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ID PMID Title PublicationDate abstract
25851594 Drug survival and causes of discontinuation of the first anti-TNF in ankylosing spondyliti 2015 May Treatment survival with biological therapy may be influenced by many factors, and it seems to be different among various rheumatic diseases and biological agents. The goal of the study was to compare the drug survival and the causes of discontinuation of anti-tumoral necrosis factor (anti-TNF) therapy in ankylosing spondylitis (AS) with rheumatoid arthritis (RA). Study participants were a cohort from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (BIOBADABRASIL) between 2008 and 2012. The observation time was up to 4 years following the introduction of the first treatment. Gender, age, disease duration, disease activity, comorbidities, and concomitant therapies were assessed. A total of 1303 patients were included: 372 had AS and 931 had RA in which 38.7 % (n = 504) used infliximab (IFX), 34.9 % (n = 455) used adalimumab (ADA), and 26.4 % (n = 344) used etanercept (ETA). The anti-TNF drug survival of patients with AS was 63.08 months (confidence interval (CI) 60.24, 65.92) and patients with RA was 47.5 months (CI 45.65, 49.36). It was significant higher in AS (log-rank; p ≤ 0.001). Patients with RA discontinued anti-TNF more than patients with AS when adjusted to gender and corticosteroid. The adjHR (95 % CI) was 1.6 (1.14, 2.31). Female patients who were also corticosteroid users, but not of advanced age, have shown lower survival for both diseases (log-rank, p ≤ 0.001). The discontinuation rate of IFX, but not of ADA or ETA, was significantly higher in RA than in SA; HR (95 % CI) was 2.49 (1.46, 4.24). The main causes of discontinuation were ineffectiveness and adverse event in both diseases. AS patients have better drug survival adjusted to gender, age, and corticosteroid. This results appear to be related to the disease mechanism.
25714613 The immune suppressive function of transforming growth factor-β (TGF-β) in human disease 2015 Apr Transforming growth factor-β (TGF-β) functions as an immune suppressor by influencing immune cells' development, differentiation, tolerance induction and homeostasis. In human diseases, TGF-β has been revealed as an essential regulator of both innate and adaptive functions in autoimmune diseases. Furthermore, it plays a significant role in cancer by inhibiting immunosurveillance in the tumor-bearing host. A variety of TGF-β neutralizing anti-cancer therapies have been investigated based on the role of TGF-β in immunosuppression. New studies are focusing on combining TGF-β blockade with tumor vaccinations and immunogene therapies.
27742546 Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic 2016 Oct 18 Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4(+) T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, proinflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11A(low) T cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.
26496968 Successful resumption of tocilizumab for rheumatoid arthritis after resection of a pulmona 2015 Oct 23 BACKGROUND: Biological agents inhibiting TNF-α and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. CASE PRESENTATION: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. CONCLUSION: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.
27966893 Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridi 2017 Feb 15 Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 ((68)Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP(9)) that can coordinate up to three Ga(3+) ions. This derivative has been conjugated to a trimeric peptide (RGD(3)) containing three peptide groups that target the α(v)β(3) integrin receptor. The resulting dendritic compound, HP(9)-RGD(3), can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP(3)-RGD and HP(3)-RGD(3) that contain only a single metal binding site. PET scanning and biodistribution studies show that [(68)Ga(HP(9)-RGD(3))] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress α(v)β(3) integrin than [(68)Ga(HP(3)-RGD)] and [(68)Ga(HP(3)-RGD(3))]. However, concomitant nontarget organ retention of [(68)Ga(HP(9)-RGD(3))] results in low tumor to nontarget organ contrast in PET images. On the other hand, the trimeric peptide homologue containing a single tris(hydroxypyridinone) chelator, [(68)Ga(HP(3)-RGD(3))], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [(68)Ga(HP(3)-RGD(3))] enables clear delineation of α(v)β(3) integrin receptor expression in vivo.
27045607 Complement receptor immunoglobulin: a control point in infection and immunity, inflammatio 2016 The B7 family-related protein, V-set and Ig domain (VSIG4) / Z39Ig / complement receptor immunoglobulin (CRIg), is a new player in the regulation of immunity to infection and inflammation. The unique features of this receptor as compared with classical complement receptors, CR3 and CR4, have heralded the emergence of new concepts in the regulation of innate and adaptive immunity. Its selective expression in tissue macrophages and dendritic cells has been considered of importance in host defence and in maintaining tolerance against self-antigens. Although a major receptor for phagocytosis of complement opsonised bacteria, its array of emerging functions which incorporates the immune suppressive and anti-inflammatory action of the receptor have now been realised. Accumulating evidence from mouse experimental models indicates a potential role for CRIg in protection against bacterial infection and inflammatory diseases, such as rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, and also in promotion of tumour growth. CRIg expression can be considered as a control point in these diseases, through which inflammatory mediators, including cytokines, act. The ability of CRIg to suppress cytotoxic T cell proliferation and function may underlie its promotion of cancer growth. Thus, the unique properties of this receptor open up new avenues for understanding of the pathways that regulate inflammation during infection, autoimmunity and cancer with the potential for new drug targets to be identified. While some complement receptors may be differently expressed in mice and humans, as well as displaying different properties, mouse CRIg has a structure and function similar to the human receptor, suggesting that extrapolation to human diseases is appropriate. Furthermore, there is emerging evidence in human conditions that CRIg may be a valuable biomarker in infection and immunity, inflammatory conditions and cancer prognosis.
24936585 Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid 2015 Oct OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.
26016635 [Mesenchymal stem cells for the treatment and repair of inflammatory arthritis]. 2015 Mesenchymal stem cells (MSCs) possess multipotent capacity and exhibit immunoregulatory properties. In particular, MSCs can be easily isolated from various organs, can differentiate into various types of cells and generate regulatory T cells. Using human MSC derived from bone marrow and adipose tissue, we have clarified the following novel findings in vitro. 1) MSCs differentiated into osteoblasts or osteocytes under osteoblast-conditioned medium including the inflammatory stimuli such as IL-1. 2) The combination of IL-6 and soluble IL-6 receptor induced differentiation of MSCs to chondrocyte, whereas IL-17 inhibited their differentiation. 3) MSCs highly produced osteoprotegerin and inhibited osteoclastogenesis. Furthermore, we developed a local delivery system of MSCs by using nano-fiber scaffold. MSCs seeded on nano-fiber scaffold suppressed arthritis and bone destruction due to inhibition of systemic inflammatory reaction and immune response by suppressing T cell proliferation and reducing anti-type II collagen antibody production in vivo. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for the treatment of destruction of bone and joints.
26415107 Prednisone Use and Risk of Mortality in Patients With Rheumatoid Arthritis: Moderation by 2016 May OBJECTIVE: Medications for rheumatoid arthritis (RA) may affect survival. However, studies often include limited followup and do not account for selection bias in treatment allocation. Using a large longitudinal database, we examined the association between prednisone use and mortality in RA, and whether this risk was modified with concomitant disease-modifying antirheumatic drug (DMARD) use, after controlling for propensity for treatment with prednisone and individual DMARDs. METHODS: In a prospective study of 5,626 patients with RA followed for up to 25 years, we determined the risk of death associated with prednisone use alone and combined treatment of prednisone with methotrexate (MTX) or sulfasalazine. We used the random forests method to generate propensity scores for prednisone use and each DMARD at study entry and during followup. Mortality risks were estimated using multivariate Cox models that included propensity scores. RESULTS: During followup (median 4.97 years), 666 patients (11.8%) died. In a multivariate, propensity-adjusted model, prednisone use was associated with an increased risk of death (hazard ratio [HR] 2.83 [95% confidence interval (95% CI) 1.03-7.76]). However, there was a significant interaction between prednisone use and MTX use (P = 0.03), so that risk was attenuated when patients were treated with both medications (HR 0.99 [95% CI 0.18-5.36]). However, combination treatment also weakened the protective association of MTX with mortality. Results were similar for sulfasalazine. CONCLUSION: Prednisone use was associated with a significantly increased risk of mortality in patients with RA. This association was mitigated by concomitant DMARD use, but combined treatment also negated the previously reported beneficial association of MTX with survival in RA.
