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ID PMID Title PublicationDate abstract
23114425 IL-17-deficient allogeneic bone marrow transplantation prevents the induction of collagen- 2012 Nov 30 IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17 ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis.
22212536 Asymptomatic celiac sprue in juvenile rheumatic diseases children. 2012 Apr BACKGROUND: Celiac disease (CD) is the most frequent enteropathy in adults and its coexistence with other autoimmune diseases is frequent. OBJECTIVE: To detect asymptomatic CD in children with rheumatic diseases by measuring tissue transglutaminase (tTG) antibodies and finding any relation to disease activity. PATIENTS AND METHODS: Setting and study design: The study included 60 children with juvenile rheumatic diseases consecutively from those attending the Rheumatology Clinics of Cairo University Hospitals: 30 juvenile rheumatoid arthritis (JRA), 10 juvenile systemic lupus erythematosus (SLE), 12 juvenile seronegative spondyloarthropathy and eight juvenile systemic sclerosis/polymyositis (SSc/PM) overlap syndrome were recruited during 2010. There were 22 male and 38 female patients. Thirty matched healthy controls were included. All children were subjected to thorough history taking, clinical examination and laboratory investigations. The body mass index (BMI) for age was used. All subjects had no gastrointestinal tract symptoms suggestive of CD and the tTG antibodies (IgA and IgG) were assessed. RESULTS: The mean age of patients was 12.03 ± 3.3 years and disease duration 4.18 ± 3.24 years. The demographic, clinical and laboratory features of the children were studied and compared. The tTG was positive in 32 (53.3%) patients compared to 20% of the controls (P = 0.03), being higher in females. In tTG-positive patients, the BMI was significantly lower, while white blood cell count, erythrocyte sedimentation rate and disease activity were significantly higher. CONCLUSIONS: tTG antibodies may be used as a screening test to identify asymptomatic CD associated with juvenile rheumatic diseases, especially those with active JRA or marked reduction in BMI.
22855391 The DBA/1 strain is a novel mouse model for experimental Borrelia burgdorferi infection. 2012 Oct Lyme arthritis, caused by Borrelia burgdorferi, has similarities to rheumatoid arthritis and its experimental murine model, collagen-induced arthritis (CIA). Currently, no common strain exists for examination of arthritis models of Lyme arthritis and CIA, which are typically studied in C3H/HeJ and DBA/1 mice, respectively. The aim of this study was to define the characteristics of Borrelia burgdorferi infection and arthritis in the DBA/1 murine strain. Murine Lyme arthritis was induced in C3H/HeJ and DBA/1 mice by subcutaneous infection with B. burgdorferi. Tibiotarsal joints were measured during infection, and mice were sacrificed for histologic, microbiologic, and serologic analysis on days 14 and 42 postinfection. All bladder cultures obtained from C3H/HeJ and DBA/1 mice at 14 days postinfection grew Borrelia. There was no significant difference in spirochetal burdens in hearts and tibiotarsal joints at days 14 and 42 postinfection. Tibiotarsal joint swelling and histologic scoring were not significantly different between the two strains. Serologic analysis revealed increased IgG2a production in C3H/HeJ mice compared to DBA/1 mice. Analysis of 2-dimensional immunoblots revealed several specific antigens (LA7, BBA03, BBA64, BBA73, OspA, and VlsE) which were not recognized by DBA/1 sera. We conclude that the DBA/1 murine strain is a suitable model for the study of Lyme arthritis and experimental B. burgdorferi infection, allowing direct comparison between Lyme arthritis and collagen-induced arthritis. The specificity of the humoral immune response differs between the two strains, further study of which may reveal important findings about how individual strains respond to B. burgdorferi infection.
21324964 Lack of specificity of anticyclic citrullinated peptide antibodies in advanced human immun 2011 Jun OBJECTIVE: To determine the prevalence and specificity of anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) for rheumatoid arthritis (RA) in human immunodeficiency virus (HIV) infection and to evaluate the effect of immune reconstitution on these markers. METHODS: Patients with advanced HIV infection without arthritis were enrolled. CD4+ T lymphocyte counts (CD4), anti-CCP, and RF were determined before initiating antiretroviral therapy (ART) and repeated after 6 months. Results were compared to those of healthy controls. Patients were followed for the development of RA for 1 year. RESULTS: Sixty patients and 26 controls were studied. Six-month followup results were available on 49 patients. Mean (SD) levels of anti-CCP were higher in patients with HIV compared to controls: respectively, 9.50 (11.41) versus 0.80 (1.32) units (p < 0.001). Mean (SD) levels decreased to 4.85 (8.12) units (p = 0.006) after 6 months of ART (HIV-infected group). Fifteen percent of patients initially tested positive for anti-CCP, 4% after 6 months versus no controls (p = 0.031). Forty-seven percent of patients initially tested positive for RF, 18% after 6 months versus 8% of controls (p < 0.001). Decreases in RF and anti-CCP after ART were accompanied by increased mean (SD) CD4: from 129 (56) to 278 (140) cells/mm(3) (p < 0.001). Anti-CCP and RF positivity was not associated with the development of RA. CONCLUSION: Increased titers of anti-CCP and RF occur in advanced HIV infection. Although more specific than RF, before immune reconstitution, anti-CCP is an unreliable diagnostic marker for RA and does not necessarily predict future RA. After immune reconstitution, the specificity of anti-CCP approaches that of a control group.
23124729 Leflunomide addition in patients with articular manifestations of psoriatic arthritis resi 2013 Nov In contrast to rheumatoid arthritis, in psoriatic arthritis (PsA), the efficacy of disease-modifying antirheumatic drugs (DMARDs) combination has not been documented. We conducted a retrospective study to evaluate the effectiveness of leflunomide (LEF) addition in 11 PsA patients with articular manifestations that failed to respond to methotrexate (MTX) monotherapy [disease activity score in 28 joints (DAS28) > 3.2)]. Eight of them, all with moderate disease activity (DAS28 < 5.1) at baseline, tolerated the combination. A statistically significant improvement of the mean DAS28, based on erythrocyte sedimentation rate (ESR), and its variables, and C-reactive protein (CRP) at 12-16 weeks after LEF addition was observed. Mean change of DAS28 in patients with polyarticular disease did not differ compared with those with oligoarticular. Based on the European League Against Rheumatism (EULAR) response criteria, none of our patients achieved a good response, seven had a moderate response, and one was a non-responder. The two patients with the lower DAS28 at baseline attained low disease activity (LDA, DAS28 ≤ 3.2), while none reached remission (DAS28 ≤ 2.6). Achievement of clinical remission or at least LDA has been recently proposed as the goal of treatment in PsA. Our results imply that LEF addition may serve as an alternative therapeutic modality for patients with moderately active PsA and, as lower as possible, residual disease activity after the initial therapy with MTX alone.
22554834 The therapeutic effects of daphnetin in collagen-induced arthritis involve its regulation 2012 Aug OBJECTIVES: Daphne odora var. marginata (D. marginata), an aiophyllus arbuscular plant, is one of the traditional Chinese medicines used to treat rheumatoid arthritis. This study investigated the therapeutic effects and mechanisms of daphnetin, an active monomer ingredient derived from D. marginata, on collagen-induced arthritis (CIA) in rats. METHODS: The effects of daphnetin on joint diseases were assessed by hematoxylin and eosin staining and radiographic and transmission electron microscopy. The protein and mRNA expression levels of T helper (Th)1/Th2/Th17-type cytokines in the spleen were determined by flow cytometry and quantitative real-time PCR. RESULTS: Our results showed that daphnetin significantly reduced paw swelling and was nontoxic in vivo at the tested doses. Synovial hyperplasia, joint destruction and chondrocyte degeneration in CIA rats were suppressed by daphnetin. Daphnetin treatment also reduced the levels of Th1/Th2/Th17 type cytokines in spleen lymphocytes in CIA rats. Moreover, the expression of Foxp3, which can down-regulate the activity of Th17 cells, was significantly increased in the daphnetin-treated groups. CONCLUSIONS: These results suggest that daphnetin may have therapeutic effects in down-regulating Th17-type responses in CIA rats. The beneficial effects of daphnetin on CIA may be related to its inhibition of Th17 cell priming and activation.
21953289 Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α-en 2011 Dec OBJECTIVE: To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α-enolase is mediated by Porphyromonas gingivalis enolase in the context of DR4 alleles. METHODS: Recombinant human α-enolase and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4-IE-transgenic mice and control mice (class II major histocompatibility complex-deficient [class II MHC(-/-)] and C57BL/6 wild-type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α-enolase and citrullinated α-enolase was assayed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α-enolase (CEP-1) and its arginine-bearing control peptide, REP-1, were also assessed by ELISA. RESULTS: Significant hind-ankle swelling (≥0.3 mm) occurred in DR4-IE-transgenic mice immunized with citrullinated human α-enolase (9 of 12 mice), uncitrullinated human α-enolase (9 of 12 mice), citrullinated P gingivalis enolase (6 of 6 mice), and uncitrullinated P gingivalis enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α-enolase, both citrullinated and unmodified, and to CEP-1 and REP-1 were detectable in all immunized mice except the class II MHC(-/-) control mice. CONCLUSION: This is the first animal model that links an immune response to P gingivalis enolase to an important subset of RA, defined by antibodies to citrullinated α-enolase in the context of DR4. The fact that arthritis and anti-CEP-1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α-enolase may be important in initiating the corresponding subset of human RA.
22576707 Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis t 2012 Sep OBJECTIVE: To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. METHODS: We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. RESULTS: NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. CONCLUSION: For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis.
22041103 Inhibitory effects of the root extract of Dipsacus asperoides C.Y. Cheng et al T.M.Ai on c 2012 Jan 6 ETHNOPHARMACOLOGICAL RELEVANCE: Dipsaci radix, the dried root of Dipsacus asperoides C.Y. Cheng et al T.M.Ai is used as a medicinal plant in oriental clinics for the treatment of bone diseases and functions by strengthening bone and healing bone fractures. AIM OF THE STUDY: This study investigated the therapeutic efficacy of Dipsaci radix in treating rheumatoid arthritis using a type II collagen (CII)-induced arthritis (CIA) mouse model. MATERIALS AND METHODS: Arthritis was induced in male DBA/1 mice by immunization with CII. Dipsaci radix water (DR-W) extract at 50mg/kg and 100mg/kg was orally administered from days to after the induction of arthritis. Arthritic score, serum levels of anti-CII IgG2a, the inflammatory mediator prostaglandin E(2) (PGE(2)), and inflammatory cytokines (TNF-α, IL-1β and IL-6), and histological changes in the ankle joint were analyzed in CIA mice. RESULTS: Arthritic induction increased the arthritic score, as well as serum levels of anti-CII IgG2a antibody, PGE(2), TNF-α, IL-1β and IL-6 in mice. However, administration of DR-W extract in CIA mice significantly reduced arthritic scores and serum levels of anti-CII IgG2a antibody, PGE(2), TNF-α, IL-1β and IL-6 compared with those in vehicle-treated CIA mice. Furthermore, histopathological improvement in joint architecture was also observed in DR-W extract-treated CIA mice. CONCLUSIONS: DR-W extract has anti-inflammatory and anti-arthritic effects in arthritic mice. This suggests that Dipsaci radix might be used as a therapeutic agent for the treatment of human arthritis.
22955798 EBV reactivation serological profile in primary Sjögren's syndrome: an underlying trigger 2013 May Antibody to Epstein-Barr virus (EBV) early antigen diffuse (anti-EA-D) is associated with viral replication. However, their possible associations with clinical/therapeutic features in primary Sjögren's syndrome (pSS) were not established. We evaluated 100 pSS patients (American-European Criteria) and 89 age/gender/ethnicity-matched healthy controls. Disease activity was measured by EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Antibodies to EBV (anti-VCA IgG/IgM, anti-EBNA-1 IgG, anti-EA-D IgG) were determined by ELISA. Patients and controls had comparable frequencies and mean levels of anti-VCA IgG (90 vs. 86.5 %, p = 0.501; 2.6 ± 1.1 vs. 2.5 ± 1.1 AU/mL, p = 0.737) and anti-EBNA-1 IgG (92 vs. 94.4 %, p = 0.576; 141.3 ± 69.8 vs. 135.6 ± 67.5 RU/mL, p = 0.464). Anti-VCA IgM was negative in all cases. Noteworthy, higher frequency and increased mean levels of anti-EA-D were observed in patients than controls (36 vs. 4.5 %, p < 0.0001; 38.6 ± 57.4 vs. 7.9 ± 26.3 RU/mL, p < 0.0001). Further analysis of patients with (n = 36) and without (n = 64) anti-EA-D revealed comparable age/gender/ethnicity (p ≥ 0.551), current prednisone dose (4.8 ± 6.9 vs. 5.1 ± 10.4 mg/day, p = 0.319), and current uses of prednisone (52.8 vs. 37.5 %, p = 0.148) and immunosuppressants (44.4 vs. 31.3 %, p = 0.201). ESSDAI values were comparable (p = 0.102), but joint activity was more frequent (25 vs. 9.4 %, p = 0.045) in anti-EA-D positive patients. Anti-EA-D antibodies were not associated with anti-Ro/SSA (p = 1.000), anti-La/SSB (p = 0.652), rheumatoid factor (p = 1.000), anti-α-fodrin (p = 0.390) or antiphospholipid antibodies (p = 0.573), not suggesting cross-reactivity. The higher anti-EA-D frequency associated with joint activity raises the possibility that a subclinical EBV reactivation may trigger or perpetuate the articular involvement in pSS.
23238606 Transfer from paediatric rheumatology to the adult rheumatology setting: experiences and e 2013 May Adolescents with juvenile idiopathic arthritis (JIA) are transferred from paediatrics to adult-oriented healthcare when they reach early adulthood. Research on the extent to which patients' expectations about the adult healthcare setting match their actual experience after transfer, may promote successful transfer from paediatrics to adult care. As part of the 'Don't Retard' project ( http://www.kuleuven.be/switch2/rheuma.html ), experiences and expectations of young adults regarding their transfer from paediatric rheumatology to adult rheumatology were explored. A qualitative study was conducted using semi-structured, in-depth interviews of 11 patients with JIA, aged 18 to 30. Data were analysed using procedures inherent to the content analysis approach. For both concepts, experiences and expectations, three main themes emerged: 'preparation', 'parental involvement' and an 'adapted setting for the late-adolescent or early adult'. The need for a gradual process covered the themes 'preparation' and 'parental involvement'. Young people with JIA prefer to have a say in the moment of transfer and in the reduction of parental involvement. The majority of the participants like their parents' presence at the first consultation at the adult rheumatology department. They expect a healthcare setting adapted to their needs and the possibility to meet peers in this setting. Sudden confrontation with older patients with severe rheumatoid arthritis at adult rheumatology was an unsettling experience for some of the young patients and they declared that better preparation is needed. This study enabled us to define three main themes important in transfer. These themes can facilitate healthcare professionals in developing specific interventions to prepare the young people to transfer, to regulate parental involvement and to arrange an adapted setting for them. Since we included patients who were in follow-up at one tertiary care centre, in which both paediatric and adult rheumatology care are located, the results of the study cannot be generalised to the entire population of patients with JIA.
21584744 Treatment of collagen-induced arthritis with recombinant plasminogen-related protein B: a 2011 Jul BACKGROUND: We have previously reported that recombinant human plasminogen-related protein B (rPRP-B), a putative 9-kDa protein that closely resembles the activation peptide of plasminogen, has shown significant inhibition of tumor growth through inhibition of angiogenesis. Based on recent reports suggesting a close relationship between rheumatoid arthritis (RA) and angiogenesis, we hypothesized that this compound would regulate inflammatory conditions in RA. The present study therefore tested the effects of rPRP-B in the treatment of collagen-induced arthritis (CIA) to elucidate the mechanisms underlying these effects. METHODS: DBA/1J mice immunized with type II collagen to induce CIA were monitored to assess the effects of rPRP-B on clinical severity of the disease. Pathological changes in joints, including vessel formation and vascular endothelial growth factor (VEGF) production, were examined histologically. Bone destruction was radiologically evaluated. In vitro studies on the effects of rPRP-B on cell proliferation and production of VEGF in interleukin (IL)-1β or basic fibroblast growth factor (bFGF)-stimulated human synoviocytes were also performed. RESULTS: Development of CIA was effectively inhibited by rPRP-B. Radiological examinations revealed that the protein reduced bone destruction in CIA. CIA-induced vessel formation and VEGF expression in vivo were also reduced. In vitro mechanistic studies demonstrated that rPRP-B affected human synoviocyte proliferation and VEGF production stimulated by IL-1β and bFGF. CONCLUSIONS: Given the ability to effectively promote multistep anti-angiogenic activities, including cell growth inhibition and cytokine regulation, rPRP-B represents a promising candidate for a novel therapeutic agent against RA.
21953520 Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles en 2012 Mar OBJECTIVE: Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. METHODS: High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S(2) , S(3P) , or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. RESULTS: We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10(-7) ). We also observed associations between individual SE alleles (HLA-DRB1*0101, *0401, *0404, *0405, *0408, and *1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S(2) /S(3P) (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). CONCLUSION: We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S(2) and S(3P) risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.
23400692 LEAPS therapeutic vaccines as antigen specific suppressors of inflammation in infectious a 2012 Sep 20 The L.E.A.P.S.(™) (Ligand Epitope Antigen Presentation System) technology platform has been used to develop immunoprotective and immunomodulating small peptide vaccines for infectious and autoimmune diseases. Several products are currently in various stages of development, at the pre-clinical stage (in animal challenge efficacy studies). Vaccine peptides can elicit protection of animals from lethal viral (herpes simplex virus [HSV-1] and influenza A) infection or can block the progression of autoimmune diseases (e.g. rheumatoid arthritis as in the collagen induced arthritis (CIA] or experimental autoimmune myocarditis (EAM) models). L.E.A.P.S. technology is a novel T-cell immunization technology that enables the design and synthesis of non-recombinant, proprietary peptide immunogens. Combination of a small peptide that activates the immune system with another small peptide from a disease-related protein, thus a conjugate containing both an Immune Cell Binding Ligand (ICBL) and a disease specific epitope, which allows the L.E.A.P.S. vaccines to activate precursors to differentiate and become more mature cells that can initiate and direct appropriate T cell responses. As such, readily synthesized, defined immunogens can be prepared to different diseases and are likely to elicit protection or therapy as applicable in humans as they are in mice. L.E.A.P.S. vaccines have promise for the treatment of rheumatoid arthritis and other inflammatory diseases and for infections, such as influenza and HSV1. The protective responses are characterized as Th1 immune and immunomodulatory responses with increased IL-12p70 and IFN-γ (Th1 cytokines) but reduced inflammatory cytokines TNF-α, IL-1 and IL-17 (Th2 and Th17 cytokines) and concomitant changes in antibody subtypes. LEAPS immunogens have been used directly in vivo or as ex vivo activators of DC which are then administered to the host.
22687356 Involvement of tachykinins and NK1 receptor in the joint inflammation with collagen type I 2012 Rheumatoid arthritis (RA) is a chronic multisystem disease characterized by persistent joint inflammation associated with severe pain. Because RA is an immune-mediated joint disease and because type II collagen is considered an autoantigen, rodent models of arthritis using collagen type II-specific monoclonal antibodies are valuable for studying the pathogenesis of autoimmune arthritis and for evaluating therapeutic strategies. The tachykinin family peptides, substance P (SP) and hemokinin-1 (HK-1), are expressed in the nervous systems and in many peripheral organs and immunocompetent cells and activate tachykinin NK1 receptors with similar affinities. NK1 receptors are involved in the inflammation and hyperalgesia associated with a variety of inflammatory diseases. In the present study, we examined the involvement of SP and HK-1 in the joint inflammation and hyperalgesia in a collagen antibody-induced arthritis (CAIA) model in mice. The messenger RNA expression levels of the TAC1 gene encoding SP and of the TAC4 gene encoding HK-1 were decreased in the dorsal root ganglia and spinal cord at the peak of the inflammatory symptoms in CAIA. Systemic injection of an NK1 receptor antagonist, WIN 51708, significantly inhibited the joint swelling, but not the mechanical allodynia, on day 7 in CAIA mice. The messenger RNA expression levels of TAC1 and TAC4 in the dorsal root ganglia and dorsal spinal cord were unaffected by treatment with WIN 51708. These findings suggest that tachykinins and NK1 receptors play a key role in joint inflammation, rather than in nociceptive sensitization, in CAIA.
21670317 IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bon 2011 Jul 15 The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4(+) T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23-induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19(-/-) mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19(-/-) mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.
20967859 Ablation of the Ccr2 gene exacerbates polyarthritis in interleukin-1 receptor antagonist-d 2011 Jan OBJECTIVE: The pathogenesis of rheumatoid arthritis (RA) involves cytokines and chemokines. Given the role of intraarticular macrophage infiltration in RA, this study was undertaken to address the pathogenic role of CCR2, a chemokine receptor that is abundantly expressed by macrophages, in Il1rn-deficient mice, a mouse model of RA. METHODS: Il1rn-deficient and Il1rn and Ccr2-double-deficient mice were subjected to clinical assessment of arthritis and histologic examination. Bone mineral density was measured with computed tomography. The types of cells infiltrating joints were determined by immunohistochemical analysis and flow cytometric analysis. Osteoclasts in joints were quantified after tartrate-resistant acid phosphatase staining. Cytokine and chemokine levels were measured by enzyme-linked immunosorbent assay and multiplex suspension array assay. The expression patterns of chemokines and osteoclastogenic factors were determined by double-color immunofluorescence analysis. Anti-mouse CXCR2 antibody was injected into Il1rn and Ccr2-double-deficient mice for blocking experiments. RESULTS: Ablation of the Ccr2 gene actually exacerbated arthritis and intraarticular osteoclastogenesis, while it enhanced intraarticular neutrophil but not macrophage accumulation in Il1rn-deficient mice. Infiltrated neutrophils expressed the osteoclastogenic factors RANKL and ADAM-8, thereby augmenting intraarticular osteoclastogenesis in Il1rn and Ccr2-double-deficient mice. Moreover, the double-deficient mice exhibited enhanced expression of the neutrophilic chemokines keratinocyte chemoattractant and macrophage inflammatory protein 2 (MIP-2), compared with Il1rn-deficient mice. Finally, neutralizing antibodies to CXCR2, the receptor for keratinocyte chemoattractant and MIP-2, dramatically attenuated arthritis in Il1rn and Ccr2-double-deficient mice. CONCLUSION: Our findings indicate that CCR2-mediated signals can modulate arthritis in Il1rn-deficient mice by negatively regulating neutrophil infiltration.
23183090 Rapid-resolution liquid chromatography TOF-MS for urine metabolomic analysis of collagen-i 2013 Jan 30 AIM OF THE STUDY: Rheumatoid arthritis (RA) is a kind of autoimmune diseases characterized by persistent synovitis, systemic inflammation and autoantibodies. Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional Chinese medicine (TCM) with anti-inflammatory activity. In the present study, a rapid-resolution liquid chromatography tandem time-of-flight mass spectrometry (RRLC-TOF-MS) based metabolomic study was developed to obtain a systematic view of the progression of RA and assess the efficacy of HLJDT and its components in collagen-induced arthritis (CIA) rats. MATERIALS AND METHODS: Forty male Wistar rats were randomly divided into five groups, including model group, normal control group, dexamethasone group, HLJDT group and the mixture of 13 components of HLJDT group after immunized with bovine type II collagen. Urine samples for metabolomic study were collected on 8, 15, 22 day during the animal experiment. RESULTS: The pharmacological changes (swelling paws and arthritis scores) showed that prophylactic treatment with HLJDT and its components significantly suppressed the swelling of rats' paws. By combining with partial least squares discriminant analysis, 24 potential biomarkers were identified and primarily involved in 12 metabolism pathways, such as tricarboxylic acids cycle metabolism, lipid metabolism, tryptophan metabolism and phenylalanine metabolism, which revealed a new insight into the RA network in vivo. These potential metabolites identified in CIA model need to be further investigated to prove their diagnostic and/or prognostic values for RA. Taking potential biomarkers found in the study as screening indexes, it revealed that HLJDT and its components could reverse the pathological process of RA through partly regulating the disturbed metabolic pathways. CONCLUSIONS: This study indicated that the metabolomic strategy based on RRLC-TOF-MS is a useful tool to search potential biomarkers related to RA and to dissect the underlying mechanisms of TCM in treating RA.
22697077 Celastrus treatment modulates antigen-induced gene expression in lymphoid cells of arthrit 2012 Apr Rheumatoid arthritis (RA) is a debilitating autoimmune disease of global prevalence and the disease process primarily targets the synovial joints. Despite improvements in the treatment of RA over the past decade, there still is a need for new therapeutic agents that are efficacious, less expensive, and free of severe adverse reactions. Celastrus has been used in China for centuries for the treatment of rheumatic diseases. Furthermore, we previously reported that ethanol extract of Celastrus aculeatus Merr. (Celastrus) attenuates adjuvant-induced arthritis (AA) in rats. However, the mechanisms underlying the anti-arthritic activity of Celastrus have not yet been fully defined. We reasoned that microarray analysis might offer useful insights into the pathways and molecules targeted by Celastrus. We compared the gene expression profiles of the draining lymph node cells (LNC) of Celastrus-treated (Tc) versus water-treated (Tw) rats, and each group with untreated arthritic rats (T(0)). LNC were restimulated with mycobacterial heat shock protein-65 (Bhsp65). We identified 104 differentially expressed genes (DEG) (8 upregulated, 96 downregulated) when comparing Tc with T(0) rats, in contrast to 28 (12 upregulated, 16 downregulated) when comparing Tw and T(0) rats. Further, 20 genes (6 upregulated, 14 downregulated) were shared by both Tw and Tc groups. Thus, Celastrus treatment (Tc) significantly downregulated a large proportion of genes compared to controls (Tw). The DEG were mainly associated with the processes of immune response, cell proliferation and apoptosis, and cell signaling. These results provide novel insights into the mechanism of Celastrus anti-arthritic activity, and unravel potential therapeutic targets for arthritis.
21932136 Anti-inflammatory effects of Clematis chinensis Osbeck extract(AR-6) may be associated wit 2012 Oct The root of Clematis chinensis Osbeck has been used widely in rheumatoid arthritis in Chinese traditional medicine, and AR-6 is a triterpene saponin isolated from it. In this present study, we investigated the in vivo effects of oral AR-6 in chronic rat with collagen-induced arthritis (CIA) and possible molecular mechanism. CIA was induced by immunizing 56 female Sprague-Dawley (SD) rats with chicken typeIIcollagen (CII). Following eighteen days, the immunization rats with CIA were treated with AR-6 (32, 16, 8 mg/kg), cyclophosphamide (7 mg/kg), and TGP (Total Glucosides of Paeonia) (180 mg/kg) for 7 days, and rats without CIA were given the same volume of purified water. TNF-α and IL-1β levels in peripheral blood will be measured by ELISA, and Western blot analysis will be used to detect the expression of NF-κB p65 subunits, TNF-α and COX-2, in synovial membrane. We found that therapeutic treatment with AR-6 markedly improves the paw swelling and histopathological changes. Moreover, the serum levels of pro-inflammatory cytokines TNF-α and IL-1β were markedly lowered, and the expression of NF-κB p65 subunits, TNF-α and COX-2, in the synovial membrane of CIA rats was significantly inhibited in the AR-6-treated groups. These results enable to prove that AR-6 has a potential anti-inflammatory effect in CIA rats, and its mechanism may relate to the inhibition of the expression of NF-κB p65 subunits, TNF-α and COX-2.