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ID PMID Title PublicationDate abstract
29116541 A cross-sectional study of vitamin D levels in a large cohort of patients with rheumatic d 2018 Mar The objective of this study is to examine 25-hydroxyvitamin D [25(OH)D] (D-25) levels and associations with patient- and disease-related factors in rheumatic diseases. This is a register-based study of D-25 levels in adult patients seen at the Central Finland Hospital rheumatology clinic (January 2011-April 2015). Demographic, clinical, laboratory, and patient-reported outcomes (PROs) were collected as part of the normal infrastructure of the outpatient clinic and examined for their association with D-25 level. Statistical analysis included descriptive statistics and univariable and multivariable regression analyses adjusting for age and gender. D-25 was measured in 3203 patients (age range 15-91 years, mean 54; 68% female) with diagnoses including RA (n = 1386), unspecified arthralgia/myalgia (n = 413), and connective tissues diseases (n = 213). The overall D-25 mean (SD) level was 78 (31) and median (IQR) 75 (55, 97). At baseline, 17.8% had D-25 deficiency, and only 1.6% severe deficiency  (< 25 nmol/l); 34%/49% had sufficient/optimal D-25 levels. Higher D-25 levels were associated with older age, lower BMI, and regular exercise (all p < 0.001) among other factors. In multivariable analyses, younger age, non-white background, higher BMI, smoking, less frequent exercise (p < 0.001), and first visit to the clinic (p = 0.033) remained significantly associated with D-25 deficiency. Among those with sub-optimal D-25 levels, 64% had improved to sufficient/optimal levels after a median (IQR) of 13 (7.8, 22) months. The proportion of patients with D-25 deficiency in this study was generally low. Older patients had considerably higher D-25 levels compared to younger patients. Lower physical exercise and higher BMI were associated with higher risk of deficiency. The study supports the benefit of strategies to help minimize the risk of D-25 deficiency.
30662920 TNFAIP3 F127C Coding Variation in Greek Primary Sjogren's Syndrome Patients. 2018 Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene encodes the A20 protein, an important negative feedback regulator of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. A coding TNFAIP3 variant, namely rs2230926, has been previously linked to B cell non-Hodgkin's lymphoma (NHL) development in patients with Sjogren's syndrome (SS) of French and UK origin. Herein, we aimed to determine the prevalence of rs2230926 in a Greek primary SS cohort and explore possible associations with disease characteristics. The rs2230926 gene variant was genotyped in 327 primary Greek SS patients (ninety-one complicated by NHL (SS-lymphoma)) and 448 Greek healthy controls (HC) of similar age and sex distribution. Clinical and laboratory characteristics were also recorded and gene expression of relevant genes of the NF-κB pathway was quantitated by real-time PCR in available whole peripheral blood (PB) from 165 primary SS patients. Increased prevalence of the rs2230926 mutant variant was detected in both SS-lymphoma and SS-nonlymphoma subgroups compared to HC (8.8% vs. 7.6% vs. 3.6%, p values: 0.04 and 0.03, respectively) in association with higher IgM, LDH serum levels, and PB Bcl-XL transcripts but lower leucocyte and neutrophil counts. Of interest, approximately one-fifth of SS-lymphoma cases with age at disease onset ≤ 40 years carried the rs2230926 variant (18.2% vs. 3.6%, OR 95% (CI): 6.0 (1.8-19.8), p value: 0.01). We postulate that deregulation of the NF-κB pathway as a result of the TNFAIP3 rs2230926 aberration increases SS and SS lymphoma susceptibility particularly in patients with early disease onset.