26923246 Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibrobl 2016 Apr Oridonin, an active diterpenoid compound from Rabdosia rubescens, has anti-tumor effects. Rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), a pathological hallmark of RA, exhibits "tumor-like" phenotype. Here, we investigated the effects of oridonin on the proliferation and apoptosis of RAFLS. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis and mitochondrial membrane potential were detected by flow cytometry. Western blot analysis was performed to examine the phosphorylation of extra-cellular regulated kinases (ERK1/2), C-Jun N-Terminal Kinase (JNK), and p38 mitogen-activated protein kinases and the expression of apoptosis-related proteins. Oridonin inhibited cell proliferation and induced cell apoptosis in interleukin-1β (IL-1β)-treated FLS. z-VAD-fmk, a pan-caspase inhibitor, significantly (P < 0.05) attenuated oridonin-induced apoptosis of FLS. Oridonin suppressed IL-1β-mediated phosphorylation of ERK1/2 and JNK in a dose-dependent manner. Meanwhile, oridonin alone dose-dependently suppressed FLS proliferation, triggered cell apoptosis, and reduced mitochondrial membrane potential (ΔΨm) through activating caspase-3, caspase-9, and PARP, leading to translocation of cytochrome c into cytoplasm. z-VAD-fmk significantly (P < 0.05) inhibited oridonin-induced apoptosis. The accumulation of cellular reactive oxygen species (ROS) was about sevenfold increase in oridonin-treated cells. Pretreatment of N-acetylcysteine (NAC), an inhibitor of ROS, significantly attenuated oridonin-triggered apoptosis, indicating the involvement of ROS production in oridonin-induced mitochondrial apoptosis. Oridonin inhibits cell proliferation, induces cell apoptosis, and decreases the phosphorylation of ERK1/2 and JNK in IL-1β-exposed RAFLS. Oridonin induces mitochondrial apoptosis by enhancing the production of ROS in FLS.
26552406 The Effect of SHH-Gli Signaling Pathway on the Synovial Fibroblast Proliferation in Rheuma 2016 Apr Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic synovitis. This study aims to investigate the role of sonic hedgehog (SHH)-Gli signaling pathway in synovial fibroblast proliferation in rheumatoid arthritis. The expression of serum SHH in RA patients group was significantly increased compared with the systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and healthy subject (healthy control, HC) groups, respectively; serum SHH expression of RA patients was positively correlated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP Ab), while there was no significant correlation between SHH expression and erythrocyte sedimentation rate (ESR). SHH, Ptch, Smo, and Gli molecules were highly expressed in rat RA-synovial fibroblast (RA-SF); after blocking the SHH-Gli signaling pathway with a Gli specific inhibitor, Gli-antagonist 61 (GANT61), RA-SF proliferation was inhibited in a dose-dependent manner and the apoptosis rate of RA-SF was increased as well; the expression levels of fibroblast growth factor receptor 1 (FGFR1) and FGFR3 declined in SF cells after GANT61 treatment. Our results suggest that SHH-Gli pathway is involved in the pathogenesis of RA, and blocking SHH-Gli pathway inhibits RA-SF cell proliferation and increases cell apoptosis, which may shed light on developing new ideas for RA treatment.
26340901 Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integr 2015 Nov Although some existing epidemiological observations and molecular experiments suggested that brain disorders in the realm of psychiatry may be influenced by immune dysregulation, the degree of genetic overlap between psychiatric disorders and immune disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies of 18 complex human traits/diseases (five psychiatric disorders, seven immune disorders, and others) and multiple genome-wide annotation resources (central nervous system genes, immune-related expression-quantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell lines). We detected pleiotropy in 24 of the 35 psychiatric-immune disorder pairs. The strongest pleiotropy was observed for schizophrenia-rheumatoid arthritis with MHC region included in the analysis (p = 3.9 x 10(-285), and schizophrenia-Crohn's disease with MHC region excluded (p = 1.1 x 10(-36). Significant enrichment (> 1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and immune disorders were detected. The MHC region on chromosome 6 appears to be the most important with other regions, such as cytoband 1p13.2, also playing significant roles in pleiotropy. We also found that most alleles shared between schizophrenia and Crohn's disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohn's disease. Our results offer a novel bird's-eye view of the genetic relationship and demonstrate strong evidence for pervasive pleiotropy between psychiatric disorders and immune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk of many psychiatric diseases.
26721805 Disentangling the effects of tocilizumab on neutrophil survival and function. 2016 Jun The synovial tissue in rheumatoid arthritis (RA) represents a hypoxic environment with up-regulated pro-inflammatory cytokines and cellular infiltrates including neutrophils. Although inhibition of the interleukin (IL)6 receptor pathway by tocilizumab is a potent treatment option for RA, it may also cause adverse effects such as an occasionally high-grade neutropenia. We analysed the impact of tocilizumab on survival, mediator secretion, oxidative burst, phagocytosis and energy availability of high-dose toll-like receptor (TLR)2/4-stimulated neutrophils (to mimic an arthritis flare) under normoxic versus hypoxic conditions. Human neutrophils were purified, pre-treated with varying doses of tocilizumab, dexamethasone or human IgG1 and high-dose-stimulated with lipopolysaccharide (LPS) alone-triggering TLR2/4-, LPS plus IL6, or left unstimulated. Cells were then incubated under normoxic (18 % O2) or hypoxic (1 % O2) conditions and subsequently analysed. Neutrophil survival and energy availability were significantly decreased by tocilizumab in a dose-dependent manner in high-dose TLR2/4-stimulated cells, but to a greater extent under normoxia as compared to hypoxia. We also found high-dose LPS-stimulated oxidative burst and phagocytosis of neutrophils to be higher under hypoxic versus normoxic conditions, but this difference was reduced by tocilizumab. Finally, we observed that tocilizumab affected neutrophil mediator secretion as a function of oxygen availability. Tocilizumab is known for both beneficial effects and a higher incidence of neutropenia when treating RA patients. Our results suggest that both effects can at least in part be explained by a reduction in neutrophil survival, a dose-dependent inhibition of hypoxia-induced NADPH oxidase-mediated oxidative burst and phagocytosis of infiltrating hypoxic neutrophils and an alteration of mediator secretion.
25989823 Assessment of parafoveal cone density in patients taking hydroxychloroquine in the absence 2015 Nov PURPOSE: To measure cone density in patients taking hydroxychloroquine (HCQ), with no clinical evidence of maculopathy. METHODS: Patients visiting for HCQ macular toxicity screening in the Besançon University Hospital Ophthalmology Department (France) were studied. They underwent routine examination including spectral-domain optical coherence tomography, fundus autofluorescence and multifocal electroretinogram to detect HCQ-induced retinal toxicity. Cone metrics (density, spacing and percentage of cones with six neighbours) were obtained using an adaptive optics camera (RTX1, Imagine Eyes, Orsay, France). The region of interest corresponded to a 0.3° × 0.3° square placed nasally and temporally at 2° of eccentricity from the fovea. RESULTS: Forty eyes of 23 patients were studied. The majority of the patients (21/23) were female. They were aged from 25 to 60 years (mean age ± SD: 40.1 years ± 10). The cumulative dose for HCQ ranged from 24 to 2160 g (777 ± 558 g). None of them displayed HCQ toxicity on screening tests. Bivariate analysis showed moderate cone loss with escalating doses of HCQ (linear regression, r² = 0.23, p = 0.018). Cone spacing also increased with increasing cumulative dose (r² = 0.17, p = 0.008). Cone packing remained unchanged (p > 0.05). Multivariate analysis showed that age and cumulative dose were additive and independent factors of cone dropout. CONCLUSIONS: In this pilot study, we observed moderate cone loss as HCQ cumulative doses increased. The early detection of parafoveal cone metric changes may represent the earliest sign of HCQ macular toxicity during screening.
27655982 Postoperative Limb-Offset Discrepancy Notably Affects Soft-Tissue Tension in Total Hip Art 2016 Sep 21 BACKGROUND: Inadequate soft-tissue tension in total hip arthroplasty is regarded as one cause of dislocation or abductor muscle weakness. The purpose of the present study was to assess how the postoperative discrepancy in limb offset (consisting of both femoral offset and acetabular offset) affects soft-tissue tension compared with other factors among patients with unilateral hip disease undergoing total hip arthroplasty. METHODS: A total of 89 consecutive patients underwent mini-incision total hip arthroplasty involving an anterolateral or posterior approach and with use of a computer navigation system. Soft-tissue tension was measured by applying traction amounting to 40% of body weight with the joint positioned at 0°, 15°, 30°, and 45° of flexion. The separation between the cup and the prosthetic head was measured using the navigation system. RESULTS: The cup-head separation differed significantly for varying angles of flexion (p < 0.001), with the greatest distance noted at 15° of flexion (mean and standard deviation, 11 ± 5 mm). Stepwise multiple regression analysis showed that postoperative limb-offset discrepancy, an anterolateral approach, and preoperative abduction range of motion were correlated with the cup-head separation at 15° of flexion. Postoperative limb-offset discrepancy was negatively correlated with the cup-head separation at 0°, 15°, and 30° of flexion. CONCLUSIONS: Postoperative limb-offset discrepancy significantly affected the soft-tissue tension in total hip arthroplasty at varying degrees of flexion. This indicated that it is important to restore normal limb offset without overlengthening to obtain adequate soft-tissue tension in total hip arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
25948596 Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanis 2016 May OBJECTIVES: Knee joint distraction (KJD) is a novel, but poorly understood, treatment for osteoarthritis (OA) associated with remarkable 'spontaneous' cartilage repair in which resident synovial fluid (SF) multipotential mesenchymal stromal cells (MSCs) may play a role. We hypothesised that SF hyaluronic acid (HA) inhibited the initial interaction between MSCs and cartilage, a key first step to integration, and postulate that KJD environment favoured MSC/cartilage interactions. METHODS: Attachment of dual-labelled SF-MSCs were assessed in a novel in vitro human cartilage model using OA and rheumatoid arthritic (RA) SF. SF was digested with hyaluronidase (hyase) and its effect on adhesion was observed using confocal microscopy. MRI and microscopy were used to image autologous dual-labelled MSCs in an in vivo canine model of KJD. SF-HA was investigated using gel electrophoresis and densitometry. RESULTS: Osteoarthritic-synovial fluid (OA-SF) and purified high molecular weight (MW) HA inhibited SF-MSC adhesion to plastic, while hyase treatment of OA-SF but not RA-SF significantly increased MSC adhesion to cartilage (3.7-fold, p<0.05) These differences were linked to the SF mediated HA-coat which was larger in OA-SF than in RA-SF. OA-SF contained >9 MDa HA and this correlated with increases in adhesion (r=0.880). In the canine KJD model, MSC adhesion to cartilage was evident and also dependent on HA MW. CONCLUSIONS: These findings highlight an unappreciated role of SF-HA on MSC interactions and provide proof of concept that endogenous SF-MSCs are capable of adhering to cartilage in a favourable biochemical and biomechanical environment in OA distracted joints, offering novel one-stage strategies towards joint repair.
27142380 An evaluation of methods correcting for cell-type heterogeneity in DNA methylation studies 2016 May 3 BACKGROUND: Many different methods exist to adjust for variability in cell-type mixture proportions when analyzing DNA methylation studies. Here we present the result of an extensive simulation study, built on cell-separated DNA methylation profiles from Illumina Infinium 450K methylation data, to compare the performance of eight methods including the most commonly used approaches. RESULTS: We designed a rich multi-layered simulation containing a set of probes with true associations with either binary or continuous phenotypes, confounding by cell type, variability in means and standard deviations for population parameters, additional variability at the level of an individual cell-type-specific sample, and variability in the mixture proportions across samples. Performance varied quite substantially across methods and simulations. In particular, the number of false positives was sometimes unrealistically high, indicating limited ability to discriminate the true signals from those appearing significant through confounding. Methods that filtered probes had consequently poor power. QQ plots of p values across all tested probes showed that adjustments did not always improve the distribution. The same methods were used to examine associations between smoking and methylation data from a case-control study of colorectal cancer, and we also explored the effect of cell-type adjustments on associations between rheumatoid arthritis cases and controls. CONCLUSIONS: We recommend surrogate variable analysis for cell-type mixture adjustment since performance was stable under all our simulated scenarios.
25113810 Relationship of CD146 expression to secretion of interleukin (IL)-17, IL-22 and interferon 2015 Mar Expression of the adhesion molecule, CD146/MCAM/MelCAM, on T cells has been associated with recent activation, memory subsets and T helper type 17 (Th17) effector function, and is elevated in inflammatory arthritis. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) and spondyloarthritides (SpA). Here, we compared the expression of CD146 on CD4(+) T cells between healthy donors (HD) and patients with RA and SpA [ankylosing spondylitis (AS) or psoriatic arthritis (PsA)] and examined correlations with surface markers and cytokine secretion. Peripheral blood mononuclear cells (PBMC) were obtained from patients and controls, and synovial fluid mononuclear cells (SFMC) from patients. Cytokine production [elicited by phorbol myristate acetate (PMA)/ionomycin] and surface phenotypes were evaluated by flow cytometry. CD146(+) CD4(+) and interleukin (IL)-17(+) CD4(+) T cell frequencies were increased in PBMC of PsA patients, compared with HD, and in SFMC compared with PBMC. CD146(+) CD4(+) T cells were enriched for secretion of IL-17 [alone or with IL-22 or interferon (IFN)-γ] and for some putative Th17-associated surface markers (CD161 and CCR6), but not others (CD26 and IL-23 receptor). CD4(+) T cells producing IL-22 or IFN-γ without IL-17 were also present in the CD146(+) subset, although their enrichment was less marked. Moreover, a majority of cells secreting these cytokines lacked CD146. Thus, CD146 is not a sensitive or specific marker of Th17 cells, but rather correlates with heterogeneous cytokine secretion by subsets of CD4(+) helper T cells.
25514036 Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produc 2015 Jan 16 Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10-producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL-10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA.
27305853 How the microbiota shapes rheumatic diseases. 2016 Jul The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease.