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ID PMID Title PublicationDate abstract
31708994 Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and 2019 BACKGROUND: Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF). RESULTS: The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-β-gal(+) SF after 14 days in culture positively correlated with donor's age. Initial exposure to H(2)O(2) or TNFα enhanced SF senescence and increased mRNA expression of IL6, CXCL8, CCL2 and MMP3 and proteins secretion. Senescent SF show a heightened IL6, CXCL8 and MMP3 mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalized IL6, CXCL8 and CCL2 mRNA expression. CONCLUSIONS: Accumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.
31226680 Occipital and external acoustic meatus to axis angle: a useful predictor of oropharyngeal 2019 Jun 21 OBJECTIVE: Dyspnea and/or dysphagia is a life-threatening complication after occipitocervical fusion. The occiput-C2 angle (O-C2a) is useful for preventing dyspnea and/or dysphagia because O-C2a affects the oropharyngeal space. However, O-C2a is unreliable in atlantoaxial subluxation (AAS) because it does not reflect the translational motion of the cranium to C2, another factor affecting oropharyngeal area in patients with rheumatoid arthritis (RA) who have reducible AAS. The authors previously proposed the occipital and external acoustic meatus to axis angle (O-EAa; i.e., the angle made by McGregor's line and a line joining the external auditory canal and the middle point of the endplate of the axis [EA line]) as a novel, useful, and powerful predictor of the anterior-posterior narrowest oropharyngeal airway space (nPAS) distance in healthy subjects. The aim of the present study was to elucidate the validity of O-EAa as an indicator of oropharyngeal airway space in RA patients with AAS. METHODS: The authors investigated 64 patients with RA. The authors collected lateral cervical radiographs at neutral position, flexion, extension, protrusion, and retraction and measured the O-C2a, C2-C6, O-EAa, anterior atlantodental interval (AADI), and nPAS. Patients were classified into 2 groups according to the presence of AAS and its mobility: group N, patients without AAS; and group R, patients with reducible AAS during dynamic cervical movement. RESULTS: Group N had a significantly lower AADI and O-EAa than group R in all but the extension position. The O-EAa was a better predictor for nPAS than O-C2a according to the mixed-effects models in both groups (marginal R2: 0.510 and 0.575 for the O-C2a and O-EAa models in group N, and 0.250 and 0.390 for the same models, respectively, in group R). CONCLUSIONS: O-EAa was superior to O-C2a in predicting nPAS, especially in the case of AAS, because it affects both O-C2a and cranial translational motion. O-EAa would be a useful parameter for surgeons performing occipitocervical fusion in patients with AAS.
30923795 Incidence and predictors of dyspnea on exertion in a prospective cohort of patients with r 2019 Mar OBJECTIVE: To investigate the incidence and predictors of dyspnea on exertion among subjects with rheumatoid arthritis (RA). METHODS: We investigated dyspnea on exertion using a prospective cohort, the Brigham RA Sequential Study (BRASS). Clinically significant dyspnea on exertion was defined as a score of ≥3 (unable to ambulate without breathlessness or worse) on the validated Medical Research Council (MRC) scale (range 0-5). We analyzed subjects with MRC score <3 at BRASS baseline and ≥1 year of follow-up. The MRC scale was administered annually. We determined the incidence rate (IR) of dyspnea on exertion. We used Cox regression to estimate the HR for dyspnea on exertion occurring one year after potential predictors were assessed. RESULTS: We analyzed 829 subjects with RA and no clinically significant dyspnea on exertion during mean follow-up of 3.0 years (SD 1.9). At baseline, mean age was 55.7 years (SD 13.6), 82.4% were female, and median RA duration was 8 years. During follow-up, 112 subjects (13.5%) developed incident dyspnea on exertion during 2,476 person-years of follow-up (IR 45.2 per 1000 person-years). Independent predictors of incident dyspnea on exertion were: older age (HR 1.03 per year, 95%CI 1.01-1.04), female sex (HR 2.22, 95%CI 1.14-4.29), mild dyspnea (HR 2.62, 95%CI 1.60-4.28), and worsened MDHAQ (HR 2.36 per unit, 95%CI 1.54-3.60). Methotrexate use, RA disease activity, and seropositivity were not associated with incident dyspnea on exertion. CONCLUSION: Dyspnea on exertion occurred commonly in patients with RA. Older women with impaired physical function were especially vulnerable to developing dyspnea on exertion.
30886998 Relapse rates after elective discontinuation of anti-TNF therapy in rheumatoid arthritis: 2019 BACKGROUND: Inhibitors of tumor necrosis factor alpha (TNF-α) are current mainstay of therapies for rheumatoid arthritis (RA). The decision when to withdraw TNF-α inhibitors after achieving remission and the incidence of relapse rates with elective discontinuation are both important questions that demand intense survey in these patients. In this meta-analysis we aimed to estimate the magnitude of relapse rate after elective TNF-α inhibitor discontinuation in RA patients with remission. METHODS: Systematic searches of PubMed/MEDLINE, Cochrane Library databases, grey literature (unpublished and ongoing trials) from the WHO International Clinical Trials Registry Platform and the US National Institutes of Health were performed for studies reporting the outcomes of elective discontinuation of TNF-α inhibitor in RA patients after remission. Random-effects models for meta-analyses were conducted on extracted data. RESULTS: Out of 390 references screened, 16 RCTs were included. Meta-analysis of 1264 patient data revealed a relapse rate of 0.47 (95% CI 0.41-0.54). Sensitivity analysis showed that none of the studies had higher influence on the results. CONCLUSIONS: Almost half of all the RA patients in remission relapse after elective TNF-α inhibitor discontinuation. This information might be useful when considering this management option with individual patients.
31144135 Diagnosis and Management of Infectious Arthritis in Children. 2019 May 29 PURPOSE OF REVIEW: Septic arthritis is limb and life-threatening condition which necessitates rapid diagnosis and treatment. It is important for a medical practitioner to be familiar with this condition. This review summarizes the epidemiology, risk factors, diagnosis and differential diagnosis, complications, as well as treatment and the following-up of this condition. RECENT FINDINGS: Different causative organisms require unique diagnostic and treatment approaches. Establishing the diagnosis often requires multiple diagnostic modalities, some of which are new and innovative. Differential diagnosis requires excluding non-infectious inflammatory causes, such as reactive arthritis, juvenile rheumatoid arthritis, transient synovitis, and pericapsular pyomyositis. There is no consensus regarding the nature or duration of pharmacological or surgical treatment. Treatment includes administration of appropriate antimicrobial therapy and including the use of steroids and drainage. The most common complications are osteonecrosis of the femoral head and chronic osteomyelitis. Complications of septic arthritis are mostly due to a missed diagnosis. Further studies are required to better evaluate the diagnostic and therapeutic choice.
29907975 Metabolite assignment of ultrafiltered synovial fluid extracted from knee joints of reacti 2019 Jan Currently, there are no reliable biomarkers available that can aid early differential diagnosis of reactive arthritis (ReA) from other inflammatory joint diseases. Metabolic profiling of synovial fluid (SF)-obtained from joints affected in ReA-holds great promise in this regard and will further aid monitoring treatment and improving our understanding about disease mechanism. As a first step in this direction, we report here the metabolite specific assignment of (1) H and (13) C resonances detected in the NMR spectra of SF samples extracted from human patients with established ReA. The metabolite characterization has been carried out on both normal and ultrafiltered (deproteinized) SF samples of eight ReA patients (n = 8) using high-resolution (800 MHz) (1) H and (1) H─(13) C NMR spectroscopy methods such as one-dimensional (1) H CPMG and two-dimensional J-resolved(1) H NMR and homonuclear (1) H─(1) H TOCSY and heteronuclear(1) H─(13) C HSQC correlation spectra. Compared with normal SF samples, several distinctive (1) H NMR signals were identified and assigned to metabolites in the (1) H NMR spectra of ultrafiltered SF samples. Overall, we assigned 53 metabolites in normal filtered SF and 64 metabolites in filtered pooled SF sample compared with nonfiltered SF samples for which only 48 metabolites (including lipid/membrane metabolites as well) have been identified. The established NMR characterization of SF metabolites will serve to guide future metabolomics studies aiming to identify/evaluate the SF-based metabolic biomarkers of diagnostic/prognostic potential or seeking biochemical insights into disease mechanisms in a clinical perspective.
31530196 Sjögren syndrome-related plasma cell disorder and multifocal nodular AL amyloidosis: clin 2019 Dec Background: Localized nodular deposits of AL amyloid are seen in different tissues/organs; however, the pathogenesis of this form of amyloidosis remains unclear. Recently, Sjögren syndrome combined with localized nodular AL amyloidosis has been noted. Here, we report Sjögren syndrome cases showing multifocal nodular AL amyloidosis and the followed benign course. Materials and methods: We investigated the clinical pictures and histopathological findings of three cases with both presence of Sjögren syndrome and localized nodular AL amyloidosis, paying a special attention to the distribution of amyloidoma. Results: All three cases were middle-aged females. In two of three cases localized deposits of AL amyloid preceded Sjögren syndrome. Amyloidoma was detected in scalp, eyelid, cheek, larynx, trachea, lung and breast, and around these amyloid-deposited lesions infiltration of plasma cells was seen. Pulmonary amyloidosis was consistently accompanied with parenchymal cystic lesions, but this amyloidosis did not produce any significant respiratory symptoms. Some of large pulmonary amyloidomas showed cavity formation and subsequent shrinkage. In two cases amyloid deposition was found on gastric mucosa. Two cases received small doses of oral prednisone, with no further appearance of amyloidoma. Conclusion: Sjögren syndrome-related plasma cell disorder may be responsible for the formation of this unique multifocal nodular AL amyloidosis.
31328441 Determinants of diagnosis and disease course in primary Sjögren's syndrome: Results from 2019 Sep BACKGROUND: Determinants of diagnosis in primary Sjögren's syndrome (pSS) in tertiary care settings is not well understood. METHODS: Patients were screened by tracing reports of anti-SSA (anti-Ro) antibody assays between January 2008 and October 2015. Electronic health records (EHR) were reviewed. Patients fulfilling the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria were included. Variables including the specialties of first consultation, initial clinical presentations, investigations ordered at first consultation, number of hospital visits prior to reaching the final diagnosis of pSS and the baseline EULAR SS Disease Activity Index (ESSDAI) were noted. RESULTS: A total of 275 patients with pSS consulted 24 different specialties at first visit. Rheumatology accounted for 128 (46.55%) patients. At first consultation, initial suspicion for pSS was 48.4% for all specialties together and 64.84% for the rheumatologist. Median number of visits prior to arriving at the final diagnosis was 1 (1-6), when the initial impression was pSS and 3 (1-14), if the initial clinical impression was a non-SS differential (P < 0.001). A first impression of pSS, enquiry about sicca symptoms and ordering anti-SSA (anti-Ro) antibody test at first consultation were strong predictors of early diagnosis with odds (95% CI) of 5.01 (1.72-14.55) P < 0.001, 4.79 (1.16-19.84) P = 0.03 and 9.60 (3.0-30.67) P < 0.0001, respectively. None of the clinical variables proved to be useful predictors of early diagnosis. CONCLUSIONS: Diagnosis of pSS is challenging even in tertiary care centers as patients present with myriad features to several specialties. Initial suspicion was limited to 48.4% for all specialties together and 64.84% for the rheumatologist. High suspicion of pSS along with ordering anti-SSA (anti-Ro) antibody could hasten diagnosis.
31278051 Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus: 2019 Sep A case of progressive multifocal leukoencephalopathy (PML) occurring on low dose immunosuppression for systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) is presented. Neurologic changes in patients with SLE or SS should not be assumed to be a disease manifestation. Importantly, serious opportunistic infections such as PML can occur in minimally immunosuppressed rheumatic patients. Early diagnosis, facilitated by scrutiny of MRI findings, should trigger measures to reconstitute immunity in an otherwise fatal disease.
30863411 Fatigue in Sjögren's Syndrome: A Search for Biomarkers and Treatment Targets. 2019 Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called "fatigue signature."
30218288 Red blood cell distribution width as a potential predictor of survival of pulmonary arteri 2019 Feb Pulmonary arterial hypertension (PAH) is a severe complication and leading cause of mortality in patients with primary Sjogren's syndrome (pSS). This study was to investigate the overall survival rates and the utility of red blood cell distribution width (RDW) as a potential prognostic factor of pSS-PAH. This cohort study retrospectively enrolled 55 patients with pSS-PAH who were followed up at the Department of Rheumatology of Peking Union Medical College Hospital (PUMCH) between August 2007 and May 2017. The patients were stratified according to the level of RDW (≤ 15.0 and > 15.0%). Baseline demographics, laboratory results, pulmonary function conditions, hemodynamic assessments, and treatment regimens were analyzed. Cox proportional hazards regression analysis was used to identify whether RDW level is a factor related to adverse outcome. A total of 55 patients were recruited, with an average age of 38.9 ± 9.3 years. Fifty-four were female (98.2%), and the average duration at the time of PAH diagnosis was 25.5 ± 33.2 months. Higher RDW levels were found in patients who deceased in follow-up (13.8 ± 2.6 vs 16.5 ± 1.6%, p = 0.003) and with higher NYHA classes (13.8 ± 1.8 vs 16.5 ± 2.9%, p < 0.001). Patients with RDW > 15% had a significantly worse overall survival than patients with RDW ≤ 15% (3-year survival rate 59.5 vs. 88.7% log-rank p = 0.015). Cox regression analysis identified RDW > 15% as a prognostic factor for adverse outcome (HR 1.786, 95% CI 1.137-2.803, p = 0.012). RDW can serve as a potential negative prognostic factor of pSS-PAH.
31886299 Epithelial Cell Adhesion Molecule in Primary Sjögren's Syndrome Patients: Characterizatio 2019 OBJECTIVE: To determine the subcellular localization of epithelial cell adhesion molecule (EpCAM) in labial salivary gland (LSG) and evaluate the diagnostic use of the extracellular domain of EpCAM (EpEX) and intracellular domain (EpICD) for primary Sjögren's syndrome (pSS). METHODS: Immunohistochemical (IHC) analysis was conducted using EpEX and EpICD domain-specific antibodies on labial salivary gland biopsy (LSGB) from participants. Chi-square or Fisher's exact analysis, Mann-Whitney U-test, and Kruskal-Wallis test compared differences among groups. Independent risk factors of pSS were determined by multiple logistic regression analysis. Receiver-operator characteristic curves (ROC) were carried out to estimate the diagnostic value. RESULTS: Compared to non-SS controls, loss of membranous EpEX and EpICD expression was observed in LSGB of pSS patients, which occurred in parallel with increased accumulation of cytoplastic and nuclear EpICD. The subcellular EpEX/EpICD expressions were associated with various features of pSS patients, especially histopathological grade of LSGB. Furthermore, high IHC scores of membranous EpEX were independent risk factors for pSS, even for the pSS patients at early stage. The IHC scores of subcellular EpEX/EpICD were of great diagnostic value for pSS with high sensitivity (70-80%) and specificity (85-95%). CONCLUSION: This study first found the aberrant expression pattern of EpCAM in LSG of pSS patients. The IHC scores of subcellular EpEX/EpICD were demonstrated to have the potential to act as diagnostic biomarkers for pSS.
31597594 Dual function of miR-1248 links interferon induction and calcium signaling defects in Sjö 2019 Oct BACKGROUND: Sjögren's syndrome (SS) is one of the most common autoimmune disorders leading to exocrine gland dysfunction. Both immune-dependent processes - like Type I Interferon (IFN) signaling and immune-independent processes - such as calcium signaling in epithelial cells - contribute to disease pathophysiology. However, a mechanistic link between these processes has not been demonstrated. METHODS: Primary human salivary gland cells were used to evaluate the differential expression of miRNAs with smRNA-seq in primary epithelial cells culture and digital PCR was conducted in SS human salivary glands (SG) biopsies to verify the results. With siRNA screening and pull-down assays to establish the role of miRNA in IFN activation. FINDINGS: Activation of IFN-β by miR-1248 is through the direct association with both RIG-I and AGO2. Further functional studies establish a unique dual functional role of miR-1248 in phSG cells: i) activation of the RIG-I pathway by acting as ligand of this sensor leading to IFN production and ii) regulation of the expression of mRNAs through the canonical microRNA function. Importantly, ITPR3, a key component of calcium signaling in epithelial cells, that has previously shown to be downregulated in SS SG, was directly targeted and downregulated by miR-1248, inducing the same functional calcium signaling changes as observed in SS SGs. INTERPRETATION: Identification of the first endogenous mammalian microRNA that binds to RIG-I inducing IFN production but also demonstrate a novel pathophysiological underlying mechanism in which miR-1248 overexpression links two major pathways associated with SS, namely activation of IFN production with modulation of calcium signaling. Together, these findings suggest a unifying hypothesis for the immune-independent and -dependent processes contributing to the pathogenesis of SS. FUND: This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR).
31540861 Autoimmune epithelitis (Sjögren's syndrome); the impact of metabolic status of glandular 2019 Nov It is well established that distinct cell metabolic alterations strongly contribute to the modulation of innate and adaptive immune responses. In the past decade the term immunometabolism has been introduced to describe the intracellular metabolic shifts of immune cells that lead to alterations of their functions. The pathogenesis of Sjögren's syndrome (SS), also referred to as autoimmune epithelitis, is not completely understood, but strong evidence supports the central role of the salivary glandular epithelial cells which are the target cells in the initiation of the autoimmune responses. Moreover, the altered epithelial functional phenotype, observed in the salivary gland lesion, may explain their disturbed secretory as well as immunoregulatory functions. From an immunometabolic perspective we have focused our studies on the endoplasmic reticulum (ER) of the salivary gland epithelial cells (SGEC) and the implication of its altered functions in the immunogenicity of these cells in SS. We showed that ER of SGEC in SS patients in situ is stressed and extensively dilated. Using salivary gland cell cultures, we studied in vitro the effect of ER stress on the metabolic behavior and viability of the cells. ER stress induced by thapsigargin increased spliced X-box binding protein-1 (XBP-1, transcription factor that increases the transcription of UPR target genes) levels in a time-dependent manner followed by autophagy and resulted to cell apoptosis. In apoptotic cells, we observed that the autoantigens Ro52 and La were redistributed in apoptotic blebs. During the induction of ER stress autophagy rescued the cells from apoptosis acting as a protective mechanism. We have also shown that adiponectin, a multifunctional hormone, is upregulated in the SGEC of SS patients acting in an autocrine or paracrine manner in the same cells. Adiponectin through activation of AMPK, the major sensor for cell energy demands, protected SGEC from apoptosis. Our results in combination with the work of others indicate that any effort of cell adaptation to ER stress may up regulate a proinflammatory milieu. This enhances the notion that metabolic alterations of the targeted epithelial cells in SS, independently of the cause, may induce an immunogenic phenotype. Therefore, SGEC have the potential to directly regulate susceptibility to and/or severity of autoimmune responses. Since adiponectin plays a vital role in the viability of SGEC through phosphorylation of AMPK, therapeutic interventions using PPAR agonists that upregulate adiponectin and concomitantly modify the energy metabolism, may be promising candidates for therapeutic intervention in SS.
31092740 Sjögren's-like syndrome in a dog. 2019 Jun 21 A neutered male Golden Retriever was referred with a 2-week history of dry mouth. Multiple and bilateral enlargement of the lacrimal and salivary glands showing heterogeneous internal enhancement was identified on contrast-enhanced computed tomography (CT). Ultrasonographic examination detected multifocal hypoechoic areas within the swollen submandibular salivary glands, which were histopathologically diagnosed as lymphoplasmacytic sialoadenitis. As both imaging and histopathological findings were in accordance with those in human Sjögren's syndrome, a provisional diagnosis of Sjögren's-like syndrome was made. Immunosuppressive drugs promptly improved clinical signs concurrently with the abnormal sonographic findings, indicating the feasibility of ultrasonography in monitoring therapeutic outcomes. Herein, we discuss a proposed criteria set for diagnosis of Sjögren's-like syndrome in veterinary medicine.
30626116 Molecular Evidence for Precursors of Sjögren's Foci in Histologically Normal Lacrimal Gla 2019 Jan 8 Understanding the formation of Sjogren's lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren's foci, including messenger RNAs (mRNAs) for C⁻X⁻C motif chemokine ligand 13 (CXCL13) and B-cell activating factor (BAFF), which dominated the major principal component. We interpreted the transcript cluster as the signature of a cluster of integrally functioning cells. Pregnancy and dryness increased the likelihood that the cluster would develop to high levels, but responses were subject to high levels of stochasticity. Analyzing microdissected samples from high- and low-cluster-level glands, we found that certain transcripts, including mRNAs for C⁻C motif chemokine ligand 21 (CCL21), CXCL13, cluster of differentiation 4 (CD4), CD28, CD25, BAFF, and interleukin 18 (IL-18) were significantly more abundant in immune cell clusters (ICs) from the high-cluster-level gland; mRNAs for CCL2, CD25, and IL-1RA were significantly more abundant in acinus-duct axis samples; mRNAs for CCL4, BAFF, IL-6, and IL-10 were more abundant in some acinus-duct samples; cells with high prolactin immunoreactivity were more frequent in interacinar spaces. In conclusion, integrated functional networks comprising Sjögren's infiltrates, such as ICs, acinar cells, ductal cells, and interacinar cells, can form in histologically normal glands, and it is feasible to detect their molecular signatures.
30391023 Synaptotagmin-1 overexpression under inflammatory conditions affects secretion in salivary 2019 Feb Sjögren's syndrome (SS) is an autoimmune exocrinopathy associated with severe secretory alterations by disruption of the glandular architecture integrity, which is fundamental for a correct function and localization of the secretory machinery. Syt-1, PI(4,5)P(2) and Ca(2+) are significant factors controlling exocytosis in different secretory cells, the Ca(2+) role being the most studied. Salivary acinar cells from SS-patients show a defective agonist-regulated intracellular Ca(2+) release together with a decreased IP3R expression level, and this condition may explain a reduced water release. However, there are not reports where Syt-1, PI(4,5)P(2) and Ca(2+) in acinar cells of SS patients had been studied. In the present study, we analyzed the expression and/or localization of Syt-1 and PI(4,5)P(2) in acinar cells of labial salivary gland biopsies from SS-patients and control individuals. Also, we evaluated whether the overexpression of Syt-1 and the loss of cell polarity induced by TNF-α or loss of interaction between acinar cell and basal lamina, alters directionality of the exocytosis process, Ca(2+) signaling and α-amylase secretion in a 3D-acini model stimulated with cholinergic or β-adrenergic agonists. In addition, the correlation between Syt-1 protein levels and clinical parameters was evaluated. The results showed an increase of Syt-1 mRNA and protein levels, and a high number of co-localization points of Syt-1/STX4 and PI(4,5)P(2)/Ezrin in the acinar basolateral region of LSG from SS-patients. With regard to 3D-acini, Syt-1 overexpression increased exocytosis in the apical pole compared to control acini. TNF-α stimulation increased exocytic events in the basal pole, which was further enhanced by Syt-1 overexpression. Additionally, altered acinar cell polarity affected Ca(2+) signaling and amylase secretion. Overexpression of Syt-1 was associated with salivary gland alterations revealing that the secretory dysfunction in SS-patients is linked to altered expression and/or localization of secretory machinery components together with impaired epithelial cell polarity. These findings provide a novel insight on the pathological mechanism implicated in ectopic secretory products to the extracellular matrix of LSG from SS-patients, which might initiate inflammation.
31757716 LncRNA PVT1 links Myc to glycolytic metabolism upon CD4(+) T cell activation and Sjögren' 2020 Feb The hyperproliferation and hyperactivation of CD4(+) T cells in salivary gland tissue is a hallmark of Sjögren's syndrome (SS). However, the role of long noncoding RNAs (lncRNAs) in the pathological process of SS and CD4(+) T cell activation has not been fully elucidated. Here, we reported that lncRNA PVT1 was involved in the glycolytic metabolism reprogramming and proliferation upon CD4(+) T cell activation. Expression of PVT1 was positively related with CD4(+) T cell activation both in SS patients and Ex vivo antigen simulation. Depletion of PVT1 decreased the proliferation of murine CD4(+) T cells and Jurkat T cells upon activation. We also showed that expression of the transcription factor Myc is regulated by PVT1 under antigen simulation. Depletion of PVT1 significantly decreased the expression of glycolytic genes, as well as several pivotal glycolytic proteins that were directly transcribed by Myc. Measurement of glucose content and lactate secretion indicated a defected lactate secretion and glucose uptake in PVT1-depleted T cells. Additionally, the real-time extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurement also affirmed that PVT1 maintains glycolytic levels, glycolytic capacity under stress and ECAR/OCR ratios during T cell activation. Polarizing assays indicate that PVT1 depletion defected the function of Th1 effector cells as well as down-regulated Myc expression and glycolytic levels. Furthermore, we observed increased glycolytic levels in CD4(+) T cells from SS-like NOD/Ltj mice. Treatment with 2-deoxy-d-glucose (2-DG), an inhibitor of glycolysis, significantly decreased the extent of lymphocyte infiltration and CD4(+) T cell numbers and attenuated the defect of salivary flow in the lesioned submandibular glands of NOD/Ltj mice. Thus, our study demonstrated that lncRNA PVT1, which was upregulated in the CD4(+)T cells of SS patients, could maintain the expression of Myc, thus controlling the proliferation and effector functions of CD4(+) T cells through regulating the reprogramming of glycolysis. Inhibition of glycolysis could attenuate the proliferation of CD4(+) T cells and the SS-like autoimmune response. Our study provides a novel mechanistic function of lncRNA PVT1 in the pathogenesis of SS.
31494513 Toxicity of cadmium in musculoskeletal diseases. 2019 Nov Epidemiological studies have reported that exposure to toxic metals like cadmium (Cd) may promote the development of musculoskeletal diseases, such as osteoporosis, rheumatoid arthritis (RA), and osteoarthritis (OA), among others. The objective of this review is to summarize the molecular mechanisms of inflammation and oxidative stress activated by Cd at the bone level, particularly in osteoporosis, RA, and OA. Cadmium can increase bone resorption, affect the activity of osteoclasts and calcium (Ca) absorption, and impair kidney function, which favors the development of osteoporosis. In the case of RA, Cd interferes with the activity of antioxidant proteins, like superoxide dismutase (SOD) and catalase (CAT). It also promotes an inflammatory state, inducing the process of citrullination, which affects the proteins of immune response. On the other hand, accumulation of Cd in the tissues and blood of smokers has been related to the development of some musculoskeletal diseases. Therefore, knowing the negative impact of Cd toxicity at the articular level can help understand the damage mechanisms it produces, leading to the development of such diseases.
31431990 Predicting disease progression and poor outcomes in patients with moderately active rheuma 2019 OBJECTIVES: Access to biologic DMARDs for RA is often restricted to those with severe disease. This systematic review aimed to identify prognostic factors in patients with moderate disease activity who may be at risk of disease progression and poor clinical outcomes. METHODS: MEDLINE, Embase and Cochrane databases were searched (final search 22 September 2017), and data from patients with moderate disease [28-joint DAS (DAS28) >3.2-≤5.1] were included. Studies were evaluated according to the measure(s) of progression/poor outcome used: radiographic, disease activity or other indicators. RESULTS: The searches identified 274 publications, of which 30 were selected for data extraction. Fourteen studies were prioritized, because they specifically analysed patients with moderate RA. Nine studies reported radiographic progression outcomes for 3241 patients, three studies reported disease activity progression for 1516 patients, and two studies reported other relevant outcomes for 2094 patients. Prognostic factors with consistent evidence for progression/poor outcome prediction were as follows: DAS28 ≥ 4.2, the presence of anti-CCP antibodies, and power Doppler ultrasound score ≥1. Some predictors were specific to either disease activity or radiographic progression. CONCLUSION: Several criteria used in standard clinical practice were identified that have the potential to inform the selection of patients with moderate RA who are at greater risk of a poor outcome. A combination of two or more of these factors might enhance their predictive potential. Further work is required to derive clinical decision rules incorporating these factors.