29925705 Expression of aquaporin 3 and 5 as a potential marker for distinguishing dry mouth from Sj 2018 A study was performed to investigate whether expression of aquaporin (AQP) 3 and 5 has potential as a marker for distinguishing dry mouth from Sjögren's syndrome. Twenty-five patients underwent labial minor salivary gland biopsy (dry mouth, n = 9; Sjögren's syndrome, n = 16; control, n = 8). All patients were interviewed about their medical history and subjective oral symptoms, and intraoral examinations were conducted. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to examine the expression and localization of AQP3 and 5. Significant differences in oral dryness, dry eye, medical history, and Saxon test results were revealed among the groups. However, there were no significant inter-group differences in expression of mRNA for AQP3 and 5. Immunohistochemical staining for AQP3 was localized mainly in the basolateral and part of the ductal cell membrane, and was barely evident in the apical membrane of acinar cells. AQP5 was localized to the basolateral and apical membrane and cytoplasm, but not the ductal cell membrane. Staining intensity for AQP3 in the apical membrane was significantly stronger in Sjögren's syndrome, and that for AQP5 was significantly weaker in dry mouth. Taken together, the present data suggest that expression of AQP3 and 5 may be a marker for distinguishing between patients with dry mouth and those with Sjögren's syndrome.
29183861 Bilateral striopallidodentate calcinosis associated with Sjögren's syndrome and IgDλ mon 2018 Mar We presented the first case of bilateral striopallidodentate calcinosis secondary to Sjögren's syndrome. Further consideration should be given to the association between Sjögren's syndrome and bilateral striopallidodentate calcinosis, because Sjögren's syndrome is latent, but more frequent than other autoimmune diseases.
29923220 Immunophenotypes and clinical features of lymphocytes in the labial gland of primary Sjogr 2018 Nov OBJECTIVE: To investigate consistency of lymphocyte immunophenotype between labial gland and peripheral blood in patients with primary Sjogren's syndrome (pSS). METHODS: Seventy-one pSS patients and 35 patients with maxillofacial trauma were included in the study. Based on the ratio of CD20 to CD3 in labial gland from 71 pSS patients, they were divided into the high and (n = 48) and low CD20 expression group (n = 23). Lymphocyte immunophenotypes in labial glands, course of disease, erythrocyte sedimentation rate (ESR), C-reactive protein, immunoglobulin, and complement levels were analyzed. RESULTS: In the labial gland, the levels of IgG, IgA, IgM, and C3c were higher, but C1q was lower in the pSS group than in the control group (all P < .05). CD20 was detected in labial gland samples of all pSS patients, in which CD3 was positive in 66 (93.0%) patients, and negative in 5 (7.0%). The plasma levels of IgG, IgA, IgM, and CRP, and ESR were higher, but serum C4 level was lower in pSS patients than in the control group (all P < .01). Serum IgG level, ESR, and labial gland CD20 were higher in the high CD20 expression group than the low expression group (all P < .05). CONCLUSION: Primary Sjogren's syndrome patients had a higher expression of CD20 positive infiltrating lymphocytes of the labial gland, accompanied with the changes of immunoglobulins, and complements in both the labial gland and peripheral blood.
29148412 Psychological comorbidities associated with subclinical atherosclerosis in Greek patients 2018 May OBJECTIVES: Impaired sleep and psychological disorders are increasingly recognised as prevalent comorbidities in patients with primary Sjögren's syndrome (pSS), as well as important contributors of atherosclerosis in the general population. In the current study we sought to explore a potential role of psychological comorbidities in the pronounced atherosclerotic risk of pSS patients. METHODS: Fifty-nine pSS patients fulfilling the ACR/EULAR criteria completed specific validated questionnaires assessing fatigue, depression, anxiety and sleep disturbances. Clinical, laboratory and histopathological characteristics together with traditional risk factors for atherosclerosis were documented in all enrolled patients. Subclinical atherosclerosis defined either as carotid and/or femoral plaque formation or increased intima media thickness (IMT) levels were assessed by Doppler ultrasound. Univariate and multivariate analysis were performed. RESULTS: Plaque formation and high IMT levels were detected by ultrasound in 41(69.5%) out of the 59 pSS patients. In univariate analysis, age and higher triglyceride serum levels were associated with both plaque formation and high IMT levels. Hypertension was associated only with high IMT levels. While increased rates of both state anxiety and impaired sleep were detected in pSS patients with plaque formation in a univariate model, only impaired sleep proved to be independently associated with plaque formation among pSS patients (OR = 4.2, 95% CI =1.1-15.6, p=0.03). CONCLUSIONS: This is the first study showing impaired sleep to confer a significantly higher risk of subclinical atherosclerosis in patients with pSS. Clinicians should take psychological disturbances into account when trying to assess and manage the cardiovascular disease risk of pSS patients.
30453645 Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in t 2018 Nov 17 Sjögren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin⁻plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.
30273538 [Nephrocalcinosis and proximal tubulopathy in Sjögren's Syndrome.]. 2018 Jun 30 Primary Sjögren's syndrome is a systemic and chronic autoimmune disease. Renal involvement may occur in up to 30% of patients. The incidence of tubulopathies ranges from 2.6 to 33%. They are manifested by defects in the urine concentration and hydroelectrolyte alterations, mainly distal tubular acidosis and exceptionally proximal tubular acidosis. These disorders can be associated with nephrocalcinosis and renal lithiasis. We report the case of a patient with primary Sjögren who presented proximal renal tubular acidosis associated with recurrent renal colic due to renal lithiasis and nephrocalcinosis. We highlight the importance of diagnosing renal tubular acidosis in patients with Sjögren's syndrome that present alterations in urinary sediment and electrolyte disorders to avoid nephrocalcinosis and nephrolithiasis. Acidosis correction treatment aims to prevent the progression of the disorder and preserve renal function.
30103522 Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's S 2018 Aug 11 The pathogenesis of Sjögren's syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients' SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.
29447268 Circulating small non-coding RNAs reflect IFN status and B cell hyperactivity in patients 2018 BACKGROUND: Considering the important role of miRNAs in the regulation of post-transcriptional expression of target genes, we investigated circulating small non-coding RNAs (snc)RNA levels in patients with primary Sjögren's syndrome (pSS). In addition we assessed if serum sncRNA levels can be used to differentiate patients with specific disease features. METHODS: Serum RNA was isolated from 37 pSS patients as well as 21 patients with incomplete Sjögren's Syndrome (iSS) and 17 healthy controls (HC) allocated to two independent cohorts: discovery and validation. OpenArray profiling of 758 sncRNAs was performed in the discovery cohort. Selected sncRNAs were measured in the validation cohort using single-assay RT-qPCR. In addition, unsupervised hierarchical clustering was performed within the pSS group. RESULTS: Ten sncRNAs were differentially expressed between the groups in the array. In the validation cohort, we confirmed the increased expression of U6-snRNA and miR-661 in the iSS group as compared to HC. We were unable to validate differential expression of any miRNAs in the pSS group. However, within this group several miRNAs correlated with laboratory parameters. Unsupervised clustering distinguished three clusters of pSS patients. Patients in one cluster showed significantly higher serum IgG, prevalence of anti-SSB autoantibodies, IFN-score, and decreased leukocyte counts compared to the two other clusters. CONCLUSION: We were unable to identify any serum sncRNAs with differential expression in pSS patients. However, we show that circulating miRNA levels are associated with disease parameters in pSS patients and can be used to distinguish pSS patients with more severe B cell hyperactivity. As several of these miRNAs are implicated in the regulation of B cells, they may play a role in the perpetuation of the disease.
29157059 90K immunostimulatory glycoprotein in children with juvenile idiopathic arthritis. 2018 Jul OBJECTIVES: To assess whether circulating levels of 90K glycoprotein are increased in children with juvenile idiopathic arthritis (JIA) at different stages of the disease, compared to healthy controls and to evaluate potential over time changes in its concentrations following treatment with the antitumor-necrosis factor (TNF) drug etanercept. METHODS: 90K glycoprotein, C-reactive protein, erythrocyte sedimentation rate, TNF, antinuclear antibodies, rheumatoid factor and the Juvenile Arthritis Disease Activity Score were assessed in 71 children: 23 with newly diagnosed JIA, 23 with established and active JIA and 25 healthy controls. Patients, eligible for anti-TNF treatment, underwent a similar clinical/laboratory assessment after 6- and 12-month etanercept therapy. RESULTS: At baseline, significant differences were found in 90K levels between the three study groups: JIA at onset (157.7 [131.4-241.5] μg/ml), JIA on treatment (90.0 [68.8-120.2] μg/ml) and control group (58.0 [44.5-79.0] μg/ml), (p for trend <.001), with the JIA at onset group showing the highest values. In the JIA on treatment group, following one-year etanercept treatment, a significant reduction in 90K was detected already at 6 months (74.3 [56.0-104.1] μg/ml p = .001) and a further decline was observed at 12 months (49.3 [46.0-67.6] μg/ml p < .001). CONCLUSION: Our study showed that 90K glycoprotein levels are increased in JIA children compared to healthy controls, suggesting a potential pathogenetic role in the JIA. Besides, 12 months of therapy with etanercept can reduce 90K levels.
30126808 Temporomandibular joint involvement in children with juvenile idiopathic arthritis: a prel 2019 Jan OBJECTIVE: Children with juvenile idiopathic arthritis (JIA) are at risk for temporomandibular joint (TMJ) arthritis. This can lead to pain, limited mouth opening, facial asymmetry, and malocclusion. Our objective was to characterize patients with JIA and TMJ involvement in a single center. STUDY DESIGN: This was a retrospective study of children with JIA evaluated at Children's Healthcare of Atlanta. Inclusion criteria were confirmed JIA and jaw complaints. Medical records were reviewed to document demographics, JIA information, age at first TMJ complaint, and involvement of other joints. Descriptive statistics were computed. RESULTS: Majority of patients were white (mean age 13 years; range 5-18 years) with polyarticular rheumatoid factor (RF) negative or oligoarticular persistent JIA. Some were antinuclear antibody (ANA) positive, RF positive, or human leukocyte antigen (HLA)-B27 positive. Patients had involvement of other joints (e.g., fingers, knees, wrists). Of those with TMJ symptoms, 6 (10%) had TMJ arthritis. CONCLUSIONS: In our cohort, 60 (10%) of patients were diagnosed with TMJ arthritis. In this population, patients who are female, white, RF negative, HLA-B27 negative, ANA negative, and polyarticular RF-negative subtype and have involvement of other joints have a higher likelihood of having TMJ symptoms. If a patient meets these criteria, careful evaluation of TMJs should take place.
30342527 Comorbid connective tissue diseases and autoantibodies in lymphangioleiomyomatosis: a retr 2018 Oct 20 BACKGROUND: Lymphangioleiomyomatosis (LAM) and connective tissue diseases (CTDs) occur more frequently among women than men. We investigated the frequency of comorbid CTD and positive serum autoantibody findings in patients with LAM. METHODS: A total of 152 patients with LAM were prospectively and consecutively registered in the National Hospital Organization Kinki-Chuo Chest Medical Centre cohort. The clinical data were retrospectively analysed, and patients were categorised into the following three groups: a CTD group, a non-CTD-autoantibody-positive group, and a non-CTD-autoantibody-negative group. RESULTS: All patients were women. We identified five patients with comorbid CTDs (3.3%): Sjögren's syndrome (SjS) (n = 3), systemic lupus erythematosus (n = 1), and rheumatoid arthritis (n = 1). One patient with SjS was also diagnosed with antiphospholipid antibody syndrome. The positive rate for anti nuclear antibody was 31.5% and 6.9% at dilution of 1:40 or higher, and those of 1:160 or higher, respectively.  It tended to be lower in patients with LAM than in healthy women. The positive rate for anti-SS-A and anti-SS-B antibody was 7.9% and 1.8%, respectively. No significant differences in age, type of LAM, smoking status, serum vascular endothelial growth factor D level, respiratory function, treatment, or prognosis were observed among the three groups. CONCLUSIONS: Comorbid CTDs, especially SjS, in LAM patients should be considered.
30429765 Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the N 2018 Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the "anti-reward" system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases.
