary Gland of Patients with Sj?gren’s Syndrome

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjögren’s syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.     

Wnt signaling pathway activities may be altered in primary Sjogren’s syndrome

Background/aimSjögren’s syndrome (SS) is an autoimmune disease and its pathogenesis is still not completely clear. The wingless (Wnt)/β-catenin pathway has recently been shown to play an important role in inflammation. This study aims to determine the serum and saliva levels of Dickkopf (DKK)1 and sclerostin and to evaluate Wnt-1 and Wnt-3a expression in the salivary gland in patients with primary SS.Materials and methods This study included 30 patients diagnosed with SS, 30 patients diagnosed with systemic lupus erythematosus (SLE), and 29 healthy controls. Serum and saliva levels of DKK1 and sclerostin were measured and the expressions of Wnt1 and Wnt3a in the salivary gland were measured immunohistochemically. ResultsSerum DKK1 and sclerostin levels were lower in the SS and SLE groups compared to the control group (both p < 0.001). Saliva DKK1 levels were higher in the SS group compared to the control and SLE groups (p = 0.004 and p = 0.009, respectively). Wnt1 and Wnt3a expression were found in salivary gland tissue samples in 71.4% of primary SS patients and relatively frequent than control group.ConclusionsSerum DKK1 and sclerostin levels in primary SS and SLE were decreased. Moreover, levels of Wnt1 and Wnt3a expression in the salivary gland were also elevated in primary SS. Therefore, it can be concluded that the Wnt/β-catenin pathway activities may be altered in case of glandular inflammation.     

Wild-type ATTR amyloidosis of the ureter in a 56-year-old woman with rheumatoid arthritis and Sj?gren’s syndrome

We present a case of acute pyelonephritis with right hydronephrosis in a middle-aged woman, who had suffered from rheumatoid arthritis and Sjögren’s syndrome. She had successfully treated with antibiotics, however, ureteral stenosis sustained. She underwent ureteroscopy and stenting of right ureter. Biopsy specimen revealed submucosal amyloid deposition in the interstitium overlying a benign urothelium. Amyloid protein was positive for transthyretin (TTR) by immunohistochemistry and amyloid deposition was not demonstrated in other organs. The patient’s TTR genes were wild type and she was diagnosed with wild-type ATTR (ATTR wt) amyloidosis. This is the first report about symptomatic ATTR wt amyloidosis, which was also called ‘systemic senile amyloidosis (SSA)’ in the ureter. We should aware that SSA can occur at younger age and cause symptomatic ureteral stenosis. Further investigation is needed to clarify the association of autoimmune diseases to develop ATTR wt amyloidosis.     

Association Between Circulating Levels of the Novel TNF Family Members APRIL and BAFF and Lymphoid Organization in Primary Sjögren’s Syndrome

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumour necrosis factor superfamily. We have examined circulating BAFF and APRIL in relation to serological deviations and lymphoid organization in the salivary glands of the chronic, autoimmune disorder Sjögren’s syndrome. Lymphoid organization in the shape of ectopic germinal centers were detected in 33 of 130 consecutive minor salivary gland biopsies and coincided with increased focus score and elevated levels of serum IgG. Follicular dendritic cell networks, proliferation of mononuclear cells and altered B/T cell ratio also separated the two subgroups. Serum levels of sBAFF and sAPRIL were increased in Sjögren’s syndrome compared to healthy blood donors, especially in anti-Ro/La+ patients. Though the differences could not be related to germinal center formation, positive correlations between serum levels of sBAFF and sAPRIL, focus score and IgG denotes their possible role in the disease progression of primary Sjögren’s syndrome.The first two authors contributed equally to this work.     

Identification of a novel PTEN mutation (L139X) in a patient with Cowden disease and Sj?gren''s syndrome.

Cowden disease is an autosomal dominant disorder associated with an increased risk of breast, thyroid, and skin cancer in which germline mutations in a candidate tumour suppressor gene (PTEN) have been identified previously. Sjögren's syndrome is a chronic inflammatory and autoimmune disorder of exocrine glands for which the genetic basis is unknown. This report describes a novel PTEN mutation (L139X) in a patient with Cowden disease and Sjögren's syndrome. This observation raises the possibility of a link between mutations in the PTEN gene and Sjögren's syndrome.     

Cytokine markers of B lymphocytes in minor salivary gland infiltrates in Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterised by the clinical presence of sicca syndrome. SS compromises the dysfunction of exocrine glands due to the presence of focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. Abnormal expression of different cytokines and chemokines such as B-cell activating factor, CXC Motif Chemokine Ligand 13, interleukin 6 (IL-6), IL-22, and FMS-like tyrosine kinase 3 ligand as well as that of their corresponding receptors has been implicated in the inflammatory process. The severity of glandular infiltration has been suggested to be associated with the presence of extra-glandular systemic manifestations, contributing to a clinical spectrum of the most severe disease. This review describes several cytokines and chemokines associated with B lymphocytes expressed in the minor salivary gland, their chemical structures, and their roles in SS as possible early predictors of lymphoma development and disease progression.     

IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans

To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren's disease.Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren's disease in the same relative time frame as patients with primary Sjögren's disease: stage 1—early hypergammaglobulinemia and autoantibody production, stage 2—decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3—lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4—large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren's disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren's disease.     

MDSC在自身免疫疾病中的作用

髓系抑制细胞（Myeloid derived suppressor cells,MDSC）是具有抑制功能的髓系来源的细胞群。在自身免疫疾病中,MDSC显著增多,并在体外有抑制功能,然而在体内研究中,MDSC的研究存在争议。最新研究发现具有抑制功能的MDSC的显著增多并不能有效缓解自身免疫疾病,而且在某些情况下甚至促进疾病的进展。因此,MDSC在自身免疫疾病的作用有待进一步研究。本文根据已有文献,综述了MDSC在不同的自身免疫疾病中的改变及机制。     

Monotypic plasma cells in labial salivary glands of patients with Sjögren's syndrome: prognosticator for systemic lymphoproliferative disease.

AIMS: To determine the prevalence of plasma cell monotypia in labial salivary gland tissue of patients with and without Sjögren's syndrome, and to evaluate its relation to the development of systemic monoclonal lymphoproliferative disorders. METHODS: A quantitative immunohistological study was performed on labial salivary gland tissue of 45 patients with Sjögren's syndrome, 18 with rheumatoid arthritis without Sjögren's syndrome, and 80 healthy controls. In none of the patients with Sjögren's syndrome was there evidence of systemic monoclonal lymphoproliferative disease at the time of biopsy. RESULTS: Monotypic plasma cell populations, defined by a kappa:lambda ratio of > or = 3, were only observed in older patients (above 43 years) with Sjögren's syndrome. In almost all these patients monotypic plasma cell populations were present in multiple labial salivary gland tissues and the IgM/kappa monotypia was observed most frequently. The prevalence of monotypic plasma cell populations in the group with Sjögren's syndrome was 22% (10/45) and there was no significant predilection for primary Sjögren's syndrome. Of special clinical interest was the observation that progression to systemic monoclonal lymphoproliferative disease had occurred exclusively in this subgroup of patients with Sjögren's syndrome, with a prevalence of 30% (3/10). CONCLUSION: Quantitative immunohistological examination of labial salivary gland tissues provides pathologists with a simple method to select those patients with Sjögren's syndrome who have an increased relative risk at the time of biopsy to develop benign or malignant lymphoproliferative disorders.     

Lessons from Sj&ouml;gren&rsquo;s syndrome etiopathogenesis: Novel cellular and molecular targets

Sjögren’s syndrome (SS) is a systemic autoimmune disease that affects primarily the lacrimal and salivary glands. In addition to a systemic autoimmune response directed against ubiquitous antigens (such as Ro and La antigens), patients with SS mount a localized response that affects the epithelial component of exocrine glands leading to the establishment of a destructive inflammatory infiltrate comprised of activated T and B cells. Local chemokine and cytokine production drive the recruitment and local activation of immune cells that cause injury to acinar cells. CD4 T cells with different functional differentiation programs including Th1 (IFN-γ), Th2 (IL-13, IL-4) and Th17 (IL-17, IL-21, IL-22) as well as diverse cytokine signaling pathways, are involved at the initiation, perpetuation, and progression of the disease. Which factors initiate this response and allow it to become chronic are unknown. Proposed mechanisms include viral infections and acinar cell apoptosis. Moreover risk-conferring genetic variants, probably through the facilitation of innate and adaptive immune activation, most certainly contribute to the creation of an underlying environment that fosters tolerance loss and facilitates perpetuation of the autoimmune response. In this review, we describe the mechanisms through which the immune response causes SS and emphasize the pathways that are amenable of being targeted with therapeutic purposes.     

Translation and validation of a Turkish version of the Xerostomia Inventory XI in patients with primary Sjögren’s syndrome

Background/aim The aim of this study was to assess the reliability and validity of Turkish version of the Xerostomia Inventory XI in patients with primary Sjögren’s syndrome (pSS).Materials and methods A cross-sectional survey study design and analysis were used to assess the reliability and validity of the Xerostomia Inventory XI. A total of 69 patients with pSS (5 males, 64 females; mean age = 54.81 ± 8.77 years) were included. The Xerostomia Inventory XI (TR) was applied twice at an interval of 15 days. The test-retest reliability was assessed with the intraclass correlation coefficient (ICC), and the internal consistency of multiitem subscales by calculating Cronbach’s alpha values. The correlations between ESSPRI, basal and stimulated salivary flow (BSF-SSF), Oral Health Impact Profile-14 (OHIP-14) and Oral Health-Related Quality of Life-UK (OHRQoL-UK) Questionnaire were evaluated to determine the construct validity.Results The ICC value for test/retest reliability of the Xerostomia Inventory XI (TR) was 0.993. The internal consistency was 0.869. There were low to high correlations between Xerostomia Inventory XI (TR) and ESSPRI, BSF, SSF, OHIR-14 total and OHRQoL-UK total.Conclusion The Turkish version of the Xerostomia Inventory XI was found to be clinically valid and reliable to be used in clinical evaluations and rehabilitation interventions in patients with pSS.     

Reactivity of Sera from Systemic Lupus Erythematosus and Sjögren’s Syndrome Patients with Peptides Derived from Human Immunodeficiency Virus p24 Capsid Antigen

We have previously demonstrated that about one-third of patients with either Sjögren’s syndrome (SS) or systemic lupus erythematosus (SLE) react to human immunodeficiency virus (HIV) p24 core protein antigen without any evidence of exposure to, or infection with, HIV itself. Herein, we further characterize the specificity of this reaction using enzyme-linked immunosorbent assay to peptides representing fragments of p24. Characteristic epitope-specific profiles were seen for SS and SLE patients. SS patients had significantly increased responses to peptides F (p24 amino acids 69 to 86) and H (amino acids 101 to 111) and diminished reactivity to peptides A (amino acids 1 to 16) and P (amino acids 214 to 228). SLE patients had increased reactivity to peptides E (amino acids 61 to 76), H, and P. Utilization of peptide P hyporeactivity as the criterion to select for SS patients results in a screen that is moderately sensitive (64%) and specific (79.3%). Adding hyperreactivity to one other peptide (F or H) as an additional criterion yields an expected decrease in sensitivity (to 41%) while increasing specificity (to 93.1%). All sera-reactive peptides from regions of known structure of HIV p24 were located in the apex of the p24 molecule. Thus, the specificity of the peptide reactivities described here indicates a specific pattern of a nonrandom cross-reactivity between HIV type 1 p24 and autoimmune sera which may be partially syndrome specific. The future focus of our work will be to optimize assays of the peptide as diagnostic tools.     

Sjögren's syndrome: An underdiagnosed condition in mixed connective tissue disease

OBJECTIVE:

To determine the prevalence of sicca symptoms, dry eye, and secondary Sjögren''s syndrome and to evaluate the severity of dry eye in patients with mixed connective tissue disease.

METHODS:

In total, 44 consecutive patients with mixed connective tissue disease (Kasukawa''s criteria) and 41 healthy controls underwent Schirmer''s test, a tear film breakup time test, and ocular surface staining to investigate dry eye. In addition, the dry eye severity was graded. Ocular and oral symptoms were assessed using a structured questionnaire. Salivary gland scintigraphy was performed in all patients. Classification of secondary Sjögren''s syndrome was assessed according to the American-European Consensus Group criteria.

RESULTS:

The patients and controls had comparable ages (44.7±12.4 vs. 47.2±12.2 years) and frequencies of female gender (93 vs. 95%) and Caucasian ethnicity (71.4 vs. 85%). Ocular symptoms (47.7 vs. 24.4%) and oral symptoms (52.3 vs. 9.7%) were significantly more frequent in patients than in controls. Fourteen (31.8%) patients fulfilled Sjögren''s syndrome criteria, seven of whom (50%) did not have this diagnosis prior to study inclusion. A further comparison of patients with mixed connective tissue disease with or without Sjögren''s syndrome revealed that the former presented significantly lower frequencies of polyarthritis and cutaneous involvement than did the patients without Sjögren''s syndrome. Moderate to severe dry eye was found in 13 of 14 patients with mixed connective tissue disease and Sjögren''s syndrome (92.8%).

CONCLUSIONS:

Sjögren''s syndrome, particularly with moderate to severe dry eye, is frequent in patients with mixed connective tissue disease. These findings alert the physician regarding the importance of the appropriate diagnosis of this syndrome in such patients.     

Diverse T cell receptor beta gene usage by infiltrating T cells in the lacrimal glands of Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by T cell infiltration into the salivary and lacrimal glands (LG). Previous studies on T cell receptor (TCR) usage in the minor salivary glands (SG) have yielded controversial results. We studied TCR beta gene usage of the T cells infiltrating to LG, which is the other major target organ of SS. Total RNA was extracted from fresh LG and SG biopsy samples, and peripheral blood mononuclear cells from five SS patients, and converted to cDNA. TCR V beta gene repertoire was then assessed with quantitative polymerase chain reaction (PCR) assay. Oligoclonality was studied by sequencing V-D-J junctional regions of the PCR products. The TCR V beta gene usage in LG was diverse in every patient irrespective of disease duration, and similar to that of peripheral lymphocytes from a corresponding patient. The junctional region sequences of over-expressed V beta families in LG T cells were heterogeneous. We did not find any identical clones shared by LG, SG and peripheral blood. These results showed that the infiltrating T cells in LG of SS patients are polyclonal, and LG and SG do not share the same dominant T cell clonotypes. These suggest that TCR-targeted disease manipulation may have a limited effect on SS.     

T cell clones from a Sjögren's syndrome salivary gland biopsy produce high levels of IL-10

Sjögren''s syndrome (SS) is characterized by a focal periductal salivary gland infiltrate consisting mainly of T and B lymphocytes. Most of the T cells bear the memory of CD4⁺ Th-1-like phenotype and express high levels of class II, though CD8⁺ cells are also present. We have studied 17 labial salivary gland and 15 peripheral blood T cell clones from a patient with primary SS. The tissue clones were 71% CD8⁺ and 29% CD4⁺, and the peripheral blood-derived clones were 60% CD8⁺ and 40% CD4⁺. The CD4⁺ T cell clones from both the salivary gland and autologous peripheral blood were of the Th1 phenotype, in that they produced interferon-gamma (IFN-γ) and IL-2 but very little IL-4 after 24 h stimulation with phorbol myristate acetate and anti-CD3 antibody. The salivary gland-derived CD4⁺ clones produced 15 times more IL-10 (7·92 ng/ml) than peripheral blood-derived CD4⁺ clones (0·52 ng/ml, P≤0·02). The tissue CD8⁺ clones produced 1·2 times (P<0·04) more IFN-γ and CD4⁺ clones produced 3·5 times less IL-2 (P<0·02) than the respective PBM-derived clones. The accumulation of Th1-type cells producing high levels of IL-10 in the salivary gland suggests a specific immunoregulatory function at the site of inflammation in SS.