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ID PMID Title PublicationDate abstract
21235539 Engagement of activated Notch signalling in collagen II-specific T helper type 1 (Th1)- an 2011 Apr Our previous study demonstrated that T helper (Th) cells from patients with rheumatoid arthritis (RA) display an altered expression profile of Notch receptors and enhanced activation of Notch signalling. The aim of this study was to investigate the role of distinct Notch receptors and ligands in the activation and differentiation of collagen II (CII)-reactive Th cells upon antigen-specific restimulation. Spleen mononuclear cells (SMNCs) from CII-immunized DBA/1J mice were restimulated by culturing with CII. CII-specific proliferation and differentiation of T cells were determined by tritiated thymidine ((3) [H]-TdR) incorporation and flow cytometric analysis, respectively. The mRNA expression of Notch receptors and Hes1 was assessed by real-time polymerase chain reaction (PCR). There was a clear increase in the percentage of Th1 cells and Th17 cells after CII restimulation. No significant difference was observed in the percentage of regulation T cells (T(reg) ) in SMNCs with or without CII restimulation. CII restimulation induced up-regulated transcript levels of Hes1 in CII-reactive CD4(+) T cells. The mRNA level of Notch3 was also up-regulated significantly, while the levels of the other three Notch receptors were not increased. Inhibition of Notch signalling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and Notch3 antibody decreased the collagen-specific T cell proliferation and attenuated Th1- and Th17-type responses, while treatment with Notch ligand Delta-like 1 promoted such a response. The present study demonstrates that Notch signalling is engaged in CII-specific Th1- and Th17-type expansion in which Notch3 and Delta-like1 were involved. Selective inhibition of Notch signalling mediated by Notch3 or Delta-like1 may offer a new strategy for the treatment of RA.
20683884 ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. 2011 Jan ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.
27027055 RESULTS FROM BI-CONTACT(®) TOTAL ELBOW ARTHROPLASTY: MULTICENTER STUDY. 2011 Sep OBJECTIVE: To describe the initial experience of four orthopedic clinics from using Bi-Contact(®) total elbow arthroplasty (TEA), reporting the results and complications of the procedure. METHODS: This was a retrospective study, through analysis on the medical records of patients who underwent primary TEA using a prosthesis model developed in conjunction with IOT-HCFMUSP. Forty-six elbows (45 patients) that were operated at four orthopedic clinics between 2000 and 2009 were evaluated. RESULTS: The majority of the patients were female (74%), and the median age was 62.5 years. The diagnoses encountered were trauma sequelae (47.83%), rheumatoid arthritis (32.61%), primary osteoarthrosis (8.7%), acute fractures (6.52%) and heterotopic ossification (2.17%). The median length of follow-up was 2.08 years (0.25-9). The procedure significantly alleviated pain and improved range of motion. It was observed that at least one complication was present in 69.57% of the cases, and the main ones were infection (28.26%), need for revision (28.26%), intraoperative fracture (15.22%) and aseptic loosening (15.22%). CONCLUSION: Bi-Contact(®) TEA provided significant alleviation of pain and improvement of range of motion in the present series. The complication rate was high, and the most frequently observed complications were infection, aseptic loosening and intraoperative fracture.
21273443 Research resource: Comparative nuclear receptor atlas: basal and activated peritoneal B-1 2011 Mar Naïve murine B cells are typically divided into three subsets based on functional and phenotypic characteristics: innate-like B-1 and marginal zone B cells vs. adaptive B-2 cells, also known as follicular or conventional B cells. B-1 cells, the innate-immune-like component of the B cell lineage are the primary source of natural antibodies and have been shown to modulate autoimmune diseases, human B-cell leukemias, and inflammatory disorders such as atherosclerosis. On the other hand, B-2 cells are the principal mediators of the adaptive humoral immune response and represent an important pharmacological target for various conditions including rheumatoid arthritis, lupus erythematosus, and lymphomas. Using the resources of the Nuclear Receptor Signaling Atlas program, we used quantitative real-time PCR to assess the complement of the 49 murine nuclear receptor superfamily expressed in quiescent and toll-like receptor (TLR)-stimulated peritoneal B-1 and B-2 cells. We report the expression of 24 nuclear receptors in basal B-1 cells and 25 nuclear receptors in basal B-2 cells, with, in some cases, dramatic changes in response to TLR 4 or TLR 2/1 stimulation. Comparative nuclear receptor profiling between B-1 and peritoneal B-2 cells reveals a highly concordant expression pattern, albeit at quantitatively dissimilar levels. We also found that splenic B cells express 23 nuclear receptors. This catalog of nuclear receptor expression in B-1 and B-2 cells provides data to be used to better understand the specific roles of nuclear receptors in B cell function, chronic inflammation, and autoimmune disease.
23183108 Anti-inflammatory effect and selectivity profile of AS1940477, a novel and potent p38 mito 2013 Jan 5 Given the key role p38 mitogen-activated protein kinase (MAPK) plays in inflammatory responses through the production of cytokines and inflammatory mediators, its inhibition is considered a promising therapeutic strategy for chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. Here, we evaluated the anti-inflammatory effect and selectivity profile of the novel p38 MAPK inhibitor AS1940477. AS1940477 inhibited the enzymatic activity of recombinant p38α and β isoforms but showed no effect against other 100 protein kinases including p38γ and δ isoforms. We also confirmed the selectivity of AS1940477 in the intracellular signaling pathway. In human peripheral blood mononuclear cells, AS1940477 inhibited lipopolysaccharide (LPS)- or phytohemagglutinin A (PHA)-induced production of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 at low concentrations (LPS/TNFα, IC(50)=0.45n M; PHA/TNFα, IC(50)=0.40 nM). In addition, equivalent concentrations of AS1940477 that inhibited cytokine production also inhibited TNFα- and IL-1 β-induced production of IL-6, PGE(2), and MMP-3 in human synovial stromal cells. AS1940477 was also found to potently inhibit TNF production in whole blood (IC(50)=12 nM) and effectively inhibited TNFα production induced by systemically administered LPS in rats at less than 0.1mg/kg (ED(50)=0.053 mg/kg) with an anti-inflammatory effect lasting for 20h after oral administration. Overall, this study demonstrated that AS1940477 is a novel and potent p38 MAPK inhibitor and may be useful as a promising anti-inflammatory agent for treating inflammatory disorders.
22796382 The stimulation of adenosine 2A receptor reduces inflammatory response in mouse articular 2012 Jul The adenosine 2A receptor (A(2A)R) is greatly involved in inflammation pathologies such as rheumatoid arthritis. By interacting with A(2A)R, the purine nucleoside adenosine acts as a potent endogenous inhibitor of the inflammatory process in a variety of tissues. Hyaluronan (HA) fragments act to prime inflammation via CD44 and the toll-like receptor 4 (TLR-4). The aim of this study was to investigate whether the inhibition/stimulation of A(2A)R modulates the inflammation cascade primed by small HA fragments in mouse articular chondrocytes. 6-mer HA treatment induced up-regulation of CD44, TLR4 and A(2A)R mRNA expression and the related protein levels, and NF-kB activation, that in turn increased TNF-α, IL-1β, and IL-6 and production. Treatment with a selective (2)A adenosine receptor agonist (2-phenylaminoadenosine) enhanced A(2A)R increase, as well as the inhibition of CD44 and TLR4 activity using two specific antibodies abolished up-regulation of CD44 and TLR4, and significantly reduced, especially by antibody inhibition, NF-kB activation and pro-inflammatory cytokine production. Furthermore, the exposure of chondrocytes to A(2A)R specific interference mRNA (A(2A)R siRNA) enhanced HA 6-mer induced NF-kB activation and inflammatory cytokine increase. Finally, the use of an exchange protein activated by cAMP (EPAC) siRNA and a specific PKA inhibitor showed a predominant EPAC involvement in the mediation of the anti-inflammatory activity exerted by A(2A)R stimulation. These data suggest that HA depolymerization occurring during inflammation contributes to priming of the inflammatory cascade, while endogenous adenosine, by exerting anti-inflammatory response via A(2A)R, could be a modulatory mechanism that attempts to attenuate the inflammation process.
22719926 Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory s 2012 The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.
22677813 Comparison of toxicokinetic and tissue distribution of triptolide-loaded solid lipid nanop 2012 Nov 20 The traditional Chinese medicine Tripterygium wilfordii Hook F (TWHF) is used clinically to treat some autoimmune and inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and skin diseases. However TWHF has a high potential for toxicity, so its clinical use is limited. Solid lipid nanoparticle (SLN) delivery systems are reported to have remarkable advantages over conventional formulations of bioactive plant extracts, such as enhancing solubility and bioavailability, offering protection from toxicity, and enhancing pharmacological activity. We reported previously that a tripterygium glycoside (TG) solid lipid nanoparticle (TG-SLN) delivery system had a protective effect against TG-induced male reproductive toxicity. To better understand this issue, we used triptolide (TP) as a model drug in a comparative study of the toxicokinetic and tissue distribution of TP-SLN and free TP in rats, allowing us to observing the in vivo behavior of this nanoformulation and to assess mechanisms of SLN-related toxicity. A fast and sensitive HPLC-APCI-MS/MS method was developed for the determination of triptolide in rat plasma. Fourteen rats were divided randomly into two groups of 7 rats each for toxicokinetic analysis, with one group receiving free TP (450μg/kg) and the other receiving the TP-SLN formulation (450μg/kg). Blood was obtained before dosing and 0.083, 0.17, 0.25, 0.33, 0.5, 0.75, 1, 1.5, 2, 3 and 4h after drug administration. Thirty-six rats were divided randomly into six equal groups for a tissue-distribution study. Half of the rats received intragastric administration of TP (450μg/kg) and the other half received TP-SLN (450μg/kg). At 15, 45, and 90min after dosing, samples of blood, liver, kidney, spleen, lung, and testicular tissue were taken. TP concentration in the samples was determined by LC-APCI-MS-MS. The toxicokinetic results for the nanoformulation showed a significant increase the area under the curve (AUC) (P<0.05), significantly longer T(max) and mean retention times (MRTs) (0-t) (P<0.05), significantly decreased C(max) (P<0.05). The nanoformulation promoted absorption with a slow release character, indicating that toxicokinetic changes may be the most important mechanism for the enhanced efficacy of nanoformulations. Tissue-distribution results suggest a tendency for TP concentrations in the lung and spleen to increase, while TP concentrations in plasma, liver, kidney, and testes tended to decrease in the TP-SLN group. At multiple time points, testicular tissue TP concentrations were lower in the TP-SLN group than in free TP group. This provides an important clue for the decreased reproductive toxicity observed with TP-SLN.
22097138 [Clinical study on the prevention of heterotopic ossification after total hip arthroplasty 2011 Oct OBJECTIVE: To explore the therapeutic effects of Xiaozhong Zhitong mixture preventing heterotopic ossification (HO) after total hip arthroplasty. METHODS: From July 2006 to October 2009, 154 patients underwent total hip replacement surgery were randomly divided into sham group (group A, 50 cases), indomethacin group (group B, 55 cases) and Xiaozhong Zhitong mixture group (group C, 49 cases). Among 154 patients, 9 cases were primary osteoarthris, 34 cases osteoarthritis secondary to acetabular dysplasia, 98 cases osteoarthritis secondary to avascular necrosis of the femoral head, 2 cases rheumatoid arthritis, 5 cases femoral neck fracture, 6 cases other diseases. Modified Gibson approach was used during the operation. After operation, group A was no preventing treatment, group B was treated by indomethacin 50 mg every time, twice a day; group C was treated by Xiaozhong Zhitong mixture 50 ml every time, twice a day for 4 weeks. Eighteen months after operation was study termination point and X-ray (including the double hip anteroposterior,obturator oblique and iliac oblique film) was used to observe whether heterotopic ossification was formed (Brooker classification was used to evaluate ossification degree); Harris scoring was used to evaluate the function of hip joint,including PAHSS 80 scores and IAHSS 20 scores. RESULTS: All the patients were followed up,with the average of duration of 21.2 months. The condition of heterotopic ossification: for group A,there were 27 cases with heterotopic ossification(54%) ,and Brooker I in 8 cases, II in 9 cases, III in 8 cases and IVin 2 cases; for group B, there were 12 cases heterotopic ossification (21.82%), and Brooker I in 10 cases, II in 2 cases; for group C, there were 11 cases heterotopic ossification(22.45%), and Brooker I in 9 cases, I in 2 cases. There was significant difference among three group in heterotopic ossification by rank test (P<0.05), but no difference between group B and C (P>0.05); there were no significant difference among three groups before treatment in Harris, PAHSS and IAHSS by analysis of variance (one-way ANOVA) (P>0.05), and has significant difference at 18 months after treatment (P<0.01). There were significant difference in Harris, PAHSS and IAHSS before and after treatment at 18 months (P<0.01). LSD-t was used to analyzed the scoring of Harris, PAHSS and IAHSS, there was significant difference among group A and group B and group C (P>0.05), but no difference between group B and C (P<0.01). There were gastrointestinal reaction in 5 of group A, 35 in group B and 4 in group C. CONCLUSION: The effect of Xiaozhong Zhitong mixture on the prevention of heterotopic ossification after total hip arthroplasty is similar to indomethacin, but Xiaozhong Zhitong mixture has the advantages of less side effects and easily acceptance by patients.
21732531 Protein-conjugated acrolein as a biochemical marker of brain infarction. 2011 Sep The relationship between acrolein (CH(2) =CH-CHO) and brain infarction is the focus of this review. It has been found that acrolein is produced mainly within cells from polyamines by polyamine oxidases (PAOs), especially from spermine by spermine oxidase during cell damage, and that acrolein is more toxic than reactive oxygen species (ROS) in a cell culture system. Thus, the possibility that acrolein and PAOs are good biochemical markers of stroke was tested because there are no other reliable biochemical markers at the early stage of stroke. Levels of protein-conjugated acrolein (PC-Acro) and PAOs (acrolein-producing enzymes) were significantly increased in the plasma of stroke patients. The multiplied value of PC-Acro by PAOs was nearly parallel with the size of stroke. Furthermore, when the combined measurements of PC-Acro, interleukin-6 (IL-6) and C-reactive protein (CRP) were evaluated along with age using a receiver operating characteristic (ROC) curve, even silent brain infarction (SBI), which is a small brain infarction, was indicated with approximately 84% sensitivity and specificity. These findings clearly indicate that acrolein is strongly correlated with cell damage during brain infarction.
23006888 Syringomyelia and arachnoid cysts associated with spinal arachnoiditis following subarachn 2012 A 66-year-old woman with primary Sjogren syndrome developed syringomyelia following two episodes of subarachnoid hemorrhage (SAH) due to the rupture of basilar artery aneurysms. Gait disturbance and abnormal sensation with pain over the foot and abdomen appeared 3 years after the last SAH. Magnetic resonance (MR) imaging revealed a syringomyelia throughout the thoracic cord, from the T2 to T11 levels. In addition, the thoracic cord was compressed by multiple arachnoid cysts in the ventral side of spinal cord. Computed tomography myelography revealed complete block of cerebrospinal fluid (CSF) flow at the T7 level. Surgery for microlysis of the adhesions and restoration of the CSF flow pathway was performed. Postoperatively, leg motor function slowly improved and she could walk unaided. However, abdominal paresthesia was persisted. Postoperative MR imaging revealed diminished size of the syrinxes. We should recognize syringomyelia and arachnoid cysts due to adhesive arachnoiditis as a late complication of SAH. Microlysis of the adhesions focusing on the lesion thought to be the cause of the symptoms is one of the choices to treat massive syringomyelia and arachnoid cysts associated with arachnoiditis following SAH.
22056398 Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for inf 2011 Dec 7 CONTEXT: Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. OBJECTIVES: To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. DESIGN, SETTING, AND PATIENTS: Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. MAIN OUTCOME MEASURE: Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens. RESULTS: Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. CONCLUSION: Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.
22801493 TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. 2012 Aug 23 Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
23144628 Informed conditioning on clinical covariates increases power in case-control association s 2012 Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1 × 10(-9)). The improvement varied across diseases with a 16% median increase in χ(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
21815968 Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren's sy 2011 Nov OBJECTIVE: Sjögren's syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. This study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of SS-like disease. METHODS: Female New Zealand Black X New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland-infiltrating cells were characterized by flow cytometry. RESULTS: Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C)-treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates, and these were followed by CD4+ T cells. CONCLUSIONS: Our data clearly demonstrate that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for SS-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of SS.
22302060 IL-7 drives Th1 and Th17 cytokine production in patients with primary SS despite an increa 2012 Jun OBJECTIVE: To study the phenotypic characteristics of and the balance between systemic IL-7 receptor (IL-7R)α+ and IL-7Rα- Tregs in primary SS (pSS) patients as compared with control subjects and to assess the functional consequences this has for (IL-7-induced) T-cell activation. METHODS: The functional properties of IL-7Rα+ and IL-7Rα- (CD25+) CD4 T cells from pSS patients were tested in vitro. Expression of CD25 and FoxP3 by IL-7Rα+ and IL-7Rα- CD4 T cells from pSS patients and healthy controls (HCs) were assessed. Also, the net ex vivo T-cell cytokine production and the capacity of IL-7 to activate total CD4 T cells from pSS patients compared with HCs in vitro was tested. RESULTS: IL-7Rα+ T cells from pSS patients strongly proliferated and their numbers were slightly reduced compared with HCs. This reduced number was caused by an increase in both anergic and suppressive IL-7Rα- CD25+ T cells expressing high levels of FoxP3, but also by increases in IL-7Rα- CD25- CD4 T cells that only moderately expressed FoxP3. This altered balance in IL-7Rα+ and IL-7Rα- CD4 T cells was accompanied by unchanged ex vivo Th1, Th2 and Th17 cytokine production of total CD4 T cells. Furthermore, the increased numbers of IL-7Rα- CD25+ T cells did not prevent specific IL-7-induced Th1 and Th17 cytokine production by IL-7Rα+ T cells. CONCLUSION: IL-7Rα+ cells are highly proliferating cells that respond strongly to IL-7 despite an increased number of IL-7Rα- T cells that express FoxP3 and CD25. The recent finding that IL-7 and IL-7Rα+ T cells were both found to be increased in exocrine glands of pSS patients indicates that IL-7 could contribute to glandular inflammation by activation of IL-7Rα+ responder T cells despite the increased numbers of Tregs.
22836197 Pathophysiological cytokine network in primary Sjögren's syndrome. 2012 Sep The continuing progress in discovering lymphocyte subsets and the lengthening list of cytokines involved, together with how they are affected in primary Sjögren's syndrome (pSS), has further fuelled the debate on pSS pathogenesis. In this review the "interferon signature" observed in the salivary glands and the role of T-cell derived cytokines (Th1/Th2 polarization, Th17 and regulatory T cells) will be discussed. A particular emphasis has been placed on the B-cell derived cytokines and especially on FLT3-Ligand, a cytokine associated with lymphoma in pSS, and B-cell activating factor (BAFF) that prevents apoptosis of autoreactive B cells. It has indeed become a challenge to understand how the interaction between several interconnected networks of cytokines impact so different cell population in the immunopathogenesis of pSS.
21979002 Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands o 2012 Feb OBJECTIVES: In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4(+) T cells and by a subset of mucosal natural killer (NK) cells expressing the receptor NKp44 (NKp44(+) NK cells). The aim of this study was to investigate the IL-22 expression in the salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS: Minor salivary gland biopsies were obtained from 19 patients with pSS and 16 with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-17, IL-22, IL-23 and STAT3 (signal transducer and activator of transcription) was performed on salivary glands from patients and controls. The cellular sources of IL-22 among infiltrating inflammatory cells were also determined by fluorescence-activated cell sorting analysis and immunohistochemistry. RESULTS: IL-22, IL-23 and IL-17 were significantly increased at both protein and mRNA levels in the inflamed salivary glands of patients with pSS. STAT3 mRNA and the tyrosine phosphorylated corresponding protein were also significantly increased in pSS. Th17 and NKp44(+) NK cells were the major cellular sources of IL-22 in patients with pSS. CONCLUSIONS: Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS.
21880134 Constitutive expression of cathepsin K in the human intervertebral disc: new insight into 2011 Aug 31 INTRODUCTION: Cathepsin K is a recently discovered cysteine protease which cleaves the triple helical domains of type I to II collagen. It has been shown to be up-regulated in synovial tissue from osteoarthritic and rheumatoid patients, and is a component in normal and nonarthritic cartilage, where it increases with aging. Studies on heart valve development have recently shown that receptor activator of nuclear factor-κB ligand (RANKL) acts during valve remodeling to promote cathepsin K expression. Since extracellular matrix remodeling is a critical component of disc structure and biomechanical function, we hypothesized that cathepsin K and RANKL may be present in the human intervertebral disc. METHODS: Studies were performed following approval of the authors' Human Subjects Institutional Review Board. Six annulus specimens from healthier Thompson grade I to II discs, and 12 specimens from more degenerate grade III to IV discs were utilized in microarray analysis of RANKL and cathepsin K gene expression. Immunohistochemistry was also performed on 15 additional disc specimens to assess the presence of RANKL and cathepsin K. RESULTS: Cathepsin K gene expression was significantly greater in more degenerated grade III to IV discs compared to healthier grade I to II discs (P = 0.001). RANKL was also identified with immunohistochemistry and molecular analyses. RANKL gene expression was also significantly greater in more degenerated discs compared to healthier ones (P = 0.0001). A significant linear positive correlation was identified between expression of cathepsin K and RANKL (r(2) = 92.2; P < 0.0001). CONCLUSIONS: Extracellular matrix remodeling is a key element of disc biology. Our use of an appropriate antibody and gene expression studies showed that cathepsin K is indeed present in the human intervertebral disc. Immunolocalization and molecular analyses also confirmed that RANKL is present in the human disc. Expression of RANKL was found to be significantly greater in more degenerated compared to healthier discs (P = 0.0001). Cathepsin K gene expression levels showed a positive, significant correlation with RANKL expression. Based on these data, we propose that cathepsin K plays a significant role in disc matrix remodeling and in matrix degradation in the proinflammatory cytokine-rich microenvironment of the degenerating disc.
21877019 [Risk factors for osteoporosis in postmenopausal women from southeast Brazilian]. 2011 Jun PURPOSE: To evaluate bone mineral density (BMD) and their risk factors associated with postmenopausal osteoporosis. METHODS: A cross-sectional clinical study was performed on 431 women (aged 40-75 years). INCLUSION CRITERIA: amenorrhea > 12 months and age > 45 years or, bilateral oophorectomy > 40 years with BMD values (T-score of lumbar spine/femur neck) by DXA of the last 12 months. Risk factors evaluated: age, age and time of menopause, smoking, physical activity (30 min/5 times/week), rheumatoid arthritis (RA), use of corticotherapy and hormone therapy (HT), previous fracture, maternal hip fracture and body mass index (BMI = weight/height²). The χ2 test and the logistic regression method (Odds Ratio--OR) were used to determine osteoporosis risk. RESULTS: According to WHO criteria, 106 (24.6%) women showed osteoporosis (T-score < -2.5 DP), 188 (43.6%) osteopenia (-1.0/-2.4 DP), and 137 (31.8%) were normal (> -1.0 DP). Osteoporosis was detected in 12% of women aged 40-49 years, in 21.8% of women aged 50-59 years and in 45.7% of women aged > 60 years (p < 0.001). Osteoporosis occurred in 11.8% of women with a menopause period < 5 years, in 29.4% with a menopause period from 6 to 10 years, and in 41% of women with a menopause period > 10 years (p < 0.001). Of the women with early menopause, 80% showed osteopenia/osteoporosis (p = 0.03), and of those with BMI < 20 kg/m², 50% were osteoporotic (p < 0.001). The risk for osteoporosis detection increased with age (OR = 1.1; CI 95% = 1.0-1.1), time of menopause (OR = 1.1; CI 95% = 1.0-1.1), smoking (OR = 1.9; CI 95% = 1.2-3.2), RA (OR = 3.6; CI 95% = 1.3-9.6) and maternal fracture history (OR = 2.1; CI 95% = 1.1-3.0) (p < 0.05). In contrast, HT use (OR = 0.3; 95% CI = 0.2-0.6) and high BMI (OR = 0.9; 95% CI = 0.8-0.9) reduced the risk (p < 0.05). CONCLUSION: In postmenopausal women, age, time of menopause, smoking and maternal history of fracture were clinical indicators of risk for osteoporosis, whereas HT use and high BMI proved to be protective factors.