30365055 Identification of the inhibitory activity of walnut extract on the E3 ligase Syvn1. 2018 Dec Synoviolin (Syvn1), an E3 ubiquitin ligase in endoplasmic reticulum‑associated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. We previously demonstrated that Syvn1 negatively regulates the function of peroxisome proliferator‑activated receptor gamma coactivator‑1β (PGC‑1β). In addition, treatment with a Syvn1 inhibitor suppressed weight gain in a mouse model of obesity by activating PGC‑1β via Syvn1 inhibition. It has been suggested that the Syvn1 inhibitors may have therapeutic benefits in obese patients. The present study tested the inhibitory activity of walnut extract, a natural product, on Syvn1 activity. Walnut extract inhibited the effect of Syvn1 on the cell proliferation of rheumatoid synovial cells and repressed the interaction between PGC‑1β and Syvn1 in an in vitro binding assay. Polyubiquitination of PGC‑1β by Syvn1 was suppressed by walnut extract in a concentration‑dependent manner, but walnut extract did not have an inhibitory effect on the autoubiquitination of Syvn1. Treatment with walnut extract in mouse embryonic fibroblasts increased the number of mitochondria, suggesting that exposure to the extract recovered PGC‑1β function. These results demonstrated that constituents of walnut extract may serve as lead compounds in drug development efforts aiming to produce drugs to treat patients with obesity and obesity‑associated metabolic diseases.
29518379 Cavitary Lung Diseases: A Clinical-Radiologic Algorithmic Approach. 2018 Jun Cavities occasionally are encountered on thoracic images. Their differential diagnosis is large and includes, among others, various infections, autoimmune conditions, and primary and metastatic malignancies. We offer an algorithmic approach to their evaluation by initially excluding mimics of cavities and then broadly classifying them according to the duration of clinical symptoms and radiographic abnormalities. An acute or subacute process (< 12 weeks) suggests common bacterial and uncommon nocardial and fungal causes of pulmonary abscesses, necrotizing pneumonias, and septic emboli. A chronic process (≥ 12 weeks) suggests mycobacterial, fungal, viral, or parasitic infections; malignancy (primary lung cancer or metastases); or autoimmune disorders (rheumatoid arthritis and granulomatosis with polyangiitis). Although a number of radiographic features can suggest a diagnosis, their lack of specificity requires that imaging findings be combined with the clinical context to make a confident diagnosis.
30209762 Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheuma 2018 Sep 12 OBJECTIVES: To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression. RESULTS: Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54-7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29-5.40, p = 0.01). CONCLUSION: Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.
29914930 Reduction of Articular and Systemic Inflammation by Kava-241 in a Porphyromonas gingivalis 2018 Sep Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of Porphyromonas gingivalis-induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by P. gingivalis bacterial inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to P. gingivalis and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand, P. gingivalis-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with P. gingivalis and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.
29618659 Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve steno 2018 Apr 5 Mesenchymal TNF signaling is etiopathogenic for inflammatory diseases such as rheumatoid arthritis and spondyloarthritis (SpA). The role of Tnfr1 in arthritis has been documented; however, Tnfr2 functions are unknown. Here, we investigate the mesenchymal-specific role of Tnfr2 in the TnfΔARE mouse model of SpA in arthritis and heart valve stenosis comorbidity by cell-specific, Col6a1-cre-driven gene targeting. We find that TNF/Tnfr2 signaling in resident synovial fibroblasts (SFs) and valvular interstitial cells (VICs) is detrimental for both pathologies, pointing to common cellular mechanisms. In contrast, systemic Tnfr2 provides protective signaling, since its complete deletion leads to severe deterioration of both pathologies. SFs and VICs lacking Tnfr2 fail to acquire pathogenic activated phenotypes and display increased expression of antiinflammatory cytokines associated with decreased Akt signaling. Comparative RNA sequencing experiments showed that the majority of the deregulated pathways in TnfΔARE mesenchymal-origin SFs and VICs, including proliferation, inflammation, migration, and disease-specific genes, are regulated by Tnfr2; thus, in its absence, they are maintained in a quiescent nonpathogenic state. Our data indicate a pleiotropy of Tnfr2 functions, with mesenchymal Tnfr2 driving cell activation and arthritis/valve stenosis pathogenesis only in the presence of systemic Tnfr2, whereas nonmesenchymal Tnfr2 overcomes this function, providing protective signals and, thus, containing both pathologies.
29636466 Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signa 2018 Apr 10 Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF(70-80), is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF(70-80) binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF(70-80). Peptides with this TNFRI sequence, such as TNFRI(206-211) bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI(206-211) does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI(206-211) inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.