Pathogenesis Of Sjögren's Syndrome Research Articles

Anti-Annexin V Antibodies in Primary Fibromyalgia Syndrome: Relation to Associated Sjögren’s Syndrome

Fibromyalgia syndrome (FMS) is a complex disorder that affects up to 5 % of the general population worldwide, more frequently in women. Sjogren’s syndrome (SS), the second most common autoimmune rheumatic disease results from immune lymphocytes that infiltrate the lacrimal and salivary glands. The distinction between FMS patients and primary SS remains difficult. Damages to the lacrimal and salivary glands and development of SS may accompany various autoimmune diseases. Apoptosis (programmed cell death) plays a fundamental role in the pathogenesis of SS. Annexins are a group of highly conserved proteins which exert several regulatory functions on cell biology and are involved in numerous cell processes including apoptosis. The aim of this study was to measure the level of serum Anti-Annexin V antibodies in FMS patients diagnosed according to the American College of Rheumatology criteria [1] and to study their significance in relation to associated SS diagnosed according to the revised version of classification criteria [2]. Fifty-six female patients with primary FMS (mean age 35.36±7.53 years) and 30 age and sex matched healthy subjects were included as controls (33.53±5.16 years) were included. Serum IgG anti-annexin V antibodies titre was assessed. The FMS patients had a mean Widespread Pain Index (WPI) of 8.98±2.93 and a symptom severity scale score (SSSS) of 8.27±2.21. Twenty seven patients gave symptoms of dry eyes or mouth of which only 12 (21.43 %) had SS. Anti-annexin V antibody level was significantly higher in FMS patients (19.96±10.29 AU/ml) compared to control (7.32±3.42 AU/ml); being higher in those with SS (29.87±10.44 AU/ml) compared to those without (17.25±8.53 AU/ml)(p 0.002) (Fig. 1). Furthermore, serum anti-Ro, anti-La and SSSS were significantly higher in those patients with SS (17.67±10.01 U/ml, 23.75± 11.14 U/ml, 9.67±1.83) compared to those without SS (7.14± 3.17 U/ml, 8.5±3.69 U/ml, 8.11±2.17) (p 0.004, 0.001, 0.02 respectively). In the FMS patients, anti-annexin V antibodies significantly correlated with SSSS (r 0.39, p 0.003) while there was a tendency to correlate with WPI (r 0.24, p 0.07). Apoptosis plays a fundamental role in the pathogenesis of SS [3]. Autoantibodies in SS directed against nuclear and cytoplasmic antigens may consequently activate the apoptotic process [4]. The role of apoptosis in FMS is not known. Anti-Annexin V antibodies are elevated in FMS with special attention to those with associated SS. In addition to the other T. A. Gheita (*) :H. A. Raafat Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt e-mail: gheitamer@hotmail.com

Altered IkBα expression promotes NF-kB activation in monocytes from primary Sjögren’s syndrome patients

To study the importance of IκBα in NF-κB signal transduction, we analysed the IκBα expression in monocytes from Sjögren's syndrome (SS) patients versus healthy controls. Monocytes were obtained from the peripheral blood of 30 SS patients and 23 healthy subjects. IκBα expression was studied by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, immunoblotting, flow cytometry and enzyme linked immunosorbent assay (ELISA). Analysis of the gene and protein expression profiles of SS monocytes revealed a down-regulation of IκBα, and in all the Sjögren's syndrome cases examined, serum IκBα levels were significantly decreased in comparison with controls. Our findings clearly demonstrate changes in the levels of IκBα in SS monocytes, suggesting that the attenuated expression of IκBα could contribute to the deregulation of NF-κB pathways in the SS pathogenesis. Decreased expression of IκBα may specifically amplify cytokines production and inflammatory response linked to Sjögren's syndrome.

Epigallocatechin-3-gallate modulates antioxidant and DNA repair-related proteins in exocrine glands of a primary Sjogren's syndrome mouse model prior to disease onset

The autoimmune disorder primary Sjogren's syndrome (SS) is associated with xerostomia and xerophthalmia. SS pathogenesis involves both genetic/epigenetic and environmental factors. A major potential contributor is oxidative stress associated with damage to cellular components, including DNA. We reported previously that the green tea polyphenol epigallocatechin-3-gallate (EGCG) normalizes the elevated levels of proliferating cell nuclear antigen (PCNA), a key component of DNA repair, in the NOD mouse model for SS and type 1 diabetes. The current study examined levels of the antioxidant enzymes peroxiredoxin 6 (PRDX6), catalase and superoxide dismutase (SOD), as well as PCNA, in NOD.B10.Sn-H2 mice, a model for primary SS, and determined the effect of EGCG on their expression. PCNA elevation was detected in the submandibular gland and pancreas by 8 weeks of age in water-fed mice, and increased through 14 weeks of age, prior to overt onset of symptoms. This early PCNA elevation was followed by a decline of peroxiredoxin 6 protein. In contrast, EGCG-fed mice exhibited normal levels of PCNA and peroxiredoxin 6, comparable to healthy untreated BALB/c mice. Similar patterns were observed in the pancreas, even though these mice do not develop diabetes. Thus, elevated PCNA is an early biomarker for exocrine glandular dysfunction associated with SS-like autoimmune disease, accompanied subsequently by decreased PRDX6 antioxidant enzyme levels that could further contribute to oxidative stress, and these changes precede inflammatory cell infiltration. Importantly, EGCG consumption normalizes the expression of these biomarkers in this model. These observations could lead to early diagnosis and intervention of autoimmune disorders.

Pathogenic role of anti-M3 muscarinic acetylcholine receptor immune response in Sjögren's syndrome

M3 muscarinic acetylcholine receptor (M3R) is expressed in exocrine glands (e.g., salivary glands [SGs] and lachrymal glands), and plays a crucial role in exocrine secretion. M3R reactive T cells have been detected in circulating mononuclear cells of 40% of patients with Sjögren's syndrome (SS), and the major T cell epitopes of M3R in those patients with HLA-DR B1×0901 are located in the second loop of M3R. Moreover, autoantibodies (autoAbs) against M3R are also present in sera of around 50% of patients with SS, and several B cell epitopes, such as N-region, 1st, 2nd, and 3rd loop of M3R, have been identified. Functional analysis using human SG cell lines showed that autoAbs against the 2nd loop of M3R suppressed intracellular Ca(2+) influx, suggesting inhibition of saliva secretion. To clarify whether the M3R reactive immune response induces autoimmune sialadenitis (AIS), M3R(-/-) mice were immunized with M3R synthetic peptides and their splenocytes transferred into Rag1(-/-) mice. The recipients developed severe sialadenitis, and cell transfer studies indicated that T cells are key factors in the pathogenesis of AIS. These results indicate that the M3R immune reaction plays a key pathogenic role in AIS, suggesting that M3R molecule acts as an autoantigen in the pathogenesis of SS.

Brief Report: First identification of H4 histamine receptor in healthy salivary glands and in focal sialadenitis in Sjögren's syndrome

The conventional H(1) and H(2) histamine receptors have >10,000-fold lower avidity for histamine than H(4) histamine receptor, which has been implicated in autoimmune diseases. This study was undertaken to compare H(4) histamine receptor levels in the salivary glands (SGs) of healthy controls with those in the SGs of patients with primary Sjögren's syndrome (SS). H(4) histamine receptor messenger RNA (mRNA) was analyzed using real-time quantitative polymerase chain reaction, and the receptor protein was examined using immunostaining. Effects of the H(4) histamine receptor agonist ST-1006 on cytokine synthesis by human SG (HSG) cells were analyzed using xMAP technology and enzyme-linked immunosorbent assay. Healthy SGs contained H(4) histamine receptor mRNA. The receptor protein was localized to the acinar and ductal epithelial cells. H(4) histamine receptor agonist stimulated HSG cells to produce the cytokines interleukin-8 and vascular endothelial growth factor. SS patients had low H(4) histamine receptor levels. H(1) and H(2) histamine receptor antagonists are not effective in the treatment of autoimmune diseases. However, such antagonists do not affect the newly discovered H(4) histamine receptor. Dendritic cells and lymphocytes are nonprofessional histamine-producing cells, which produce histamine at 100-1,000-fold lower rates than mast cells do. Saliva contains only 0.31-12.4 ng/ml histamine, which is too low to stimulate H(1) or H(2) histamine receptor, but stimulates H(4) histamine receptor half maximally. Our findings show that H(4) histamine receptor is strongly expressed in tubuloacinar SG cells, which emphasizes the role of these cells in the pathogenesis of SS.

Molecular-Targeted and Cell-Based Therapies for Sjogren Syndrome

Sjogren’s syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands, in particular the salivary and lachrymal glands. The etiology and pathogenic mechanisms of SS remain largely unknown. Accordingly there are no treatments that completely reverse the disease in patients. The purpose of this invited review is not to provide a comprehensive overview of treatment approaches for SS, but rather to comment on emerging molecular targeted therapies and cell-based therapies. Although a number of molecular-targeted therapies are currently available for autoimmune diseases, very few but Rituximab and Epratuzumab appear to be efficacious for patients with SS, suggesting the importance of an enhanced understanding of SS pathogenesis. Cell-based therapy has been demonstrated as a promising approach to treat salivary gland dysfunction in SS mouse models. Further assessment for functional restoration of damaged salivary glands in organotypic culture or in SS patients is necessary to translate the cellbased therapies into the clinic. Keywords: B-cell targeted therapies, bone marrow-derived cells (BMDCs), cell-based therapies, cytokines, epratuzumab, immunoproteasome, interferons (IFNs), molecular-targeted therapies, rituximab, tumor necrosis factor-alpha (TNF-α), sjogren’s syndrome, T-cell targeted therapies

Impaired expression of Act1mRNA in B cells of patients with Sjögren's syndrome

Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by profound lymphocytic infiltration into the lacrimal and salivary glands, thereby diminished secretory function. B cell hyper-activation is a predominant feature of SS related to hypergammaglobulinemia and production of autoantibodies. The adaptor molecule NF-kB activator 1 (Act1) plays an important role in the homeostasis of B cells by attenuating CD40 and B cell-activating factor belonging to the tumor necrosis factor family receptor (BAFFR) signaling. Act1-deficient mice develop autoimmune manifestations similar to SS, which are hypergammaglobulinemia, high levels of anti-SSA and anti-SSB autoantibodies. In this study, to investigate the role of Act1 in the pathogenesis of SS, we examined Act1mRNA expressions in B cells from patients with SS and discussed the association of Act1 with parameters and clinical manifestations of SS. We showed the low level of Act1mRNA expression in patients with SS and reciprocal association of Act1 with serum IgG level. Diminished Act1mRNA expression in SS may be associated with B cell hyperactivity and elevated immunoglobulin production in SS by uncontrolled B cell activation signal through CD40 and BAFFR.

An autoimmunized mouse model recapitulates key features in the pathogenesis of Sjogren's syndrome

The pathogenesis of Sjögren's syndrome (SS) is poorly understood. To evaluate an autoimmunization-induced experimental SS model, we firstly observed the phenotype of lymphocyte infiltration in the enlarged submandibular gland (SG). Furthermore, significant activation of caspase-3 and a high ratio of Bax-to-Bcl-2 were detected, indicating the inflammatory apoptosis associated with developmental foci. Meanwhile, the dysregulated cytokines, such as tumor necrosis factor α, IL-1β and IL-6 mRNA expression, were found to be over-expressed. A progressive decrease of aquaporin 5 and its subcellular translocation from apical to basal membrane in SG was found to be associated with the abnormally expressed M3 muscarinic acetylcholine receptor. This pattern was found to be similar to that seen in human SS and possibly contributed to the saliva secretion deficiency. Thus, this autoimmunization-induced model recapitulates the key features of human SS and may have potential for studying the pathogenesis of human SS.

Altered miR‐146a expression in Sjögren's syndrome and its functional role in innate immunity

