Browse

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

ID PMID Title PublicationDate abstract
30243784 Advances in the treatment of systemic lupus erythematosus: From back to the future, to the 2019 Jul There have been many advances in the diagnosis and therapeutic management of systemic lupus erythematosus (SLE) over the past decades. Following more than eleven centuries of therapeutic uncertainty, the discovery of the therapeutic properties of glucocorticoids is without any doubt one of the most significant advance in the field of autoimmune diseases. The many progresses made by rapidly growing chemical industry of the 19th century chemistry have allowed the identification of valuable therapeutic compounds such as anti-malarials, cyclophosphamide, azathioprine, cyclosporine and later mycophenolate mofetil, which have all profoundly changed the face of the disease. A very visible consequence of this is the profound improvement in the prognosis of the disease, with 10-year survival rates of more than 90% in most dedicated centres. Following the development of biotherapies in rheumatoid arthritis, the late 20th century has slowly opened a new era for the treatment of SLE, that of targeted therapies. With the approval of belimumab in 2011 and 74 targeted therapies in clinical development, we may expect great changes in the therapeutic management of SLE. Those molecules target inflammatory cytokines or chemokines and their receptors, B cells or plasma cells, intracellular signalling pathways, B/T cells co-stimulation molecules, interferons, plasmacytoid dendritic cells, as well as various other targets of interest. Current challenges are now slowly shifting from whether some new drugs will be available to how to select the most adequate drug (or drug combination) at the patient-level.
31733607 B cell targeted therapies in autoimmune disease. 2019 Dec PURPOSE OF REVIEW: FDA-approved B cell-targeted therapy has expanded to a multitude of autoimmune diseases ranging from organ specific diseases, like pemphigus and multiple sclerosis, to systemic diseases such as ANCA-associated vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this review, we discuss the variability in response to B cell-targeted therapies with a focus on the diversity of human B cells and plasma cells, and will discuss several of the promising new B cell-targeted therapies. RECENT FINDING: The pathogenic roles for B cells include autoantibody-dependent and autoantibody-independent functions whose importance may vary across diseases or even in subsets of patients with the same disease. Recent data have further demonstrated the diversity of human B cell subsets that contribute to disease as well as novel pathways of B cell activation in autoimmune disease. The importance of eliminating autoreactive B cells and plasma cells will be discussed, as well as new approaches to do so. SUMMARY: The past several years has witnessed significant advances in our knowledge of human B cell subsets and function. This has created a nuanced picture of the diverse ways B cells contribute to autoimmunity and an ever-expanding armamentarium of B cell-targeted therapies.
31645725 Structural basis of species-selective antagonist binding to the succinate receptor. 2019 Oct The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species(1). The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family(2) and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation(3-5). Because SUCNR1 senses succinate as an immunological danger signal(6)-which has relevance for diseases including ulcerative colitis, liver fibrosis(7), diabetes and rheumatoid arthritis(3,8)-it is of interest as a therapeutic target. Here we report the high-resolution crystal structure of rat SUCNR1 in complex with an intracellular binding nanobody in the inactive conformation. Structure-based mutagenesis and radioligand-binding studies, in conjunction with molecular modelling, identified key residues for species-selective antagonist binding and enabled the determination of the high-resolution crystal structure of a humanized rat SUCNR1 in complex with a high-affinity, human-selective antagonist denoted NF-56-EJ40. We anticipate that these structural insights into the architecture of the succinate receptor and its antagonist selectivity will enable structure-based drug discovery and will further help to elucidate the function of SUCNR1 in vitro and in vivo.
31664391 Influence of physical performance on elderly mortality, functionality and life satisfactio 2019 OBJECTIVE: To verify the influence of physical performance on elderly mortality, functionality and life satisfaction. MATERIALS AND METHODS: A follow-up was performed on 900 Brazilian non-hospitalized elderly in the period 2008-2016, in which 154 deaths from natural causes were included in the survival analysis. RESULTS: the worst grip strength (RR = 1.60; CI 95% = 1.15-2.23, p = 0.005) and gait speed (RR = 1.82; CI 95% = 1.30-2.55, p < 0.001) performances were associated with increased mortality risk. Age was a confounding factor for strength (RR = 1.06; CI 95%  =  1.03-1.09, p < 0.001) and rheumatoid arthritis was a confounding factor for speed (RR = 2.02; CI 95% = 1.36-3.01, p < 0.001). The elderly with good physical performance realized more instrumental and advanced activities of daily living, and good gait performance had a significant effect on life satisfaction (F = 6.87, p = 0.009). CONCLUSIONS: good physical performance seems to be fundamental for longevity and for accomplishing daily tasks. Furthermore, good mobility can affect life satisfaction-related mechanisms.
30763763 Porphyromonas gingivalis promotes the motility of esophageal squamous cell carcinoma by ac 2019 Aug Esophageal carcinoma, with a increasing incidence, is one of the most aggressive carcinomas in gastrointestinal tract. Epidemiologic studies demonstrate an association of oral pathogens with multiple diseases, including rheumatoid arthritis, cardiovascular diseases, diabetes, and gastrointestinal malignancies. Nevertheless, a causal relationship between oral pathogens and esophageal squamous cell carcinoma (ESCC) has not been elucidated. Here, we found that Porphyromonas was significantly enriched in the saliva of patients with ESCC, compared with that in normal human. In vitro studies showed that Porphyromonas gingivalis (P. gingivalis) promoted the proliferation and motility of ESCC cells, as evidenced by up regulated expression of key molecules implicated in NF-κB signaling pathway. These findings, for the first time, demonstrated a role of oral pathogens in inducing ESCC tumorigenesis and metastasis, which might involve regulation of NF-κB signaling pathway.
30718510 CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes. 2019 Feb 4 CEMIP (for "Cell migration-inducing protein" also called KIAA1199 and Hybid for "Hyaluronan-binding protein") expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, αSMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated β-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted αSMA expression, a fibrosis marker, and TGFβ signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. αSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with αSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into "chondro-myo-fibroblasts" expressing α-SMA and type III collagen, two fibrosis markers. Moreover, these "chondro-myo-fibroblasts" were found in OA cartilage but not in healthy cartilage.
35021545 Recent Development of Metal Nanoparticles for Angiogenesis Study and Their Therapeutic App 2019 Dec 16 Angiogenesis is a crucial biological process of development of blood vessels from pre-existing vasculature, which helps in several physiological functions including embryonic development, hair growth, ovulation, menstruation, tissue repair, and regeneration. Contrastingly, it is also imperative in various pathological conditions like cardiovascular/ischemic diseases, rheumatoid arthritis, cancers, ocular/retinal diseases, and others. These disease conditions are often treated by manipulating angiogenesis using different pro-angiogenic or antiangiogenic factors/molecules through either promoting or inhibiting this complex process, respectively. However, these conventional angiogenic treatment strategies fall short in attaining the desired therapeutic effect due to several limitations including low bioavailability, rapid clearance, high cost, nonspecificity, drug resistance and side effects. Therefore, it is high time for the advancement of different pro- and antiangiogenic materials that could overcome aforesaid limitations, followed by their effective use for the therapy of angiogenesis related diseases. Recently, nanotechnology has drastically advanced in various areas of biology and medicine including therapeutic angiogenesis. Globally, many research groups including ours explored various inorganic metal nanomaterials that could efficiently manipulate the angiogenesis process either by augmenting or inhibiting it. The extensive investigation of the mechanisms underlying nanomaterials-mediated manipulation of angiogenesis is also well-documented. In the present review article, we intend to introduce the recent developments of inorganic nanomedicine manipulating angiogenesis with major focus on pro-angiogenic nanomaterials and their therapeutic applications along with associated challenges and future directions.
27327630 Novel treatment of 99Tc-MDP improves clinical and radiographic results for patients with o 2019 Jun BACKGROUND: Management of osteochondral lesions of talus (OLT) remains controversial. 99Tc-MDP, a decay product of 99mTc-MDP which is widely used for bone scan, is effective in the clinical treatment of rheumatoid arthritis. The purpose of the study is to investigate the effects of 99Tc-MDP treatment on OLT. METHODS: In the clinical evaluation, 66 patients with a total of 83 lesions of OLT who failed appropriate non-operative treatment and surgery were retrospectively included and treated with intravenous injection of 99Tc-MDP and Chinese herbal fumigation (CHF). The effects of 99Tc-MDP and CHF on OLT were evaluated by the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), Visual Analog Scale (VAS), activities of daily living (Barthel Index), and MRI, 99mTc-MDP SPECT/CT and CT. Radiographic changes were also assessed by the transverse long diameter of the cyst on CT. RESULTS: At the last follow-up, AOFAS, VAS and Barthel Index improved significantly from 68.66±9.76, 3.05±0.34 and 85±8.31 to 85.4±8.31, 1.85±0.36 and 94.7±4.99 (P<0.01), respectively after one course treatment in 66 patients with OLT. Thirty one (31/66) patients had a second treatment course. Their AOFAS, VAS and Barthel Index also improved significantly after the mean follow-up of 7±2 (6-15) months. And the average diameter of the cysts decreased from 8.01±3.35 mm to 4.74±2.83 mm (P<0.01) in the 31 patients. CONCLUSIONS: The retrospective study indicates that a combination treatment of 99Tc-MDP and CHF is effective in pain relief and return of function in a short term of follow-up for patients with OLT. Our results suggest that the small cystic lesions with increased uptake of 99mTc-MDP on SPECT/CT can be well treated by 99Tc-MDP and CHF. This novel technique holds the potential to emerge as an effective conservative treatment for OLT without adverse effects. The level of evidence for 99Tc-MDP is medium for the number of patients and retrospective study.
32173002 IRAK1 polymorphisms are associated with susceptibility to neuromyelitis optica spectrum di 2020 Jan BACKGROUND: X chromosome-linked interleukin-1 receptor-associated kinase (IRAK1) polymorphisms have been demonstrated to be associated with the risks of several autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and autoimmune thyroid diseases. However, no studies have investigated the association of IRAK1 polymorphisms with neuromyelitis optica spectrum disorder (NMOSD). This case-control study was performed to determine the correlation between IRAK1 polymorphisms and the risk of NMOSD. METHODS: Two single nucleotide polymorphisms (SNPs) rs1059703G>A and rs3027898C>A of IRAK1 were selected and genotyped using SNPscan in a Chinese cohort, including 332 patients with NMOSD and 520 healthy controls. Chi-square tests and logistic regression analyses were used to determine the associations between IRAK1 polymorphisms and the risk of NMOSD. RESULTS: Patients with NMOSD showed a lower frequency of the minor allele A of rs1059703 than did controls (Odds ratio [OR] = 0.68; 95% confidence intervals [CI], 0.52-0.88; P(corr) = 0.007). Compared with wild genotype GG of rs1059703, homozygous mutation AA and heterozygous mutation GA were significantly associated with the decreased risk of NMOSD after adjusting for sex and age (adjusted OR = 0.64; 95%CI, 0.49-0.84; P(corr) = 0.002). Similar associations were also observed for IRAK1 rs3027898C>A. Stratification analysis according to sex revealed that the significantly different allele distributions of the two SNPs were mainly found in females. However, IRAK1 polymorphisms were not correlated with aquaporin-4-IgG, onset symptoms, or age at onset. CONCLUSIONS: This study is first to demonstrate that X-chromosome-linked IRAK1 polymorphisms are associated with the risk of NMOSD and provide novel insights into the underlying mechanisms of this disease. Further studies are needed to elucidate the function of IRAK1 variants in the pathogenesis of NMOSD and the underlying molecular mechanisms.
32038631 Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressin 2019 B cells fulfill multifaceted functions that influence immune responses during health and disease. In autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, depletion of functional B cells results in an aggravation of disease in humans and respective mouse models. This could be due to a lack of a pivotal B cell subpopulation: regulatory B cells (Bregs). Although Bregs represent only a small proportion of all immune cells, they exhibit critical properties in regulating immune responses, thus contributing to the maintenance of immune homeostasis in healthy individuals. In this study, we report that the induction of Bregs is differentially triggered by the immunogenicity of the host microbiota. In comparative experiments with low immunogenic Bacteroides vulgatus and strong immunogenic Escherichia coli, we found that the induction and longevity of Bregs depend on strong Toll-like receptor activation mediated by antigens of strong immunogenic commensals. The potent B cell stimulation via E. coli led to a pronounced expression of suppressive molecules on the B cell surface and an increased production of anti-inflammatory cytokines like interleukin-10. These bacteria-primed Bregs were capable of efficiently inhibiting the maturation and function of dendritic cells (DCs), preventing the proliferation and polarization of T helper (Th)1 and Th17 cells while simultaneously promoting Th2 cell differentiation in vitro. In addition, Bregs facilitated the development of regulatory T cells (Tregs) resulting in a possible feedback cooperation to establish immune homeostasis. Moreover, the colonization of germfree wild type mice with E. coli but not B. vulgatus significantly reduced intestinal inflammatory processes in dextran sulfate sodium (DSS)-induced colitis associated with an increase induction of immune suppressive Bregs. The quantity of Bregs directly correlated with the severity of inflammation. These findings may provide new insights and therapeutic approaches for B cell-controlled treatments of microbiota-driven autoimmune disease.
31918241 Effectiveness of subcutaneous tocilizumab in neuromyelitis optica spectrum disorders. 2019 Dec 30 BACKGROUND: Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown. METHODS: We retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014-2019. RESULTS: Twelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two - for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75-0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0-0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75-1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0-0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack. CONCLUSIONS: Effectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.
31847314 The Role of NF-κB in Physiological Bone Development and Inflammatory Bone Diseases: Is NF 2019 Dec 14 Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-κB occurs via two pathways: inflammatory cytokines, such as TNF-α and IL-1β, activate the "classical pathway", and cytokines involved in lymph node formation, such as CD40L, activate the "alternative pathway". NF-κB1 (p50) and NF-κB2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-κB activation is required for osteoclast differentiation. These results indicate that NF-κB may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of IκB kinase (IKK)-β specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-κB is thought to promote bone formation. Taken together, the inhibition of NF-κB leads to "killing two birds with one stone": it suppresses bone resorption and promotes bone formation. This review describes the role of NF-κB in physiological bone metabolism, pathologic bone destruction, and bone regeneration.
31806422 Ebola virus disease: An emerging and re-emerging viral threat. 2020 Jan The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, and Ebola virus (previously known as Zaire ebolavirus). These viruses have a large non-segmented, negative-strand RNA of approximately 19 kb that encodes for glycoproteins (i.e., GP, sGP, ssGP), nucleoproteins, virion proteins (i.e., VP 24, 30,40) and an RNA dependent RNA polymerase. These viruses have become a global health concern because of mortality, their rapid dissemination, new outbreaks in West-Africa, and the emergence of a new condition known as "Post-Ebola virus disease syndrome" that resembles inflammatory and autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus and spondyloarthritis with uveitis. However, there are many gaps in the understanding of the mechanisms that may induce the development of such autoimmune-like syndromes. Some of these mechanisms may include a high formation of neutrophil extracellular traps, an uncontrolled "cytokine storm", and the possible formation of auto-antibodies. The likely appearance of autoimmune phenomena in Ebola survivors suppose a new challenge in the management and control of this disease and opens a new field of research in a special subgroup of patients. Herein, the molecular biology, pathogenesis, clinical manifestations, and treatment of Ebola virus disease are reviewed and some strategies for control of disease are discussed.
31772500 METTL3 Attenuates LPS-Induced Inflammatory Response in Macrophages via NF-κB Signaling Pa 2019 Methyltransferase-like 3 (METTL3), an RNA N(6)-methyladenosine (m(6)A) methyltransferase, is essential for the m(6)A mRNA modification. As a key enzyme of m(6)A methylation modification, METTL3 has been implicated in immune and inflammation regulation. However, little is known of the role and underlying mechanism of METTL3 in rheumatoid arthritis (RA). The aim of the present study is to elucidate the function and potential mechanism of METTL3 in RA pathogenesis. We used quantitative real-time polymerase chain reaction to detect the expression of METTL3 in RA patients and controls as well as the macrophage cell line. CCK-8 was used for cell proliferation assay. Enzyme-linked immunosorbent assay (ELISA) was adopted to estimate the generation of IL-6 and TNF-α in macrophages. Western blot and immunofluorescence were applied to evaluate the activation of NF-κB in macrophages. The expression of METTL3 was significantly elevated in patients with RA. It was positively associated with CRP and ESR, two common markers for RA disease activity. Besides, LPS could enhance the expression and biological activity of METTL3 in macrophages, while overexpression of METTL3 significantly attenuated the inflammatory response induced by LPS in macrophages. Moreover, the effect of METTL3 on LPS-induced inflammation in macrophages was dependent on NF-κB. This study firstly demonstrates the critical role of METTL3 in RA, which provides novel insights into recognizing the pathogenesis of RA and a promising biomarker for RA.
31723356 A cross-sectional investigation into the association between Porphyromonas gingivalis and 2019 BACKGROUND: Porphyromonas gingivalis (P.g) is unique among pathogens due to its ability to generate citrullinated proteins in an inflammatory milieu, potentially mediating the loss of immune tolerance, the production of anticitrullinated protein antibodies (ACPAs), and subsequently the development of rheumatoid arthritis (RA). Based on this hypothesis, we set out to investigate whether P.g is linked to ACPAs in a well-characterized German population. PARTICIPANTS AND METHODS: A total of 600 participants (292 women and 308 men with a mean age of 67 years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam study were selected in 2013, and paired saliva and serum samples were collected. Salivary P.g DNA and serum anticyclic citrullinated peptide (anti-CCP2) levels were quantified by real-time polymerase chain reaction and anti-CCP2 enzyme-linked immunosorbent assay, respectively. In selected participants, additional ACPA fine-specificities were also analysed on a custom-made multiplex peptide array. RESULTS: Among participants with C-reactive protein greater than 3.0 mg/l, a one-unit increase in P.g DNA was associated with an almost twofold increase in anti-CCP2 levels. Moreover, participants with high P.g DNA had on average approximately 2.8-times higher anti-CCP2 levels when compared with participants with low P.g DNA, (Holm-adjusted p value = 0.01). Furthermore, citrullinated epitopes on α-enolase and vimentin were common ACPA reactivities among participants who also had high P.g DNA and elevated C-reactive protein. CONCLUSIONS: Our study suggests that in specific subgroups of individuals with systemic inflammation, higher salivary P.g DNA is associated with elevated serum ACPA. These data support a role for P.g in the development of anticitrulline immunity.
31639408 Long non-coding RNAs and nuclear factor-κB crosstalk in cancer and other human diseases. 2020 Jan The regulation of the pleiotropic transcription factor, nuclear factor-κB (NF-κB) by miRNAs and proteins is extensively studied. More recently, the NF-κB signaling was also reported to be regulated by several long non-coding RNAs (lncRNAs) that constitute the major portion of the noncoding component of the human genome. The common NF-κB associated lncRNAs include NKILA, HOTAIR, MALAT1, ANRIL, Lethe, MIR31HG, and PACER. The lncRNA and NF-κB signaling crosstalk during cancer and other diseases such as cardiomyopathy, celiac disease, cerebral infarction, chronic kidney disease, diabetes mellitus, Kawasaki disease, pregnancy loss, and rheumatoid arthritis. Some NF-κB related lncRNAs can affect gene expression without modulating NF-κB signaling. Most of the lncRNAs with a potential to modulate NF-κB signaling are regulated by NF-κB itself suggesting a feedback regulation. The discovery of lncRNAs have provided a new type of regulation for the NF-κB signaling and thus could be explored for therapeutic interventions. The manner in which lncRNA and NF-κB crosstalk affects human pathophysiology is discussed in this review. The challenges associated with the therapeutic interventions of this crosstalk are also discussed.
31375581 Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered 2019 Oct 15 We previously demonstrated that Epstein-Barr virus (EBV) DNA increases the production of the proinflammatory cytokine interleukin-17A (IL-17A) in mice. This property may contribute to the established association between EBV and autoimmune diseases. The objective of the present study was to elucidate mechanisms through which EBV DNA modulates IL-17A levels in mice. To determine whether endosomal Toll-like receptors (TLRs) played a role in this pathway, the expression of TLR3, -7, or -9 was assessed by real-time reverse transcription-PCR in mouse spleens after injection of EBV DNA. Moreover, specific inhibitors were used for these TLRs in mouse peripheral blood mononuclear cells (PBMCs) cultured with EBV DNA and in mice injected with this viral DNA; IL-17A levels were then assessed using an enzyme-linked immunosorbent assay. The expression of the endosomal receptors TLR3, -7, and -9 was increased in mice injected with EBV DNA. When mouse immune cells were cultured with EBV DNA and a TLR3, -7, or -9 inhibitor or when mice were injected with the viral DNA along with either of these inhibitors, a significant decrease in IL-17A levels was detected. Therefore, endosomal TLRs are involved in the EBV DNA-mediated triggering of IL-17A production in mice. Targeting these receptors in EBV-positive subjects with autoimmunity may be useful pending investigations assessing whether they play a similar role in humans.IMPORTANCE Epstein-Barr virus is a pathogen that causes persistent infection with potential consistent viral DNA shedding. The enhancement of production of proinflammatory cytokines by viral DNA itself may contribute to autoimmune disease development or exacerbation. In this project, we identified that endosomal Toll-like receptors are involved in triggering proinflammatory mediators in response to viral DNA. Pathways and receptors involved may serve as future therapeutic targets for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.
31063818 Investigation of the anti-inflammatory and the analgesic effects of the extracts from Smil 2019 Aug 10 ETHNOPHARMACOLOGICAL RELEVANCE: Smilax ornata Lem. is used in folklore medicine to treat rheumatoid arthritis and rheumatic pain. This particular claim has never been scientifically validated before in this plant species and hence, it forms the reason for this investigation. OBJECTIVE: To investigate whether the methanol and ethyl acetate extracts of Smilax ornata Lem. possess anti-inflammatory and analgesic properties in Sprague-Dawley rats. METHODS: The anti-inflammatory and analgesic activities were investigated using carrageenan-induced paw oedema model and the tail-flick model respectively. RESULTS: The methanol extracts (200 and 400 mg/kg) and the ethyl acetate extract (400 mg/kg) exhibited significant (P < 0.05) anti-inflammatory activity when compared with that of their control groups (saline and vegetable oil respectively), with an onset of 150 min and a duration of 2.5 h. The methanol extract (200 mg/kg) exhibited significant (P < 0.05) analgesic activity, with an onset of 60 min and a duration of 2 h. Also, the methanol and the ethyl acetate extracts (400 mg/kg) exhibited significant (P < 0.05) analgesic activity when compared with that of their control groups (saline and vegetable oil respectively), with an onset of 30 min and a duration of 2.5 h. CONCLUSION: The present study provided scientific justification that the extracts of Smilax ornata Lem. possess significant anti-inflammatory and analgesic activities.
31006146 Corticosteroids and methotrexate as adjuvants to costimulation blockade in non-human prima 2019 Jun Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.
30700695 Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusi 2019 Jan 16 Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1(-/-) mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs.