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ID PMID Title PublicationDate abstract
27913060 Outcome of pregnancy and neonatal complications with anti-tumor necrosis factor-α use in 2017 Jan BACKGROUND: Immune mediated diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and inflammatory bowel disease (IBD) commonly affect young and adolescent females. Anti-tumor necrosis factor (TNF)-α agents are increasingly used to treat these conditions, but their safety during pregnancy remains unclear. OBJECTIVES: To evaluate the risk of pregnancy related outcomes in patients with various immune mediated diseases treated with anti-TNF-α agents. METHODS: Electronic databases were searched for studies assessing the outcome of pregnancy in female patients with various immune mediated diseases who were treated with anti-TNF-α agents. Direct and network meta-analyses were performed between anti-TNF-α users, non-users, and the general population. RESULTS: Thirteen studies (including RA, IBD and various immune mediated diseases) were identified. Among the studies that compared the outcome between anti-TNF-α users and the general population, anti-TNF-α users had a non-significant trend towards reduced rate of live birth (odds ratio (OR) = 0.38 (P = 0.081), 95% confidence interval (CI) = 0.13-1.13) and were at significantly increased risk of preterm birth (OR = 2.62 (P < 0.0001), 95% CI = 2.12-3.23), spontaneous abortion (OR = 4.08 (P = 0.033), 95% CI = 1.12-14.89) and low birth weight (OR = 5.95 (P = 0.032), 95% CI = 1.17-30.38) compared to the general population. Risk of anomalies was not elevated (OR = 1.46 (P = 0.18), 95% CI = 0.84-2.56). Among the studies that compared the outcome between anti-TNF-α users and non-users, there were no significant differences in the rates of live birth and pregnancy related complications. Among the studies that compared the outcome between non-anti-TNF-α users and the general population, risk of spontaneous abortion was elevated (OR = 2.60 (P = 0.033), 95% CI = 1.08-6.27), but there were no significant differences in the rates of live birth and other pregnancy related complications. Network meta-analysis confirmed the rank order of all outcomes as general population, non-users and users of anti-TNF-α agents (ascending order based on safety). CONCLUSIONS: Female patients with immune mediated diseases treated with anti-TNF-α agents were at significantly increased risks of preterm birth, spontaneous abortion and low birth weight compared to the general population, but had comparable outcomes with non-users. These results provide useful information for female patients in their reproductive age and raise awareness of the conditions that they are facing among clinicians managing their care.
27823620 Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death vi 2016 Dec 1 BACKGROUND: Chloroquine, a lysosomal inhibitor, is used for malaria, rheumatoid arthritis, and lupus erythematosus therapy. In our previous study, FIP-gts, an immunomodulatory protein from Ganoderma tsugae, inhibited cell viability in lung cancer cells and urothelial cancer cells. Urothelial carcinoma is the most common type of bladder cancer. Cisplatin resistance is an important issue in urothelial carcinoma therapy. PURPOSE: The aim of this study is to investigate the effect of combination treatment with FIP-gts and chloroquine on cytotoxicity to resensitize the cisplatin-resistant cells. METHODS: FIP-gts and chloroquine cytotoxicity were determined by evaluating CCK-8 assay. Cell death pathways, ROS and cell cycle arrested were analysed through flow cytometry and Western blot. ShRNA targeting to autophagy-related genes were tested to evaluate their autophagic cell death for resistant urothelial cells. RESULTS: Using CCK-8 assay, chloroquine increased FIP-gts-induced cytotoxicity in parental and cisplatin-resistant urothelial cancer cell lines. On flow cytometry, chloroquine enhanced FIP-gts-mediated sub-G1 accumulation, annexin V positive signal and mitochondrial membrane potential loss. Caspase-3/PARP cascade and z-VAD-fmk were performed to prove that FIP-gts and chloroquine induced caspase-independent cell death. Using H2DCFDA staining and flow cytometry, FIP-gts and chloroquine did not induce ROS production. N-acetyl cysteine, a ROS scavenger, inhibited the cytotoxicity and LC3-II accumulation in FIP-gts and chloroquine-treated N/P cells. To elucidate the role of autophagy in caspase-independent cell death by FIP-gts and chloroquine, LC3 shRNA were used to inhibit autophagy in N/P cells. The capabilities of FIP-gts and chloroquine to induce cytotoxicity and sub-G1 phase accumulation were abolished in autophagy-defective cells. This is the first study to reveal the novel function of FIP-gts in triggering caspase-independent cell death in cisplatin-resistant urothelial cancer cells. CONCLUSION: Chloroquine enhanced FIP-gts-induced autophagy dependent caspase-independent cell death via abundant autophagosome accumulation. Combination treatment with FIP-gts and chloroquine may provide a new strategy for urothelial cancer therapy.
26555695 Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing 2015 Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.
25888644 General Approach for Tetramer-Based Identification of Autoantigen-Reactive B Cells: Charac 2015 May 15 Autoreactive B cells are associated with the development of several autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. The low frequency of these cells represents a major barrier to their analysis. Ag tetramers prepared from linear epitopes represent a promising strategy for the identification of small subsets of Ag-reactive immune cells. This is challenging given the requirement for identification and validation of linear epitopes and the complexity of autoantibody responses, including the broad spectrum of autoantibody specificities and the contribution of isotype to pathogenicity. Therefore, we tested a two-tiered peptide microarray approach, coupled with epitope mapping of known autoantigens, to identify and characterize autoepitopes using the BXD2 autoimmune mouse model. Microarray results were verified through comparison with established age-associated profiles of autoantigen specificities and autoantibody class switching in BXD2 and control (C57BL/6) mice and high-throughput ELISA and ELISPOT analyses of synthetic peptides. Tetramers were prepared from two linear peptides derived from two RNA-binding proteins (RBPs): lupus La and 70-kDa U1 small nuclear ribonucleoprotein. Flow cytometric analysis of tetramer-reactive B cell subsets revealed a significantly higher frequency and greater numbers of RBP-reactive marginal zone precursor, transitional T3, and PDL-2(+)CD80(+) memory B cells, with significantly elevated CD69 and CD86 observed in RBP(+) marginal zone precursor B cells in the spleens of BXD2 mice compared with C57BL/6 mice, suggesting a regulatory defect. This study establishes a feasible strategy for the characterization of autoantigen-specific B cell subsets in different models of autoimmunity and, potentially, in humans.
25416720 Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc. 2015 Jun OBJECTIVE: The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version. METHODS: A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that 'grey' literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus. RESULTS: Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a lay-understandable wording and in the format of checklist questions was developed. An example is SOC 5: "People with OA should achieve optimal pain control using pharmacological and non-pharmacological means." The matching patient-centred checklist question reads: "Do I know how to control pain associated with OA?" CONCLUSIONS: The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe.
25104173 Elevated risk for autoimmune disorders in iraq and afghanistan veterans with posttraumatic 2015 Feb 15 BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with endocrine and immune abnormalities that could increase risk for autoimmune disorders. However, little is known about the risk for autoimmune disorders among individuals with PTSD. METHODS: We conducted a retrospective cohort study of 666,269 Iraq and Afghanistan veterans under age 55 who were enrolled in the Department of Veterans Affairs health care system between October 7, 2001, and March 31, 2011. Generalized linear models were used to examine if PTSD, other psychiatric disorders, and military sexual trauma exposure increased risk for autoimmune disorders, including thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus, adjusting for age, gender, race, and primary care visits. RESULTS: PTSD was diagnosed in 203,766 veterans (30.6%), and psychiatric disorders other than PTSD were diagnosed in an additional 129,704 veterans (19.5%). Veterans diagnosed with PTSD had significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared with veterans with no psychiatric diagnoses (ARR = 2.00; 95% confidence interval, 1.91-2.09) and compared with veterans diagnosed with psychiatric disorders other than PTSD (ARR = 1.51; 95% confidence interval, 1.43-1.59; p < .001). The magnitude of the PTSD-related increase in risk for autoimmune disorders was similar in women and men, and military sexual trauma exposure was independently associated with increased risk in both women and men. CONCLUSIONS: Trauma exposure and PTSD may increase risk for autoimmune disorders. Altered immune function, lifestyle factors, or shared etiology may underlie this association.
27621203 Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensio 2016 Dec Traditional in vitro human liver cell culture models lose key hepatic functions such as metabolic activity during short-term culture. Advanced three-dimensional (3D) liver coculture platforms offer the potential for extended hepatocyte functionality and allow for the study of more complex biologic interactions, which can improve and refine human drug safety evaluations. Here, we use a perfusion flow 3D microreactor platform for the coculture of cryopreserved primary human hepatocytes and Kupffer cells to study the regulation of cytochrome P450 3A4 isoform (CYP3A4) activity by chronic interleukin 6 (IL-6)-mediated inflammation over 2 weeks. Hepatocyte cultures remained stable over 2 weeks, with consistent albumin production and basal IL-6 levels. Direct IL-6 stimulation that mimics an inflammatory state induced a dose-dependent suppression of CYP3A4 activity, an increase in C-reactive protein (CRP) secretion, and a decrease in shed soluble interleukin-6 receptor (IL-6R) levels, indicating expected hepatic IL-6 bioactivity. Tocilizumab, an anti-IL-6R monoclonal antibody used to treat rheumatoid arthritis, has been demonstrated clinically to impact small molecule drug pharmacokinetics by modulating cytochrome P450 enzyme activities, an effect not observed in traditional hepatic cultures. We have now recapitulated the clinical observation in a 3D bioreactor system. Tocilizumab was shown to desuppress CYP3A4 activity while reducing the CRP concentration after 72 hours in the continued presence of IL-6. This change in CYP3A4 activity decreased the half-life and area under the curve up to the last measurable concentration (AUC(last)) of the small molecule CYP3A4 substrate simvastatin hydroxy acid, measured before and after tocilizumab treatment. We conclude that next-generation in vitro liver culture platforms are well suited for these types of long-term treatment studies and show promise for improved drug safety assessment.
27629486 Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical di 2016 Sep 14 Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. IL-6-induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6-stimulated CD4(+) T cells from patients revealed previously unreported IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due, in part, to an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6-targeted therapeutic intervention such as the one that is being currently tested (NCT02293837).
27288918 Sanguiin H-6, a constituent of Rubus parvifolius L., inhibits receptor activator of nuclea 2016 Jul 15 BACKGROUND: Osteoclasts are multinucleated bone-resorbing cells that differentiate in response to receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). Enhanced osteoclastogenesis contributes to bone diseases, such as osteoporosis and rheumatoid arthritis. Rubus parvifolius L. is traditionally used as an herbal medicine for rheumatism; however, its detailed chemical composition and the molecular mechanisms responsible for its biological action have not been elucidated. PURPOSE: To investigate the mechanisms by which R. parvifolius L. extract and its major constituent sanguiin H-6, inhibit osteoclastogenesis and bone resorption. METHODS: Cell proliferation, cell differentiation, and bone resorption were detected in vitro. Inhibition of signaling pathways, marker protein expression, and protein nuclear translocation were evaluated by western blot analysis. Tumor necrosis factor-α (TNF-α)-mediated osteoclastogenesis was examined in vivo. RESULTS: R. parvifolius L. extract inhibited the bone-resorption activity of osteoclasts. In addition, sanguiin H-6 markedly inhibited RANKL-induced osteoclast differentiation and bone resorption, reduced reactive oxygen species production, and inhibited the phosphorylation of inhibitor of NF-κB alpha (IκBα) and p38 mitogen-activated protein kinase. Sanguiin H-6 also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), cathepsin K, and c-Src. Moreover, sanguiin H-6 inhibited the nuclear translocation of NFATc1, c-Fos, and NF-κB in vitro, as well as TNF-α-mediated osteoclastogenesis in vivo. CONCLUSIONS: Our data revealed that R. parvifolius L. has anti-bone resorption activity and suggest that its constituent, sanguiin H-6, can potentially be used for the prevention and treatment of bone diseases associated with excessive osteoclast formation and subsequent bone destruction.
27183574 IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Redu 2016 Jun 15 Osteoarthritis (OA) is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. These degenerative changes are further aggravated by proinflammatory cytokines including IL-1β and TNF-α. Previously, we have reported that IL-3, a cytokine secreted by activated T cells, protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis. However, how IL-3 protects cartilage degeneration is not yet known. In this study, we investigated the role of IL-3 on cartilage degeneration under both in vitro and in vivo conditions. We found that both mouse and human chondrocytes show strong expression of IL-3R at gene and protein levels. IL-3 increases the expression of mouse chondrocyte-specific genes, Sox9 and collagen type IIa, which were downregulated by IL-1β. Moreover, IL-3 downregulated IL-1β- and TNF-α-induced expression of matrix metalloproteinases in both mouse and human chondrocytes. Interestingly, IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in a mouse model of human OA. Moreover, IL-3 showed the preventive and therapeutic effects on cartilage degeneration induced by IL-1β in micromass pellet cultures of human mesenchymal stem cells. Thus, to our knowledge, we provide the first evidence that IL-3 has therapeutic potential in amelioration of degeneration of articular cartilage and subchondral bone microarchitecture associated with OA.
27039969 Cancer Recurrence Following Immune-Suppressive Therapies in Patients With Immune-Mediated 2016 Jul BACKGROUND & AIMS: Physicians frequently encounter patients with immune-mediated diseases and a history of malignancy. There are limited data on the safety of immunosuppressive therapy for these patients. Published studies have been small with few events, precluding robust estimates of risk. METHODS: We searched Medline, EMBASE, and conference proceedings for terms related to immune-mediated disease, immune-suppressive therapy, and cancer recurrence from inception to April 2015. We included 16 studies (9 of patients with rheumatoid arthritis, 8 of patients with inflammatory bowel disease, and 1 of patients with psoriasis) and stratified studies by type of immune-suppressive therapy (monoclonal antibodies to tumor necrosis factor [anti-TNF], conventional immune-modulatory agents, or no immune suppression). A random-effects meta-analysis was performed to calculate the pooled incidence rates as well as risk differences between the various treatments. RESULTS: Our analysis included 11,702 persons contributing 31,258 person-years (p-y) of follow-up evaluation after a prior diagnosis of cancer. Rates of cancer recurrence were similar among individuals receiving anti-TNF therapy (33.8 per 1000 p-y), immune-modulator therapy (36.2 per 1000 p-y), or no immunosuppression (37.5 per 1000 p-y), but were numerically higher among patients receiving combination immune suppression (54.5 per 1000 p-y) (P > .1 for all). Subgroup analysis of new and recurrent cancers separately, type of immune-modulator therapy, or immune-mediated disease showed similar results, with no increase in risk. We found similar pooled incidence values for new or primary cancers when immunosuppression was initiated within 6 years (33.6 per 1000 p-y for immune-modulatory agents and 43.7 per 1000 p-y for anti-TNF agents) vs more than 6 years after the index cancer (32.9 per 1000 p-y for immune-modulatory agents, P = .86; and 21.0 per 1000 p-y for anti-TNF agents, P = .43). CONCLUSIONS: In a meta-analysis of 16 studies, we observed similar rates of cancer recurrence among individuals with prior cancer who received no immunosuppression, anti-TNF therapy, immune-modulator therapy, or combination treatments. Prospective studies are needed to ascertain optimal intervals for re-initiation of immune-suppressive therapies for individuals with specific cancers.
26968919 Salivary proteomics: A new adjuvant approach to the early diagnosis of familial juvenile s 2016 Apr Systemic lupus erythematosus (SLE) is a chronic multisystemic disease characterized by autoimmune inflammatory disturbance. Pleomorphic manifestations are present and a potentially progressive and debilitating course can be detected. SLE rarely manifests before age 5, and its onset peaks is around puberty. Although clinical manifestations, immunological alterations and treatment do not differ between juvenile and adult SLE, children tend to present with a more aggressive disease course than adults. Hence, autoimmune rheumatic diseases are the most common cause of morbidity and mortality in pediatric populations. Blood serum analysis plays an especially important role in the detection and monitoring of autoantibodies in SLE. However, since blood sampling is an uncomfortable procedure, especially in children, novel less invasive techniques and approaches are of utmost importance to evaluate pediatric subjects. In this regard, saliva samples have several advantages, such as: easy access, fast collection, painless and riskless procedure. Saliva has antimicrobial, immunomodulatory and anti-inflammatory properties, as well as several other relevant features. The whole saliva is a complex mixture of major and minor salivary gland secretion, gingival crevicular fluid, transudates plasma protein, keratinocyte products and oral microbiota. This biological fluid reflects the physiological state of the body, including the emotional condition, and endocrine, nutritional and metabolic changes. Therefore, salivary proteomics is becoming increasingly used for the early diagnosis of several diseases such as breast cancer, oral cancer, Sjögren's syndrome, diffuse systemic sclerosis, rheumatoid arthritis, among others. Considering the detection of some potential markers related to SLE in serum and urine, this study aims to conduct an initial evaluation of the possible presence of such biomarkers in saliva. Furthermore, it is expected to track down new salivary proteins that could be correlated with the disease. As such, it is important to evaluate whether the analysis of the salivary proteome of children whose mothers have SLE may help identify biomarkers for the early detection and monitoring of the condition.
26792199 Predictors of outcomes and hospital charges following atlantoaxial fusion. 2016 May BACKGROUND CONTEXT: Atlantoaxial fusion is used to correct atlantoaxial instability that is often secondary to traumatic fractures, Down syndrome, or rheumatoid arthritis. The effect of age and comorbidities on outcomes following atlantoaxial fusion is unknown. PURPOSE: This study aimed to better understand trends and predictors of outcomes and charges following atlantoaxial fusion and to identify confounding variables that should be included in future prospective studies. STUDY DESIGN: A retrospective analysis of data from the Nationwide Inpatient Sample (NIS), a nationally representative, all-payer database of inpatient diagnoses and procedures in the United States. PATIENT SAMPLE: We included all patients who underwent atlantoaxial fusion (International Classification of Disease, Ninth Revision, Clinical Modification code 81.01) between 1998 and 2011 who were 18 years or older at the time of admission. OUTCOME MEASURES: Outcome measures included in-hospital charges, hospital length of stay (LOS), in-hospital mortality, and discharge disposition. METHODS: Predictors of outcome following atlantoaxial fusion were assessed using a series of univariable analyses. Those predictors with a p-value of less than .2 were included in the final multivariable models. Independent predictors of outcome were those that were significant at an alpha level of 0.05 following inclusion in the final multivariable models. Logistic regression was used to determine predictors of in-hospital mortality and discharge disposition whereas linear regression was used to determine predictors of hospital charges and LOS. Discharge weights were used to produce generalizable results. RESULTS: From 1998 to 2011, there were 8,914 hospitalizations recorded wherein atlantoaxial fusion was performed during the inpatient hospital stay. Of these hospitalizations, 8,189 (91.9%) met inclusion criteria. Of the study sample, 62% was white, and the majority of patients were either insured by Medicare (47.2%) or had private health insurance (35.6%). The most common comorbidity as defined by the NIS and the Elixhauser comorbidity index was hypertension (43.2%). The in-hospital mortality rate for the study population was 2.7%, and the median LOS was 6.0 days. The median total charge (inflation adjusted) per hospitalization was $73,561. Of the patients, 48.9% were discharged to home. Significant predictors of in-hospital mortality included increased age, emergent or urgent admissions, weekend admissions, congestive heart failure, coagulopathy, depression, electrolyte disorder, metastatic cancer, neurologic disorder, paralysis, and non-bleeding peptic ulcer. Many of these variables were also found to be predictors of LOS, hospital charges, and discharge disposition. CONCLUSION: This study found that older patients and those with greater comorbidity burden had greater odds of postoperative mortality and were being discharged to another care facility, had longer hospital LOS, and incurred greater hospital charges following atlantoaxial fusion.
26732631 Evaluation of the effects of active fractions of chinese medicine formulas on IL-1β, IL-6 2016 Feb 17 ETHNOPHARMACOLOGICAL RELEVANCE: Yaotongning (YTN) is a traditional Chinese Medicine (TCM) that contains ten component medicinal materials (CMMs) and uses Chinese rice wine as a vehicle to enhance its efficacy. YTN has been used for rheumatoid arthritis (RA) treatment in China for decades and has been reported to have anti-inflammatory and analgesic effects, as well as to strengthen the immune system. AIM OF THE STUDY: The present work quantitatively evaluated the in vitro effects of active fractions from the ten CMMs that make up YTN and eight additional herbs commonly used in TCM formulas for RA treatment, as well as different combinations of these active fractions, on cellular immune response; the findings were used to determine which active fractions are responsible for promoting an immune response, and to assess whether YTN is superior to other similar formulas and whether YTN can be improved by simplifying its formula from the point of its cellular immunomodulatory activity. MATERIALS AND METHODS: Using the YTN formulation principles and some concepts in combinatorial chemistry, 27 TCM samples were designed by combining some or all of the active fractions of YTN and other eight herbs used for RA treatment. Release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) from ANA-1 murine macrophages was measured using an enzyme-linked immunosorbent assay (ELISA). The immunoregulatory effects of the TCM samples were evaluated by comparing their half-effective concentrations (EC50) for stimulating the release of these cytokines. RESULTS: Among the investigated active fractions, the flavonoids from Carthamus tinctorius (Fct), Davallia mariesii (Fdm), and Cinnamomum cassia Twig volatile oils (Vca) from the eight selected herbs effectively promoted IL-1β and IL-6 release from ANA-1 cells. Saponins from the YTN CMM Glycyrrhiza uralensis (Sgu) were the most potent promoters of IL-1β and TNF-α release. The aqueous extract of YTN CMM Eupolyphaga sinensis (Ves) strongly enhanced the release of IL-1β, IL-6, and TNF-α from ANA-1 cells. The EC50 values for stimulating the secretion of IL-1β, IL-6, and TNF-α could be determined for only six samples. The full YTN formula and the sample containing 50% Glycyrrhiza uralensis saponins, 25% of the mixture of alkaloids, and 25% of the mixture of all flavonoids exhibited good comprehensive cellular immunomodulatory activity. The immunomodulatory activity of the complete YTN formula was better than that of the sample containing all active fractions of YTN without Chinese rice wine (the YTN vehicle). CONCLUSIONS: Sgu and Ves are the primary active fractions of YTN involved in stimulating immune responses. The YTN prescription was reasonably effective at promoting cellular immune responses. Chinese rice wine, the YTN vehicle, strengthened the immunoregulatory activity of YTN. The results of this study demonstrate that the YTN recipe could be improved by reducing the number of CMMs and altering some active fractions without reducing its activity to promote cellular immune responses.
26683155 Negative regulation of TLR signaling in myeloid cells--implications for autoimmune disease 2016 Jan Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment.
26475926 TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased 2015 Nov 15 TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein-specific 2D2 TCR transgenic mice. Disease in TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein-specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to TNFR2(-/-) 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.
26032265 Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibilit 2015 Jul Low-affinity Fcγ receptors (FcγR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcγR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcγR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcγR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcγR. In a two-stage study, we analyzed whether the FcγR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcγR genes affect FcγR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcγR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcγR genotype association patterns, pointing towards different disease etiologies.
25887667 Early postoperative mortality after simultaneous or staged bilateral primary total hip art 2015 Apr 8 BACKGROUND: Approximately a fifth of all total hip arthroplasty (THA) patients suffers from bilateral osteoarthritis of the hip. It is unclear whether mortality risks differ between simultaneous bilateral THA and staged bilateral THA. We investigated mortality after simultaneous THA compared with staged bilateral THA in the largest cohort hitherto reported. METHODS: The 42,238 patients reported to have received bilateral primary THA from 1992 to 2012 in the Swedish Hip Arthroplasty Register were included. Tumours and fractures as underlying diagnoses were excluded. The time interval between the first and second THA was divided into four categories or treated as a continuous variable. Unadjusted survival was calculated according to Kaplan-Meier and adjusted Cox regression models were fitted in order to calculate crude and adjusted hazard ratios (HR) for the risk of death within different time frames. RESULTS: Patients selected for simultaneous bilateral surgery were younger, more often male, and had lower ASA (American Society of Anesthesiologists) class than patients receiving staged procedures. The adjusted 90-day mortality after the second procedure did not differ between the four investigated groups (simultaneous bilateral [HR 1.3, CI 0.5-3.3], surgeries within 6 months [HR 1.1, CI 0.6-2.0], surgeries between 7 and 12 months [HR 0.7, CI 0.4-1.2], with second surgery after >12 months as the reference group). For patients older than 75 years, men, patients with ASA class 3 or above, and for patients with rheumatoid arthritis (RA) the 90-day mortality was increased. The unadjusted risk of implant revision of any hip was slightly higher for patients with simultaneous bilateral THA compared to those with staged procedure within one year, but after adjustment for age, gender, diagnosis and implant fixation these differences were no longer statistically significant. CONCLUSION: There were no clinically relevant differences in early postoperative mortality between simultaneous and staged bilateral surgery in healthy patients. Advanced age, RA, a high ASA class and male sex increased the risk of death within 90 days. There may be an issue with enhanced risk of implant revision in patients with simultaneous bilateral THA that needs to be explored further.
25512478 Elevated serum levels of syndecan-1 are associated with renal involvement in patients with 2015 Feb OBJECTIVE: Syndecan-1 (SDC-1) is a major constituent of the endothelial glycocalyx, which plays a role in maintaining vascular homeostasis and functions as a glomerular filtration barrier. SDC-1 is readily shed into the blood under various conditions, but the clinical implication of circulating SDC-1 in patients with systemic lupus erythematosus (SLE) remains unclear. We aimed to investigate the association of serum SDC-1 level with certain clinical manifestations of SLE. METHODS: We measured serum SDC-1 levels by ELISA in 111 patients with SLE, 18 with rheumatoid arthritis (RA), and 20 healthy subjects, and investigated its association with clinical manifestations and laboratory variables. RESULTS: Serum SDC-1 levels were higher in patients with SLE than in those with RA and healthy controls (both p < 0.001) and were positively correlated with SLE Disease Activity Index (SLEDAI; r = 0.367, p < 0.001) and anti-dsDNA antibody level (r = 0.259, p = 0.007), but inversely correlated with serum C3 and CH50 levels (r = -0.305, p = 0.001 and r = -0.244, p = 0.012). Patients with active nephritis had higher serum SDC-1 levels than patients with inactive nephritis and those without nephritis (both p < 0.001). In addition, serum SDC-1 levels were correlated with renal SLEDAI score (r = 0.540, p < 0.001) and excretion of proteinuria as measured by spot urine protein/creatinine ratio (r = 0.538, p < 0.001). In 14 patients with lupus nephritis (LN) whose serum samples were obtained at the time of renal biopsy, there was a positive correlation between serum SDC-1 levels and activity index (r = 0.632, p = 0.015). CONCLUSION: Serum SDC-1 levels are increased in SLE patients with nephritis, indicating that SDC-1 might be a useful serum biomarker for active LN.
27909085 A Negative Antinuclear Antibody Does Not Indicate Autoantibody Negativity in Myositis: Rol 2017 Feb OBJECTIVE: To evaluate the utility of anticytoplasmic autoantibody (anti-CytAb) in antisynthetase antibody-positive (anti-SynAb+) patients. METHODS: Anti-SynAb+ patients were evaluated for antinuclear antibody (ANA) and anti-CytAb [cytoplasmic staining on indirect immunofluorescence (IIF)] positivity. Anti-SynAb+ patients included those possessing anti-Jo1 and other antisynthetase autoantibodies. Control groups included scleroderma, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and healthy subjects. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy of anti-CytAb, and ANA were assessed. Anti-CytAb and ANA testing was done by IIF on human epithelial cell line 2, both reported on each serum sample without knowledge of the clinical diagnosis or final anti-SynAb results. RESULTS: Anti-SynAb+ patients (n = 202; Jo1, n = 122; non-Jo1, n = 80) between 1985-2013 with available serum samples were assessed. Anti-CytAb showed high sensitivity (72%), specificity (89%), NPV (95%), and accuracy (86%), but only modest PPV (54%) for anti-SynAb positivity. In contrast, ANA showed only modest sensitivity (50%) and poor specificity (6%), PPV (9%), NPV (41%), and accuracy (12%). Positive anti-CytAb was significantly greater in the anti-SynAb+ patients than ANA positivity (72% vs 50%, p < 0.001), and 81/99 (82%) ANA-negative patients in the anti-SynAb+ cohort had positive anti-CytAb. In contrast, the control groups showed high rates for ANA positivity (93.5%), but very low rates for anti-CytAb positivity (11.5%). Combining anti-CytAb or Jo1 positivity showed high sensitivity (92%) and specificity (89%) for identification of anti-SynAb+ patients. CONCLUSION: Assessing patients for anti-CytAb serves as an excellent screen for anti-SynAb+ patients using simple IIF. Cytoplasmic staining should be assessed and reported for patients suspected of having antisynthetase syndrome and a negative ANA should not be used to exclude this diagnosis.