MicroRNAs (miRNAs), small non-coding RNA molecules that post-transcriptionally regulate gene expression, are known to play key roles in regulating immune responses and autoimmunity. We investigated miR-146a expression in Sjögren's syndrome (SjS) patients as well as in the SjS-prone C57BL/6.NOD-Aec1Aec2 mouse model, to elucidate its involvement in SjS pathogenesis. Expression of miR-146a was examined in the PBMCs of 25 SjS patients and ten healthy donors, as well as in PBMCs, salivary and lacrimal glands of SjS-prone mice and WT C57BL/6J mice. Functional assays using THP-1 human monocytes were conducted to determine the biological roles of miR-146a in innate immunity. Expression of miR-146a was significantly increased in SjS patients compared with healthy controls, and was upregulated in the salivary glands and PBMCs of the SjS-prone mouse at both 8 wk (prior to disease onset) and 20 wk (full-blown disease) of age. More importantly, functional analysis revealed roles for miR-146a in increasing phagocytic activity and suppressing inflammatory cytokine production while migration, nitric oxide production and expression of antigen-presenting/costimulatory molecules are not affected in human monocytic THP-1 cells. Taken together, our data suggest that abnormal expression/regulation of microRNAs in innate immunity may contribute to, or be indicative of, the initiation and progression of SjS.

Genetics and genomics of Sjögren's syndrome: research provides clues to pathogenesis and novel therapies

Although the key inciting events that drive the progression from autoantibodies to clinical disease remain to be clarified, new light has been shed on the factors contributing to disease susceptibility and the role of genetic factors in determining Sjögren's syndrome (SS) disease phenotypes. The purpose of this article is to provide an update on the role of genetic markers in the susceptibility to and pathogenesis of SS. This article also discusses how genomic and proteomic technology can help in the design of specific therapeutics. Recent evidence suggests that inflammatory genes associated with interferon pathways, and specific regulatory genes that control the maturation and proliferation of B cells, contribute to the pathogenesis of SS. Both gene expression profiling technology and gene association studies have been used to identify these key biological pathways. Molecularly, defined subsets of pSS patients are also being revealed by these studies. Previously, identified gene loci that predispose to multiple autoimmune disorders have been confirmed supporting the paradigm of "general" autoimmune disease genes. Association of SS with many additional susceptibility loci are likely to be established through ongoing genome-wide association scans (GWAS). Clues from genetic studies suggest that targeting B cells will prove to be an effective way of reducing the systemic manifestations of pSS and are supported by early clinical trials. Genome-wide technologies are likely to identify new genes and molecular pathways in the pathogenesis of SS that will be useful not only to identify patients at risk for SS, but also to identify subsets of patients at risk for variable levels of disease severity. In the future, these studies could identify novel biomarkers that will lead to significant advances in management by providing the means to tailor therapeutic strategies to individual patients.

Dysfunction of Lacrimal and Salivary Glands in Sjögren′s Syndrome: Nonimmunologic Injury in Preinflammatory Phase and Mouse Model

Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity.

Impact of interleukin-21 in the pathogenesis of primary Sjogren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands

IntroductionInterleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.MethodsSerum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.ResultsPrimary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.ConclusionsPrimary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.

Importance of serine727 phosphorylated STAT1 in IFNγ‐induced signaling and apoptosis of human salivary gland cells

It is reported that in salivary glands of Sjögren's syndrome (SS), interferon gamma (IFNγ) and IFNγ-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser(727)) or tyrosine701 (Tyr(701)) of STAT1, is important for IFNγ signaling and IFNγ-induced apoptosis in salivary gland cells. We established STAT1 Tyr(701) variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser(727) variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNγ-inducible genes and apoptosis after stimulation with IFNγ. In Y701F mutant-STAT1 transfected HSG cells (Ser(727)-dominant HSG cells), IFNγ-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNγ. In Ser(727)-dominant HSG cells, the induction of apoptosis after stimulation with IFNγ was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr(701)-dominant HSG cells). Phosphorylation of Ser(727) in STAT1 might be more important in IFNγ signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr(701). Accordingly, we propose that phosphorylation of Ser(727) in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands.

Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome

We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

Significance of B cells and B cell clonality in Sjögren's syndrome

Sjogren’s syndrome (SS) is a chronic autoimmune disease in which the exocrine glands become sites of intense immunologic activity, leading to tissue damage that is manifested as mucosal dryness (1). This disorder can occur either alone, as primary SS, or on a background of another connective tissue disease, such as rheumatoid arthritis (RA), systemic sclerosis (SSc; scleroderma), or systemic lupus erythematosus (SLE), as secondary SS. One theory of the disease immunopathogenesis proposes that the syndrome is initiated by epitheliitis and is sustained by the ensuing influx of lymphocytes (2). Hence, the disease was referred to by those investigators as autoimmune epitheliitis. All affected organs, especially the salivary glands, exhibit a lymphoproliferative sialadenitis. Lymphoproliferative sialadenitis in SS is associated with lymphocyte infiltration, epithelial cell proliferation, and apoptosis (3). Compared with healthy individuals, patients with SS are at greater risk of developing non-Hodgkin’s lymphoma (4). Lymphocytes are therefore central to the pathophysiology of this autoimmune condition. However, there is controversy about which set of lymphocytes directs the immunopathologic process. Examination of the available evidence at a glance suggests that T lymphocytes play the principal role in the immunopathogenesis of these diseases. This proposition is based on the numerical predominance of T lymphocytes in the cellular composition of the inflamed tissues and on the restriction of the T cell receptor (5). One potential contradiction of this proposition, however, is that if the T lymphocytes were indeed the principal driving cells, then no increases in monoclonal Ig and B cell lymphoma would be seen in primary SS. Therefore, because the numerical predominance of T lymphocytes is not consistent with the clonal expansion of B cells in SS patients, attention has recently focused on the possibility that B lymphocytes play the leading role. Furthermore, there is good evidence to indicate that B lymphocytes promote the immune responses to self and non-self antigens through antibody-dependent and antibodyindependent mechanisms (6). Accumulation of B cells in exocrine glands results in their clustering into aggregates (7). There is nonetheless evidence from phenotype analyses suggesting that these aggregates are benign (8). Such findings raise questions as to why lymphomas frequently develop on a background of polyclonal proliferation of B cells in patients with SS (9). The frequent leukemic transformation in these patients with primary SS was first noted by Bunim and Talal (10). Subsequent studies by these investigators indicated that the two B cell aberrations were associated (11). They went on further to show a whole range of benign-to-malignant B cell proliferations in patients with primary SS, but not in those with secondary SS (12). Lymphoma in these patients has thus changed from an all-or-nothing phenomenon to one of a continuous spectrum of disease. This concept fits in with, but does not explain, the high frequency of lymphoma in patients with primary SS. In this review, we venture into the area of the ambiguous relationship between primary SS and B cell lymphoma. This analysis is focused in part on highlighting the centrality of B lymphocytes to the pathogenesis of primary SS and on exploring the likely processes that underpin the polyclonality or monoclonality of B cells in the disease. Our paradigm does not exclude a key role of Supported by the Association Francaise du Gougerot-Sjogren et des Syndromes Secs, the French Ministry for Education and Research, and the Institut Francais pour la Recherche Odontologique. Pierre Youinou, MD, DSc, Valerie Devauchelle-Pensec, MD, PhD, Jacques-Olivier Pers, DDS, PhD: EA2216 Immunology and Pathology, IFR 148 ScInBioS, European University of Brittany, and Brest University Medical School Hospital, Brest, France. Address correspondence and reprint requests to Pierre Youinou, MD, DSc, Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest, France. E-mail: youinou@univbrest.fr. Submitted for publication March 19, 2010; accepted May 11, 2010.

Activation of the type I interferon pathway in primary Sjogren’s syndrome

Sjogren’s syndrome (SS), a chronic autoimmune systemic disease affecting middle aged women, is characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and dry mouth. Recent advances have revealed a major role for activation of the type I interferon (IFN) pathway in the pathogenesis of the syndrome, as evidenced by the increased circulating type I IFN activity and an IFN “signature” in peripheral blood mononuclear cells (PBMC) and minor salivary gland (MSG) biopsies from these patients. Polymorphisms in genes involved in the IFNα pathway, such as IRF5 and STAT4, have been found to be associated with disease susceptibility. While the initial triggers of the innate immune response in SS remain elusive, preliminary evidence supports the role of inappropriately expressed endogenous LINE-1 (L1) retroelements as potential triggers of type I IFN activation in SS, possibly through Toll-like receptor (TLR) dependent or independent pathways. Proteins of the methylation machinery and the APOBEC family of cytidine deaminases are coordinately overexpressed, suggesting that those proteins might contribute to regulation of the inappropriately expressed L1 endogenous retroelements in SS. Given the apparent central role of IFNα in the pathogenesis of SS, blockade of this cytokine may be a rational therapeutic approach. In the current review we summarize the current evidence regarding the potential triggers of type I IFN activation as well as the data supporting genetic and epigenetic regulation of the type I IFN system in SS.

Dendrobium candidum extract increases the expression of aquaporin-5 in labial glands from patients with Sjögren's syndrome

This study aimed to investigate the mechanism of Dendrobium candidum extract in promoting expression of aquaporin-5 for treatment of Sjögren's syndrome (SS). Sixteen patients with SS suffered from deficient secretion of saliva due to an autoimmune destruction of salivary glands leading to dry mouth symptoms (xerostomia). However, glandular dysfunction also occurred without destruction. Based upon its abnormal distribution in SS salivary glands, a potential role of the water channel protein aquaporin-5 (AQP-5) in the pathogenesis of SS was proposed. After oral administration of D. candidum extracted liquid (DCEL) for 1 week, saliva and salivary gland biopsies from labial glands of patients were collected and examined by employing immunoreactivity and immunohistochemistry techniques. Results showed that salivary secretion increased by about 65% in patients treated with DCEL as compared with the control group. Higher labeling indices (percentage of acinus area immunoreactive for AQP-5) in the biopsies were found in SS patients who had taken DCEL. This study demonstrated that D. candidum would regulate the expression of AQP-5 in labial glands of SS patients and thereby promoted secretion of saliva to improve dry mouth symptoms.

The Role of Fractalkine as an Accelerating Factor on the Autoimmune Exocrinopathy in Mice

Sjögren's syndrome (SS) is an organ-specific autoimmune disease caused by the progressive loss of exocrine glands and is associated with several autoimmune phenomena. Various research studies have been performed, and many molecules have been suggested as responsible for the pathogenesis of SS. Here the authors show the increased expression of fractalkine (CX(3)CL1) in lacrimal glands of SS model mice. Among more than 50 known chemokines, fractalkine is the sole member of the CX(3)C family and has unique structural and functional attributes. The purpose of this study was to analyze the role of fractalkine in exocrine glands. The expression of fractalkine in the lacrimal glands of thymectomized NFS/sld mice was investigated by immunohistochemistry and RT-PCR. To confirm the effects of fractalkine in exocrine glands, tissue-specific fractalkine transgenic mice were generated using the salivary amylase promoter. The results demonstrated the upregulated fractalkine expression in thymectomized NFS/sld mice. Furthermore, the lacrimal and salivary gland-specific fractalkine transgenic mice showed the expression of fragmented fractalkine and lymphocytic infiltration in their lacrimal and submandibular glands. Interestingly, the dominant population was B cells in the lacrimal glands, whereas B cells and CD4(+) T cells were infiltrated in the submandibular glands. These mice also demonstrated slightly decreased tear and salivary secretion compared with wild-type mice. Based on these results, it may be that fractalkine contributes to the development of SS, especially in lymphocyte migration to exocrine glands, and that it accelerates the disease in association with other molecules.

Peripheral blood gene expression profiling in Sjögren's syndrome

Sjögren’s syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Affected cases commonly present with oral and ocular dryness, thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in peripheral blood. We first analyzed 21 SS cases and 23 controls and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent dataset of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B and T cell receptor, IGF-1, GM-CSF, PPARα/RXRα, and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease revealed that expression levels for most IFN-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting IFN signaling pathway may prove most effective in the subset of SS cases who produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS and provide numerous candidate disease markers for further study.

Controversies on Rituximab Therapy in Sjögren Syndrome-Associated Lymphoproliferation

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of salivary and lachrymal glands, and frequently accompanied by systemic symptoms. A subgroup of SS patients develops malignant B cell non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) type and very often located in the major salivary glands. Currently, there is a lack of evidence-based intervention therapy which may influence SS-related chronic inflammation and lymphoproliferation. B cells are involved in the pathogenesis of SS, and B cell downregulation may lead to a decrease of disease activity. Rituximab (RTX), a chimeric monoclonal antibody targeting the CD20 antigen on the B cell surface, has been successfully investigated in other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis, and mixed cryoglobulinemic syndrome. Preliminary experiences of RTX therapy in SS patients with or without a lymphoproliferative disorder suggest that SS patients with more residual exocrine gland function might better benefit from RTX. Efficacy of RTX in SS-associated B-cell lymphoma, mainly in low-grade salivary gland lymphomas, remains an open issue.