Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
25942351 Triphala exhibits anti-arthritic effect by ameliorating bone and cartilage degradation in 2015 The present study was aimed to investigate the anti-arthritic effect of triphala and its underlying mechanism on adjuvant-induced rat model. For comparison purpose, non-steroidal anti-inflammatory drug indomethacin was used. Arthritis was induced by intradermal injection of complete Freund's adjuvant (0.1 ml) into the right hind paw of the Wistar albino rats. Triphala (100 mg/kg body weight [bwt]) was administered intraperitoneally (from 11th to 20th day) after the arthritis induction. Arthritis induction increased the levels of reactive oxygen species (LPO and NO), elastase, and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-β, IL-17, IL-6 and MCP-1), inflammatory marker enzymes (iNOS and COX-2), receptor activator of nuclear factor kappa-B ligand (RANKL), and transcription factors (NF-kB p65 and AP-1) in the paw tissues of rats. The levels of bone collagen were found to decrease with increased urinary constituents (hydroxyproline and total glycosaminoglycans) in arthritic rats. In addition, the immunohistochemistry analysis revealed increased expression of NF-kBp65 and COX-2 in the paw tissues of arthritic rats. However, administration of triphala significantly inhibited the biochemical and molecular alterations in adjuvant-induced arthritic rats compared to indomethacin (3 mg/kg bwt) as evidenced by the radiological and histopathological analysis. In conclusion, our results suggest that triphala administration ameliorate bone and cartilage degradation during rheumatoid arthritis.
25823138 [Relations of synovial angiogenesis and PTEN/PI3K/AKT signaling pathway in rats with adjuv 2015 Jan OBJECTIVE: To observe the change of PTEN/PI3K/AKT pathway hypoxia-inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) in rats with adjuvant arthritis and to explore the mechanism of neovasculization in rheumatoid arthritis. METHODS: Thirty rats were randomly divided into normal control group and model control group. The model control group were established the model of adjuvant arthritis using Freund's complete adjuvant. At 19 days after modeling, the expression of microvascular density (MVD), HIF-1α, VEGF were detected by ELISA assay and PTEN, PI3K, AKT were detected by Werstern Blotting. RESULTS: Compared with the normal control group, paw swelling, arthritic index were increased, and the expression of MVD, VEGF, HIF-1α of serum, PI3K, AKT of synovial tissue were significantly increased, PTEN was significantly decreased in model control group. PI3K, HIF-1α were positively correlated with MVD; VEGF, AKT were positively correlated with paw swelling; PTEN was negatively correlated with the arthritis index; HIF-1α was positively correlated with VEGF; PI3K was positively correlated with AKT, PTEN was negatively correlated with PI3K, AKT, VEGF. CONCLUSION: Imbalance of PTEN/PI3K/AKT pathway in rats with adjuvant arthritis is one of the mechanisms of synovial neovasculization.
27014880 Spinal antinflammatory action of Diclofenac. 2016 Jun Diclofenac is a non-steroidal antinflammatory drug (NSAID) that finds indication in the treatment of debilitating pathologies characterized by chronic pain sustained by inflammation, such as in rheumatic disease (rheumatoid arthritis or osteoarthritis) or periarthritis, bursitis, tendonitis, myositis and sciatica. Its properties differentiate it from other NSAIDs. In fact, diclofenac's increased effect on spinal nociception and chronic neuro-inflammatory pain may be referred to: 1) its synergistic effects on peroxisome proliferator-activated receptor-γ (PPAR- γ) activation and prostaglandin synthesis inhibition (COX-2 inhibition); 2) its capacity of suppressing neuronal hyperexcitability through the blockage of neuronal K+ channels in a concentration-dependant manner; and 3) its facility to cross the blood-brain barrier.
25708718 Glucocorticoid-induced leucine zipper governs the therapeutic potential of mesenchymal ste 2015 Jun OBJECTIVE: Mesenchymal stem cells (MSCs) are potent immunosuppressive cells that have shown promise in the treatment of rheumatoid arthritis (RA). Deciphering the intrinsic characteristics of MSCs that correlate with their biologic activity will facilitate their clinical use. Recently, the role of glucocorticoid-induced leucine zipper (GILZ) in the development of RA has been documented. The aim of this study was to evaluate whether GILZ expression by MSCs may contribute to their therapeutic effect. METHODS: MSCs were isolated from GILZ-deficient (GILZ(-/-) ) mice and wild-type mice. MSCs (1 × 10(6) cells) were injected twice via the tail vein into mice with collagen-induced arthritis (CIA). RESULTS: In vitro, we showed that GILZ is a key factor involved in the immunosuppressive potential of MSCs. MSCs derived from GILZ(-/-) mice did not suppress the proliferation of CD4+ T cells and were less efficient than MSCs derived from WT mice in altering Th17 cell polarization. Thus, we investigated the role of GILZ in an experimental model of arthritis and demonstrated that although WT MSCs significantly reduced paw swelling in arthritic mice, GILZ(-/-) MSCs did not. Moreover, the magnitude of the effects of GILZ(-/-) MSCs on Th17 cell frequency was significantly lower than that of WT MSCs. The therapeutic effect of MSCs correlated with the generation of Treg cells bearing the CD4 + RORγt+IL-17(low) IL-10+ signature, and Th17 cell polarization was GILZ dependent. CONCLUSION: This study demonstrates that GILZ has an essential role in the therapeutic effectiveness of MSCs in arthritis by favoring Th17 cell polarization toward a regulatory phenotype. Therefore, potentiation of GILZ expression in MSCs could represent a means to enhance their therapeutic effect in autoimmune diseases.
25829793 Anti-inflammatory and antiarthritic activity of UNIM-301 (a polyherbal unani formulation) 2015 Apr BACKGROUND: UNIM-301 is a polyherbal formulation used in the Unani system of medicine for the treatment of joint pain and rheumatoid arthritis (RA). OBJECTIVE: The objective was to evaluate the anti-inflammatory and antiarthritic activity of UNIM-301 in carrageenan-induced paw edema and complete Freund's Adjuvant (CFA) induced arthritis. MATERIALS AND METHODS: The anti-inflammatory and antiarthritic activity of UNIM-301 was evaluated using carrageenan-induced paw edema and CFA induced animal arthritis models, respectively, in doses of 250, 500, and 1000 mg/kg body weight. Anti-inflammatory activity of UNIM-301 was evaluated using carrageenan-induced paw edema model using a digital plethysmometer. Anti-arthritic activity was evaluated using CFA induced arthritis, and joint sizes were measured at regular intervals using a micrometer screw gauge. Serum was collected and subjected to estimation of pro-inflammatory cytokine. Indomethacin 3 mg/kg body weight) was used as a standard drug in both the models. The acute and chronic toxicity study was carried out to evaluate the safety of the test drug. RESULTS: UNIM-301 treatment produced a dose-dependent reduction in paw edema and paw thickness in carrageenan-induced paw edema and CFA-induced arthritis, respectively, as compared to control. UNIM 301 also reduced the expression of pro-inflammatory mediator in a dose-dependent manner as compared to control. CONCLUSION: The result of the present study suggests that anti-inflammatory and anti-arthritic activity of UNIM-301, which might be accredited to inhibitory activity on pro-inflammatory cytokines to its various individual constituents.
27199510 Icariin Prevents Cartilage and Bone Degradation in Experimental Models of Arthritis. 2016 BACKGROUND: Icariin (ICA) is an active compound extracted from Epimedium brevicornum Maxim. Previous reports have shown that icariin has a clinically significant therapeutic effect on rheumatoid arthritis. However, little is known about the mechanism by which icariin inhibits cartilage and bone degradation. METHODS: New Zealand rabbits were immunized with antigen-induced arthritis (AIA) and treated with icariin. Joint tissues from rabbits were studied by histological analysis, transmission electron microscopy (TEM), and micro-CT. The expression levels of receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG) in joint tissues were determined using immunohistochemistry and real-time PCR analysis. RESULTS: Histological analysis and TEM sections of cartilage in the ICA treated group showed a low level of chondrocyte destruction. Micro-CT analysis showed that the bone mineral density value and bone structural level in ICA treated rabbits were significantly higher compared with those in the AIA group. Immunohistochemistry and real-time PCR analysis showed that icariin treatment reduced RANKL expression and enhanced OPG expression levels, as compared to the AIA group. CONCLUSION: These data indicate that ICA suppresses articular bone loss and prevents joint destruction. This study also determined that ICA regulated articular bone loss in part by regulating RANKL and OPG expression.
26431344 Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the C 2015 Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10(-6) M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors.
25471597 B-cell inhibition by cross-linking CD79b is superior to B-cell depletion with anti-CD20 an 2015 Mar Depletion of B cells with the anti-CD20 antibody rituximab is an established therapy for rheumatoid arthritis. However, rituximab has only moderate efficacy, most likely due to insufficient depletion of B cells in lymphoid organs and expansion of pathogenic B cells. We found that an antibody against mouse CD79b profoundly blocks B-cell proliferation induced via the B-cell receptor, CD40, CD180, and chondroitin sulfate, but not via TLR4 or TLR9. Treatment with anti-CD79b also induces death in resting and activated B cells. B-cell inhibition is mediated by cross-linkage of CD79b, but independent of Fc-receptor engagement. In the model of collagen-induced arthritis, an antibody against mouse CD20 depletes B cells very efficiently but fails to suppress the humoral immune response against collagen and the development of arthritis. In contrast, the antibody against CD79b, and a deglycosylated variant of this antibody, almost completely inhibits the increase in anti-collagen antibodies and the development of arthritis. In mice with established arthritis only the fully glycosylated antibody against CD79b is effective. Our data show that targeting B cells via CD79b is much more effective than B-cell depletion with anti-CD20 antibodies for therapy of arthritis. These findings may have important implications for treatment of B-cell-mediated autoimmune diseases.
27363579 Enhanced excitability and suppression of A-type K(+) currents in joint sensory neurons in 2016 Jul 1 Pain is a dominant symptom of rheumatoid arthritis (RA) and its adequate treatment represents a major unmet need. However, the cellular mechanisms that drive arthritis pain are largely unexplored. Here, we examined the changes in the activity of joint sensory neurons and the associated ionic mechanisms using an animal model of antigen-induced arthritis (AIA). Methylated-bovine serum albumin (mBSA), but not vehicle challenge, in the ankle of previously immunized mice produced time-dependent symptoms of arthritis, including joint inflammation, primary mechanical hyperalgesia in the ipsilateral ankle, and secondary mechanical and heat hyperalgesia in the ipsilateral hindpaw. In vivo electrophysiological recordings revealed that Dil-labeled joint sensory neurons in AIA mice exhibited a greater incidence of spontaneous activity, mechanically evoked after-discharges, and/or increased responses to mechanical stimulation of their receptive fields, compared to control animals. Whole-cell recordings in vitro showed that AIA enhanced the excitability of joint sensory neurons. These signs of neuronal hyperexcitability were associated with a significant reduction in the density of A-type K(+) currents. Thus, our data suggest that neuronal hyperexcitability, brought about in part by reduced A-type K(+) currents, may contribute to pain-related behaviors that accompany antigen-induced arthritis and/or other antigen-mediated diseases.
27774484 Hypoxic regulation of osteoclast differentiation and bone resorption activity. 2015 Bone integrity is maintained throughout life via the homeostatic actions of bone cells, namely, osteoclasts, which resorb bone, and osteoblasts, which produce bone. Disruption of this balance in favor of osteoclast activation results in pathological bone loss, which occurs in conditions including osteoporosis, rheumatoid arthritis, primary bone cancer, and cancer metastasis to bone. Hypoxia also plays a major role in these conditions, where it is associated with disease progression and poor prognosis. In recent years, considerable interest has arisen in the mechanisms whereby hypoxia and the hypoxia-inducible transcription factors, HIF-1α and HIF-2α, affect bone remodeling and bone pathologies. This review summarizes the current evidence for hypoxia-mediated regulation of osteoclast differentiation and bone resorption activity. Role(s) of HIF and HIF target genes in the formation of multinucleated osteoclasts from cells of the monocyte-macrophage lineage and in the activation of bone resorption by mature osteoclasts will be discussed. Specific attention will be paid to hypoxic metabolism and generation of ATP by osteoclasts. Hypoxia-driven increases in both glycolytic flux and mitochondrial metabolic activity, along with consequent generation of mitochondrial reactive oxygen species, have been found to be essential for osteoclast formation and resorption activity. Finally, evidence for the use of HIF inhibitors as potential therapeutic agents targeting bone resorption in osteolytic disease will be discussed.
26664127 Profile of secukinumab in the treatment of psoriasis: current perspectives. 2015 Secukinumab (Cosentyxâ„¢) is a human monoclonal IgG1k antibody that has been developed to target and block the actions of IL-17A. It is known that this cytokine is elevated in lesions of psoriasis. Interleukins in the Th17 pathway play a pivotal role in the pathogenesis of psoriasis and have thus become targets for recent biologic drug development. As a monoclonal antibody immune modulator, secukinumab exhibits the expected pharmacokinetic properties of slow subcutaneous absorption, low clearance, and long half-life, although formal studies examining the impact of impaired hepatic or renal function on the overall pharmacokinetic profile have not been conducted. Both Phase II and III clinical trials have demonstrated the effectiveness of secukinumab in the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and noninfectious uveitis. In June 2015, secukinumab was approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis, with a wealth of clinical trials showcasing its efficacy in improving psoriasis area and severity index scores, and it is superior to other comparable biologics on the market, including the TNF inhibitor etanercept. As such, this review focuses on the marquee clinical trials involving secukinumab treatment of plaque psoriasis, while also exploring this drug's efficacy in treating patients with psoriatic arthritis, a disease that has a well-documented comorbidity in patients diagnosed with moderate-to-severe plaque psoriasis. Finally, the safety and tolerability of this drug in a variety of clinical trials to date have also been reviewed, and will undoubtedly have a large impact on this drug's postmarketing surveillance and future studies regarding its long-term safety.
25946983 Screening and referral for axial spondyloarthritis--need of the hour. 2015 Jun Although axial spondyloarthritis (axSpA) is as prevalent as rheumatoid arthritis, it is commonly under recognized due to variety of reasons. AxSpA contributes to significant loss of function and disability among young adults. With the availability of newer assessment methods and effective therapeutic agents, early diagnosis and appropriate treatment are possible. As mechanical back pain is widely prevalent in general population, selection of patients with high likelihood of having axSpA and referral to rheumatologists is very important to allow prompt diagnosis and management of axSpA yet avoid improper utilization of resources. Various referral strategies have been developed for this purpose which have included patients with chronic back pain for >3 months with age of onset <45 years and one or more typical spondyloarthritis features with high sensitivity and specificity. Consistent application of both simple and complex strategies has demonstrated similar results in various clinical studies. About 35-45 % of patients referred to rheumatologists using these strategies were finally diagnosed to have axSpA. Potential referring providers include primary care physicians, physical therapists, orthopedic and spine surgeons, chiropractors, rehabilitation medicine physicians, ophthalmologists, gastroenterologists, and dermatologists. Increasing the awareness and education of the referring providers are two very important steps in the success of the referral strategy. With proper application of any strategy described below, a rheumatologist will need to see two to three patients with chronic back pain to identify one patient with axSpA.
26058549 Inflammatory diseases: Integrating biosimilars into clinical practice. 2015 Jun OBJECTIVES: To discuss considerations regarding the selection, prescribing, and monitoring of biosimilars in the clinical management of patients with inflammatory disorders. METHODS: A search of the Internet as well as PubMed was conducted through August 2014 for information related to the clinical use of biosimilars in chronic inflammatory disorders using the keywords biosimilar, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn׳s disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were searched for biosimilar guidelines. RESULTS: Articles and guidelines relating to integrating biosimilars into the clinical management of patients with inflammatory disorders have been published by regulatory agencies, professional associations, healthcare providers, and others. CONCLUSIONS: The recent approval of the biosimilar infliximab in some countries makes biosimilars a reality for rheumatologists and others involved in the care of patients with inflammatory disorders. To successfully and confidently integrate biosimilars into clinical practice, physicians must understand factors such as variation in innovator/reference products, extrapolation of data, naming and labeling, interchangeability and automatic substitution, and pharmacovigilance.
25956572 Treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop: Prospective doub 2015 Oct OBJECTIVE: To describe the clinical efficacy of the treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop. DESIGN: Prospective double-blind randomized study. SETTING: Institutional outpatient clinic. PARTICIPANTS: Forty-eight eyes of twenty-four patients with dry eye related to Sjögren syndrome were enrolled in this study. The patients were randomized in 2 groups: tacrolimus (n=14) and vehicle (n=10) group. INTERVENTION: The tacrolimus group received a vial containing tacrolimus 0.03% (almond oil as vehicle) and the other group received the almond oil vehicle. All patients were instructed to use the eye drops every 12h in the lower conjunctival sac. MAIN OUTCOME MEASURES: Schirmer I test, break-up-time (BUT), corneal fluorescein and Rose Bengal staining scores were evaluated in all patients one day before the treatment (baseline), 7, 14, 28 and 90 days after treatment with the eye drops. RESULTS: The average fluorescein and Rose Bengal scores improved statistically after 7 days of treatment and even more after 90 days. The average Schirmer I and BUT values were unchanged after 7, 14 and 21 days but did show an improvement relative to baseline after 28 days of treatment. Schirmer I, BUT, fluorescein and Rose Bengal did not show any statistical significance in the vehicle group. CONCLUSION: Topical 0.03% tacrolimus eye drop improved tear stability and ocular surface status in cases of inflammatory or SS-related dry eye. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01850979.
26879356 Phenotypic Characterization of Juvenile Idiopathic Arthritis in African American Children. 2016 Apr OBJECTIVE: Juvenile idiopathic arthritis (JIA) affects children of all races. Prior studies suggest that phenotypic features of JIA in African American (AA) children differ from those of non-Hispanic white (NHW) children. We evaluated the phenotypic differences at presentation between AA and NHW children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and replicated the findings in a JIA cohort from a large center in the southeastern United States. METHODS: Children with JIA enrolled in the multicenter CARRA Registry and from Emory University formed the study and replication cohorts. Phenotypic data on non-Hispanic AA children were compared with NHW children with JIA using the chi-square test, Fisher's exact test, and the Wilcoxon signed-rank test. RESULTS: In all, 4177 NHW and 292 AA JIA cases from the CARRA Registry and 212 NHW and 71 AA cases from Emory were analyzed. AA subjects more often had rheumatoid factor (RF)-positive polyarthritis in both the CARRA (13.4% vs 4.7%, p = 5.3 × 10(-7)) and the Emory (26.8% vs 6.1%, p = 1.1 × 10(-5)) cohorts. AA children had positive tests for RF and cyclic citrullinated peptide antibodies (CCP) more frequently, but oligoarticular or early onset antinuclear antibody (ANA)-positive JIA less frequently in both cohorts. AA children were older at onset in both cohorts and this difference persisted after excluding RF-positive polyarthritis in the CARRA Registry (median age 8.5 vs 5.0 yrs, p = 1.4 × 10(-8)). CONCLUSION: Compared with NHW children, AA children with JIA are more likely to have RF/CCP-positive polyarthritis, are older at disease onset, and less likely to have oligoarticular or ANA-positive, early-onset JIA, suggesting that the JIA phenotype is different in AA children.
27957617 Neuromyotonia as an unusual neurological complication of primary Sjögren's syndrome: case 2017 Feb Primary Sjögren's syndrome (PSS) is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands such as the lachrymal and salivary glands, leading to xerophthalmia and xerostomia. Neurological manifestations are sometimes found in patients with PSS. A variety of neurological complications has been reported in patients with PSS, and both the central nervous system (CNS) and peripheral nervous system (PNS) can be involved in PSS. Several forms of neuropathy, including polyneuropathy, cranial neuropathy, and multiple mononeuropathy, are often seen in PSS patients. Herein, we report for the first time typical neuromyotonia (NMT) symptoms appearing in a patient with PSS. Neuromyotonia is a rare disorder caused by the hyperexcitability of peripheral nerves, causing spontaneous and continuous muscle contraction. We provide an overview of the literature relating to neurological involvement in PSS, and the etiology of acquired NMT. We also discuss the existence of contactin-associated protein-like 2 (Caspr2) antibodies in NMT patients.
27782867 Predictive significance of CCL21 and CXCL13 levels in the minor salivary glands of patient 2017 Mar OBJECTIVES: To investigate whether CCL21 and CXCL13 expression levels in the minor salivary gland are associated with the laboratory and clinical manifestations of Sjögren's syndrome (SS). METHODS: Sociodemographic data on 106 SS patients were obtained and the glandular and extraglandular manifestations of the disease were documented. In addition, minor salivary gland biopsies were performed and the patients' laboratory findings were analysed. European League Against Rheumatism SS disease activity index (ESSDAI) values of SS disease activity at the time of biopsy and the SS disease damage index (SSDDI) values were also recorded. An immunohistochemical approach was used to semiquantitatively measure the CCL21 and CXCL13 expression in the minor salivary glands. RESULTS: The minor salivary glands of SS patients stained positively for CCL21 and CXCL13 in 46.2% (49/106) and 70.7% (75/106) of all cases, respectively. Higher-level expression of CCL21 and CXCL13 was associated with increases in ESR, IgG and rheumatoid factor levels, as well as anti-SS-A and -SS-B titers. A higher focus score and ESSDAI value at the time of biopsy were also associated with these chemokines. In patients with extraglandular manifestations of SS, the prevalence of lymphadenopathy increased with increasing CCL21 levels. CONCLUSIONS: The expression levels of CCL21 and CXCL13 within the lymphocytic infiltrates of SS patients were associated with several laboratory features of the disease as well as lymphadenopathy and the extent of clinical disease activity. CCL21 and CXCL13 levels can therefore serve as useful markers to predict the disease activity and prognosis of patients with SS.
27260411 TLR2 signals via NF-κB to drive IL-15 production in salivary gland epithelial cells deriv 2017 Aug Toll-like receptors (TLRs) are pattern recognition receptors linking innate and adaptive immune responses, which resulted overexpressed in primary Sjögren's syndrome (pSS). Interleukin-15 (IL-15) is a pro-inflammatory cytokine which was recently demonstrated to be involved in pSS pathogenesis. The study was undertaken to clarify whether TLR2 is involved in the production of IL-15 in human salivary gland epithelial cells (SGEC) from pSS patients. SGEC primary cell cultures were established from pSS minor salivary gland tissues explanted from patients with a sure diagnosis of SS. After neutralization of TLR2 with a blocking monoclonal antibody, IL-15 production was assayed by immunoblotting and flow cytometry, IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real-time PCR. The production of IL-15 by pSS SGEC decreased in culture supernatants and in protein lysates (p < 0.01) when TLR2 signaling was inhibited in pSS SGEC. In addition, a control at the transcriptional level was also detected; in fact, inhibition of nuclear factor (NF)-κB through the transfection of pSS SGEC with the dominant-negative inhibitory κBα proteins (IκBα) vector (IκBαDN) abrogated the stimulatory effect of TLR2 on IL-15 production. These data suggest that TLR2 activation is involved in the induction of IL-15 production by pSS SGEC and promotes inflammation through NF-κB activation. Therefore, therapeutic strategies that target TLR2/IL-15 pathway might be strong candidates for preventing or treating pSS.
26446936 Changes in Saliva Rheological Properties and Mucin Glycosylation in Dry Mouth. 2015 Dec Saliva is vital for the maintenance of normal oral physiology and mucosal health. The loss of salivary function can have far-reaching consequences, as observed with dry mouth, which is associated with increased orodental disease, speech impairment, dysphagia, and a significant negative effect on quality of life. The timely diagnosis of oral dryness is vital for the management of orodental disease and any associated often-undiagnosed systemic disease (e.g., Sjögren syndrome). Our aim was to investigate differences in mucin glycoproteins and saliva rheological properties between sufferers and nonsufferers of dry mouth in order to understand the relationship between saliva composition, rheological properties, and dryness perception and provide additional potential diagnostic markers. All patients exhibited objective and subjective oral dryness, irrespective of etiology. Over half of the patients (n = 20, 58.8%) had a saliva secretion rate above the gland dysfunction cutoff of 0.1 mL/min. Mucin (MUC5B and MUC7) concentrations were generally similar or higher in patients. Despite the abundance of these moisture-retaining proteins, patients exhibited reduced mucosal hydration (wetness) and significantly lower saliva spinnbarkeit (stringiness), suggesting a loss of the lubricating and retention/adhesion properties of saliva, which, at least partially, are associated with mucin glycoproteins. Over 90% of patients with dry mouth (DMPs) consistently had unstimulated whole mouth saliva (UWMS) spinnbarkeit below the proposed normal cutoff (10 mm). Further analysis of mucins revealed the reduced glycosylation of mucins in DMPs compared to healthy controls. Our data indicate that UWMS mucin concentrations are not reduced in dry mouth but that the mucin structure (glycosylation) is altered. UWMS from DMPs had reduced spinnbarkeit, the assessment of which, in conjunction with sialometry, could improve sensitivity for the diagnosis of dry mouth. Additionally, it may be useful to take into consideration the altered mucin glycosylation and saliva rheological properties when designing synthetic or purified mucins for saliva substitutes and dry mouth therapy.
25327574 Identification of potential genomic biomarkers for Sjögren's syndrome using data pooling 2015 May Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. The diagnosis of SS can be challenging due to lack of a specific test for the disease. The purpose of this study is to examine the accuracy of using gene expression profile for diagnosis of SS. We identified 9 publically available datasets that included gene expression data from saliva and salivary gland biopsy samples of 52 patients with SS and 51 controls. Out of these datasets, we compiled and pooled data from three datasets that included 37 and 29 samples from SS patients and healthy controls, respectively, which were designated as "training set." Then, we performed cross-listing in a group of independent gene expression datasets from patients with SS to identify consensus gene list of differentially expressed genes. We performed Linear Discriminant Analysis (LDA) to quantify the accuracy of discriminating genes to predict SS in both the "training set" and an independent group of datasets that was designated as "test set." We identified 55 genes as potential classifier genes to differentiate SS from healthy controls. An LDA by leave-one-out cross-validation method identified 19 genes (EPSTI1, IFI44, IFI44L, IFIT1, IFIT2, IFIT3, MX1, OAS1, SAMD9L, PSMB9, STAT1, HERC5, EV12B, CD53, SELL, HLA-DQA1, PTPRC, B2M, and TAP2) with highest classification accuracy rate (95.7 %). Moreover, we validated our results by reproducing the same gene expression profile as a discriminatory test in the "test set," which included data from salivary gland samples of 15 patients with SS and 22 controls with 94.6 % accuracy. We propose that gene expression profile in the saliva or salivary glands could represent a promising simple and reproducible diagnostic biomarker for SS.