Sjögren’s syndrome can involve the central nervous system; however, spontaneous intracranial hemorrhage has rarely been reported as the initial manifestation.
We report a 39-year-old woman with primary Sjögren’s syndrome presenting with intracranial hemorrhage. The diagnosis of primary Sjögren’s syndrome was based on the presence of ocular dryness, salivary gland secretory and excretory dysfunction confirmed with dynamic tracer emission CT, and positive anti-Sjögren’s syndrome A and anti-Sjögren’s syndrome B antibodies.
Primary Sjögren’s syndrome can present with variable central nervous system signs, which may precede the classic sicca symptoms. Therefore, Sjögren’s syndrome-associated indicators should be investigated in patients without the common risk factors for stroke who present with spontaneous intracranial hemorrhage.
Sjögren’s syndrome; Vasculitis; Intracranial hemorrhage; Internal carotid artery; Moyamoya disease; Anti-Sjögren’s syndrome A antibody; Anti-Sjögren’s syndrome B antibody
Sjögren’s syndrome is a tissue-specific autoimmune disease that affects exocrine tissues, especially salivary glands and lacrimal glands. Despite a large body of evidence gathered over the past 60 years, significant gaps still exist in our understanding of Sjögren’s syndrome. The goal of this study was to develop a database that collects and organizes gene and protein expression data from the existing literature for comparative analysis with future gene expression and proteomic studies of Sjögren’s syndrome.
To catalog the existing knowledge in the field, we used text mining to generate the Sjögren’s Syndrome Knowledge Base (SSKB) of published gene/protein data, which were extracted from PubMed using text mining of over 7,700 abstracts and listing approximately 500 potential genes/proteins. The raw data were manually evaluated to remove duplicates and false-positives and assign gene names. The data base was manually curated to 477 entries, including 377 potential functional genes, which were used for enrichment and pathway analysis using gene ontology and KEGG pathway analysis.
The Sjögren’s syndrome knowledge base (
http://sskb.umn.edu) can form the foundation for an informed search of existing knowledge in the field as new potential therapeutic targets are identified by conventional or high throughput experimental techniques.
Purpose of review
To summarize recent developments in our understanding of the pathogenesis of Sjögren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction.
Animal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjögren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial.
Recent discoveries from studies in patients with Sjögren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjögren's syndrome.
autonomic nervous system; exocrinopathy; innate immunity; sex steroids
Sjögren's syndrome (SS) is a chronic slowly progressive autoimmune disorder characterized by symptoms of oral and ocular dryness, exocrine dysfunction, and lymphocytic infiltration of exocrine glands. Multiple myeloma (MM) is a bone-marrow-based malignant neoplasm of plasma cells associated with serum/urine monoclonal paraproteins and lytic skeletal lesions. There have been very few reported cases of MM, who had SS as the first presentation. We report a case of a woman diagnosed with Sjögren's syndrome, who was later suspected to have multiple myeloma on serum protein electrophoresis. Fluorescence in situ hybridization (FISH) was carried out to check for deletions of loci 13q14.3, ATM, p53, and IGH (14q32) rearrangements on a bone marrow aspirate. Monosomy 13 was observed in 49% of cells, and a rearrangement at the IGH locus was seen in 42% of cells. To determine the partner chromosome associated with the IGH rearrangement, further FISH tests were set up for t(4;14)(p16;q32) followed by t(14;16)(q32;q22) on fresh slides. The test was negative for t(4;14) but positive for t(14;16) in 27% of cells. This confirmed the diagnosis of MM. We report the first case from India, having an association of Sjögren's syndrome with multiple myeloma, which showed t(14;16) and monosomy 13 by FISH analysis.
This study suggests that the activation of cathepsin proteases and cytokines accompanies lipid deposition in NOD mouse lacrimal glands, which develop an autoimmune inflammatory disease similar to human Sjögren's syndrome. Insights into the onset and progression of inflammatory lacrimal gland disease which, in this model, resembles the inflammation associated with obesity, suggest new biomarkers and targets for diagnosis and treatment of Sjögren's syndrome, such as cathepsin S.
Lacrimal glands (LGs) of male NOD mice, a model of Sjögren's syndrome (SjS), exhibit immune cell infiltration and lipid deposition. The mechanism of SjS was further investigated by characterizing gene expression profiles of NOD mouse LGs in comparison with those of healthy control mice. Differentially expressed genes were further investigated at the protein level to correlate changes in location and abundance with development of disease.
Microarray followed by real-time RT-PCR was conducted to compare the gene expression in 12-week-old male NOD mouse LG relative to that in matched BALB/c mouse LG. Immunofluorescence and Western blot analyses were used to localize and quantify proteins of interest. Enzymatic assays measured catalytic activity of cathepsins.
Cathepsin H (Ctsh), S (Ctss), and Z (Ctsz) and proinflammatory factors, including tumor necrosis factor (Tnf), interleukin 6 (Il6), and interleukin 1 beta (Il1b), were upregulated at the mRNA level. Increased cathepsin S immunofluorescence was detected in lysosomes and secretory vesicle-like organelles in LG acinar cells and CD68-positive infiltrating macrophages in NOD mouse LG. Cathepsin S (CATS) and cathepsin H (CATH) activities were significantly higher in NOD mouse LG lysate than in control lysates, and CATS was also significantly elevated in NOD mouse tears.
Expression of CATS and CATH increases in parallel with proinflammatory cytokines during the development of autoimmune inflammatory disease in the NOD mouse disease model. Tear CATS may represent a biomarker for diagnosis of dacryoadenitis in SjS.
Chronic infiltration of lymphocytes into the salivary and lacrimal glands of Sjögren’s Syndrome patients leads to destruction of acinar cells and loss of exocrine function. Protein kinase C-delta (PKCδ) is known to play a critical role in B cell maintenance. Mice in which the PKCδ gene has been disrupted have a loss of B cell tolerance, multiple organ lymphocytic infiltration, and altered apoptosis. To determine if PKCδ contributes to the pathogenesis of Sjögren’s Syndrome, we quantified changes in indicators of Sjögren’s Syndrome in PKCδ−/− mice as a function of age. Salivary gland histology, function, the presence of autoantibodies, and cytokine expression were examined. Materials and Methods: Submandibular glands were examined for the presence of lymphocytic infiltrates, and the type of infiltrating lymphocyte and cytokine deposition was evaluated by immunohistochemistry. Serum samples were tested by autoantibody screening, which was graded by its staining pattern and intensity. Salivary gland function was determined by saliva collection at various ages. Results: PKCδ−/− mice have reduced salivary gland function, B220+ B cell infiltration, anti-nuclear antibody production, and elevated IFN-γ in the salivary glands as compared to PKCδ+/+ littermates. Conclusions: PKCδ−/− mice have exocrine gland tissue damage indicative of a Sjögren’s Syndrome-like phenotype.
PKCδ; autoimmunity; Sjögren’s syndrome
The presence of multiple calculi in the major salivary glands is an uncommon finding. Sjögren’s syndrome is a chronic autoimmune disease characterized by lymphocyte-mediated destruction of the exocrine glands. The case is presented of a 49-year-old female with Sjögren’s syndrome found to have bilateral multiple sialolithiasis in the parenchyma of the parotid glands. The patient presented with a right sided painful inflamed swelling of the parotid region. Even though she had been diagnosed with primary Sjögren’s syndrome 3 years prior to admission, she did not report any previous episode of sialadenitis. Full blood count showed leukocytosis (white blood cells = 14,900/106L) with neutrophilia (75%). Radiological assessment included ultrasound and computed tomography scan of the parotids which demonstrated intra-parenchymal multiple calculi of both parotid glands and obstruction of the right Stensen’s duct. The patient was treated with intravenous antibiotics and anti-inflammatory drugs. On the second day of hospitalisation, she reported spontaneous extrusion of a calculus during massage of the gland, with immediate relief of symptoms. In patients with Sjögren’s syndrome and radiological findings of calculi in the major salivary glands, close observation is mandatory for better control of recurrent sialadenitis and early recognition of mucosa-associated lymphoid tissue lymphomas.
Parotid gland; Sialolithiasis; Sjögren’s syndrome
The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multi-factorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjögren’s syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands, such as the salivary and lacrimal glands, and loss of secretory function, resulting in dry mouth and dry eyes in patients. Although, every Sjögren’s syndrome mouse model resembles the major symptoms or phenotypes of Sjögren’s syndrome conditions in humans, the characteristics of each model are variable. Moreover, to date there is no single mouse model that can completely replicate the human conditions. However, unique features of each mouse model provide insights into the roles of potential etiological and immunological factors in the development and progression of Sjögren’s syndrome. Here, we will overview the Sjögren’s syndrome mouse models. Lessons from these mouse models will aid us to understand underlying immune dysregulation in autoimmune diseases in general, and will guide us to direct future research towards appropriate diagnostic and therapeutic strategies to predict autoimmune disease including Sjögren’s syndrome.
Sjögren’s Syndrome; mouse models; T/B lymphocytes; autoantibodies; autoimmunity
Sjögren syndrome is an autoimmune disease characterized by hyposecretion of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. Individuals may experience primary Sjögren syndrome or a secondary form accompanying another rheumatic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The pathogenic mechanisms of Sjögren syndrome remain largely unknown, in part a consequence of the heterogeneity of the disease. Animal models have shed light on the connections between specific pathways and symptoms, but an ideal system is wanting. Improved disease models will enable a better understanding of Sjögren syndrome, including how immune tolerance is lost and potential therapeutic interventions. Most importantly, an optimal model will enable detection of disease biomarkers, since injury to the salivary glands may precede lymphocytic infiltration. This review aims to characterize available mice models of Sjögren syndrome, including advantages and disadvantages, from the researcher’s perspective.
Sjögren syndrome; Mouse models; Autoimmunity
Sjögren's syndrome is an autoimmune disease with a complex etiology depending on hereditary and environmental factors. The disease is characterized by lymphocytic infiltration and inflammation in the salivary and lacrimal glands, leading to oral and ocular dryness. To understand the genetic susceptibility in Sjögren's syndrome, studies of disease phenotypes have been performed in the non-obese diabetic (NOD) mouse. By the identification of genetic regions controlling development of autoimmune exocrinopathy in the NOD mouse and by reducing one of these regions considerably, Nguyen et al. in a recent issue of Arthritis Research and Therapy propose candidate genes for development of 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.
Sjögren’s syndrome; dental caries; Autoimmune
A coordinated upregulation of gene expression in the lacrimal glands of C57BL/6.NOD-Aec1Aec2 mice defines focal adhesion maturation associated with infiltrating leukocytes as the earliest detectable biomarker of Sjögren's syndrome development.
Despite considerable efforts, the molecular and cellular events in lacrimal gland tissues initiating inflammatory responses leading to keratoconjunctivitis sicca (KCS), autoimmunity, and Sjögren's syndrome (SjS) have yet to be defined. To determine whether altered glandular homeostasis occurs before the onset of autoimmunity, a temporal transcriptome study was carried out in an animal model of primary SjS.
Using oligonucleotide microarrays, gene expression profiles were generated for lacrimal glands of C57BL/6.NOD-Aec1Aec2 mice 4 to 20 weeks of age. Pairwise analyses identified genes differentially expressed, relative to their 4-week expression, during the development of SjS-like disease. Statistical analyses defined differentially and coordinately expressed gene sets. The PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system was used to define annotated biological processes or functions.
Temporal transcript expression profiles of C57BL/6.NOD-Aec1Aec2 lacrimal glands before, or concomitant with, the first appearance of inflammatory cells revealed a highly restricted subset of differentially expressed genes encoding interactive extracellular matrix proteins, fibronectin, integrins, and syndecans. In contrast, genes encoding interepithelial junctional complex proteins defined alterations in tight junctions (TJ), adherens, desmosomes, and gap junctions, suggesting perturbations in the permeability of the paracellular spaces between epithelial barriers. Correlating with this were gene sets defining focal adhesion (FA) maturation and Ras/Raf-Mek/Erk signal transduction. Immunohistochemically, FAs were associated with infiltrating leukocytes and not with lacrimal epithelial cells.
For the first time, FA maturations are implicated as initial biomarkers of impending autoimmunity in lacrimal glands of SjS-prone mice. Changes in TJ complex genes support an increased movement of cells through paracellular spaces.
Sjögren syndrome (SS) is an autoimmune-lymphoproliferative disorder characterized by mononuclear cell infiltration of exocrine glands. Clinically, Sjögren syndrome (SS) has a wide spectrum, varying from autoimmune exocrinopathy to systemic involvement. There have been few cases reporting that primary SS developed with distal renal tubular acidosis clinically.
Here, we present a case with primary Sjögren syndrome accompanied by hypopotassemic paralysis due to renal tubular acidosis. Severe hypopotassemia, hyperchloremic metabolic acidosis, alkaline urine and disorder in urinary acidification test were observed in the biochemical examination of the 16-year-old female patient, who had applied to our clinic for extreme loss of muscle force. After the examinations it was determined that the patient had developed Type 1 RTA (distal RTA) due to primary Sjögren syndrome. Potassium and alkaline replacement was made and an immediate total recovery was achieved.
Hypopotassemic paralysis due to primary Sjögren syndrome is a rare but severe disorder that could lead to death if not detected early and cured appropriately. Thus, effective treatment should be immediately initiated in cases where severe hypopotassemia is accompanied by metabolic acidosis, and the cases should also be examined for extraglandular involvement of SS.
Sjögren syndrome; hypopotassemic paralysis; distal renal tubular acidosis
Previously, a dominant role of the adaptive immune system in the pathogenesis of Sjögren's syndrome was suspected. Recent advances, however, have revealed a major role of the type I IFN pathway, documented by an increased circulating type I IFN activity and an IFN 'signature' in peripheral blood mononuclear cells and minor salivary gland biopsies from the patients. Polymorphisms in the genes IRF5 and STAT4 leading to increased IFN activation are associated with disease susceptibility. In the pathogenesis of Sjögren's syndrome, the activation of salivary gland epithelial cells appears to be the initial event. Once intrinsically activated, they express costimulatory and Toll-like receptors (TLRs) and MHC class I and II molecules, can present autoantigens and produce proinflammatory cytokines. The subsequent activation of plasmacytoid dendritic cells induces the production of high levels of proinflammatory cytokines in individuals with the risk alleles of the susceptibility genes IRF5 and STAT4. Under the influence of the high IFN concentration in the glands and through TLR ligation, B-cell activating factor is produced by epithelial cells and, together with autoantigen presentation on salivary gland epithelial cells, stimulates the adaptive immune system. In view of the central role of IFNalpha in at least the initiation of the pathogenesis of Sjögren's syndrome, blockade of this cytokine may be a rational therapeutic approach.
Sjögren’s syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. The current study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of Sjögren’s syndrome-like disease.
Female New Zealand Black × New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland infiltrating cells were characterized by flow cytometry.
Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C) treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates and these were followed by CD4+ T cells.
Our data clearly demonstrates that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren’s syndrome-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of Sjögren’s syndrome.
Sjögren’s Syndrome; Innate Immunity; Sialoadenitis; mouse
Sjögren’s Syndrome is a human autoimmune disease characterized by immune-mediated destruction of the lacrimal and salivary glands. Here, we show that the Aire-deficient mouse represents a new tool to investigate autoimmune dacryoadenitis and keratoconjunctivitis sicca, features of Sjögren’s Syndrome. Previous work in the Aire-deficient mouse suggested a role for alpha-fodrin, a ubiquitous antigen, in the disease process. Using an unbiased biochemical approach, however, we have identified a novel lacrimal gland autoantigen, odorant binding protein 1a, targeted by the autoimmune response. This novel autoantigen is expressed in the thymus in an Aire-dependent manner. The results from our study suggest that defects in central tolerance may contribute to Sjögren’s Syndrome and provide a new and clinically relevant model to investigate the pathogenic mechanisms in lacrimal gland autoimmunity and associated ocular surface sequelae.
T cells; Autoimmunity; Autoantibodies; Tolerance; Thymus
Sjögren's syndrome is a chronic autoimmune process that primarily affects the exocrine glands and leads to their functional impairment. The exocrine gland involvement is characterized by a focal, mononuclear cell infiltrate which is accumulated around ducts and, in some patients, extends and replaces the secretory functional units. The mechanisms of this autoimmune 'exocrinopathy' are not fully understood. The immune attack that follows activation or apoptosis of glandular epithelial cells exposing autoantigens in genetically predisposed individuals may drive the immune-mediated tissue injury. Abnormalities related to the upregulation of type I interferon-regulated genes (interferon signature), abnormal expression of B-cell-activating factor (BAFF) and activation of the IL-23/TH17 pathway are among the immune mediators implicated in the pathogenesis of autoimmune lesions within the salivary glands. Such abnormalities demonstrate the complex interplay between innate and adaptive immunity that contributes to autoimmune 'exocrinopathy'.
Sjögren's syndrome; pathogenesis; cytokines; apoptosis; autoimmune exocrinopathy
Innate immune responses direct the nature and specificity of downstream adaptive responses in autoimmune diseases. One of the strongest markers of innate immunity is the up-regulated expression of interferon (IFN) and IFN-responsive/stimulated genes (IRGs/ISGs). While multiple IRGs are induced during the innate phase of host responses, transcriptome data suggest unique IRG-signatures for different diseases. Sjögren’s syndrome (SjS) is characterized by chronic immune attacks against exocrine glands leading to exocrine dysfunction, plus strong up-regulated expressions of IFN IRG transcripts. Genome-wide transcriptome analyses indicate that differentially expressed IRGs are restricted during disease development and therefore define underlying etiopathological mechanisms. Here we review the innate immune-associated IFN-signature of SjS and show how differential gene expressions of IRG/ISG sets interact molecularly and biologically to identify critical details of SjS etiopathogenesis.
interferons; biomarkers; Sjögren syndrome; animal models; human disease; gene expression profiling
Sjögren's syndrome is an autoimmune disease characterized by an autoimmune exocrinopathy involving mainly salivary and lacrimal glands. The histopathological hallmark is periductal lymphocytic infiltration of the exocrine glands, resulting in loss of their secretory function. Several systemic manifestations may be found in patients with Sjögren's syndrome including neurological disorders. Neurological involvement ranges from 0 to 70% among various series and may present with central nervous system and/or peripheral nervous system involvement. This paper endeavors to review the main clinical neurological manifestations in Sjögren syndrome, the physiopathology, and their therapeutic response.
Sjögren’s syndrome is a systemic autoimmune disease in which lymphatic cells destroy the salivary and lacrimal glands. Glomerulonephritis is thought to be a rare occurrence in primary Sjögren’s syndrome. Furthermore, concurrent glomerular involvement and lymphoma in patients with Sjögren’s syndrome has seldom been reported.
A 52-year-old woman with primary Sjögren’s syndrome developed membranous glomerulonephritis and Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL). She was diagnosed with Sjögren’s syndrome based on the dry eyes, dry mouth, positive anti-nuclear antibody test, anti-Ro (SS-A) antibody, salivary gland biopsy, and salivary scintigraphy. Moreover, renal biopsy confirmed the diagnosis of membranous glomerulonephritis. Three months later, her small bowel was perforated with pneumoperitoneum, and the biopsy revealed Epstein-Barr virus-positive DLBCL.
We observed the first case of primary Sjögren’s syndrome associated with Epstein-Barr Virus-positive DLBCL and membranous glomerulonephritis. Because of the possibility of malignancy-associated membranous glomerulonephritis in patients with primary Sjögren’s syndrome, we should be careful and examine such patients for hidden malignancy.
Primary Sjögren’s syndrome; Membranous glomerulonephritis; EBV-positive diffuse large B-cell lymphoma
Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration of the lacrimal and salivary glands, leading to dryness of eyes (kerato-conjunctivitis sicca) and mouth (xerostomia). The skin lesions in Sjögren's syndrome are usually manifested as xeroderma, but sometimes appear as annular erythema or vasculitis. Central nervous system symptoms may be presented as one of extraglandular manifestations, though rare in incidence, and need differential diagnosis from multiple sclerosis. We report a case of a 45-year-old woman diagnosed as multiple sclerosis at first but later as neurologic manifestation of primary Sjögren's syndrome, showing signs of multiple sclerosis and cutaneous erythematous lesions.
MicroRNAs are endogenous non-coding RNAs, approximately 22 nucleotides in length. They regulate gene expression and are important in a wide range of physiological and pathological processes. MicroRNA expression is tightly regulated during hematopoiesis and lymphoid cell differentiation and disruption of the entire microRNA network or selected microRNAs may lead to dysregulated immune responses. Abnormalities in microRNA expression related to inflammatory cytokines, Th-17 and regulatory T cells as well as B cells have been described in several autoimmune diseases. Sjögren’s syndrome is characterized by features of systemic autoimmunity and chronic inflammation and dysfunction in exocrine organs. Its clinical characteristics along with the relatively easy access to the target tissue and its product makes Sjögren’s syndrome appealing to study many aspects of microRNAs in a systemic autoimmune disease, such as their potential as diagnostic or prognostic biomarkers and their role in pathogenesis of autoimmunity, inflammation or organ dysfunction. Encouraging preliminary data from pilot studies in Sjögren’s syndrome demonstrate the potential of microRNAs as putative diagnostic and prognostic biomarker candidates which should be tested in larger more definite studies. Combining the comparison of microRNA expression profiles between various clinical subsets of Sjögren’s syndrome with bioinformatic modeling tools may predict formerly unsuspected pathways which may contribute to the disease process and lead to the generation of testable novel hypothesis of pathogenesis.
biomarker; autoimmunity; epigenetics; exocrine dysfunction; pathogenesis
Sjögren's syndrome is an autoimmune exocrinopathy, mainly affecting the lacrimal and salivary glands, and resulting in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown, and only palliative treatment is currently available. Data obtained from experimental animal and human studies using biological agents or gene therapeutics can offer insight into the disease process of Sjögren's syndrome. This article reviews the current literature on these approaches and assesses the lessons learnt about the pathogenesis of Sjögren's syndrome.
In Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome.
Male NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21. Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein. Leukocytes from lacrimal glands were analyzed by flow-cytometry. Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining. The chemokine CXCL13 was measured by ELISA in sera from Sjögren's syndrome patients (n = 27) and healthy controls (n = 30). Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores.
LTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands. Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression. The reduction of CXCL13, CCL21, CCL19 mRNA and the HEV-associated gene GLYCAM-1 was confirmed by PCR analysis. CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg/mg (+/- 2.7) from 51 pg/mg (+/-5.3) in lacrimal glands of 16 week old control mice. Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (P = 0.001), and had a significantly improved ocular surface integrity score (P = 0.005). The mean CXCL13 concentration in sera from Sjögren's patients (n = 27) was 170 pg/ml, compared to 92.0 pg/ml for sera from (n = 30) healthy controls (P = 0.01).
Blockade of LTBR pathways may have therapeutic potential for treatment of Sjögren's syndrome.
Lymphotoxin-beta; Sjogren's syndrome; chemokine; CXCL13; keratoconjuntivitis sicca; NOD mouse
Primary Sjögren's syndrome (pSS) is an autoimmune disorder of the exocrine glands presenting with progressive ocular and oral dryness, parotid gland enlargement, and often with extraglandular manifestations. In this group of patients the risk of development of non-Hodgkin's lymphoma is 16-fold compared to healthy population, mainly of the MALT lymphoma type. This case reports a 52-year-old woman with pSS developing a progressively growing mass at face and neck compatible with blastoid variant mantle cell lymphoma and a fatal outcome.