Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
ID | PMID | Title | PublicationDate | abstract |
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19030019 | Inhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small che | 2009 Jan | The interaction of immune complexes with the human Fc receptor, FcgammaRIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three-dimensional structure of an FcgammaRIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand-binding sites. These small chemical entities (SCEs) blocked immune complex-induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for FcgammaRIIa, as they inhibited only immune complex-induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in FcgammaRIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen-induced arthritis (CIA). The SCEs were more potent than methotrexate and anti-CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE FcgammaRIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes. | |
20722035 | Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. | 2010 Nov | OBJECTIVE: Interleukin-20 (IL-20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti-IL-20 antibody treatment would modulate the severity of the disease in a collagen-induced arthritis (CIA) rat model. METHODS: We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti-IL-20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme-linked immunosorbent assay. To analyze gene regulation by IL-20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL-17, and TNFα. We also used real-time quantitative polymerase chain reaction analysis and flow cytometry to determine IL-20-regulated RANKL in mouse osteoblastic MC3T3-E1 cells and Th17 cells. RESULTS: In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL-20, IL-1β, IL-6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL-20 induced TNFα expression in SFs from rats with CIA. IL-20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells. CONCLUSION: Selectively blocking IL-20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL-20 is a novel target and that 7E may be a potential therapeutic agent for RA. | |
20500834 | Toll-like receptor 3 upregulation in macrophages participates in the initiation and mainte | 2010 | INTRODUCTION: Toll-like receptors (TLRs) are involved in both innate and adaptive immune responses and are likely to play a complex role in the pathogenesis of human rheumatoid arthritis (RA) and experimental arthritis. The objective of this study was to identify the key TLR in pristane-induced arthritis (PIA), a rat model for RA, and to clarify its roles in the initiation and maintenance of arthritis. METHODS: Arthritis in DA rats was induced by pristane and the severity was evaluated by macroscopic and microscopic score systems. Spleen TLR and cytokine expression was detected at different time points by real-time polymerase chain reaction (PCR) and flow cytometry. Polyinosine-polycytidylic acid (polyI:C, a ligand of TLR3) or TLR3 specific short-hairpin RNA plasmid for RNA interference was administrated to PIA rats in vivo. Serum nitrogen oxide concentration was determined by Griess method, and tumor necrosis factor alpha (TNF-alpha) was determined by L929 biotest. In splenic macrophages, TLR3 expression was measured by flow cytometry. A rat macrophage cell line (NR8383) was stimulated by pristane, and anti-TLR3 antibody were used to block TLR3 pathway. TLR3 and cytokine expression in NR8383 were detected by real-time PCR. RESULTS: By screening the TLR expression profile in spleen of DA rats after pristane injection, we found that TLR3 was the most early and prominently upregulated TLR. Both TLR3 mRNA and protein expression of spleen were upregulated at 6 and 26 days after pristane injection. Furthermore, administration of polyI:C exacerbated, whereas RNA interference targeting TLR3 ameliorated, the arthritis. Particularly, TLR3 expression was induced in splenic macrophages of PIA rats, and also in the NR8383 cell line after pristane stimulation in a dose- and time- dependent manner. Upregulation of interferon beta (IFN-beta) and TNF-alpha by pristane stimulation was blocked by anti-TLR3 antibody in NR8383. CONCLUSIONS: TLR3 plays a pivotal role in the initiation and development of PIA which may dependent on macrophage. These findings are useful to understand the pathogenesis of RA and may provide an intriguing therapeutic opportunity for RA. | |
20589421 | Dickkopf-1 as potential biomarker to evaluate bone erosion in systemic lupus erythematosus | 2010 Sep | OBJECTIVE: This study aims to explore the potential role of circulating Dickkopf-1 (Dkk-1) and osteoprotegerin (OPG) in evaluating erosive arthritis in systemic lupus erythematosus (SLE). METHODS: Serum Dkk-1 and OPG levels were examined in 130 SLE patients including eight with erosive arthritis, 100 rheumatoid arthritis (RA) patients and 50 healthy individuals by ELISA. Comparison of serum Dkk-1 levels with presence of anti-cyclic citrullinated peptides (CCP) antibodies in evaluating erosive arthritis in SLE was carried out. Associations of Dkk-1 and OPG levels with results of clinical examination were also noted. RESULTS: Dkk-1 levels were significantly increased in eight SLE patients with erosive arthritis, compared to 58 SLE patients with non-erosive arthritis, 64 SLE patients without arthritis, and healthy controls, while similar with RA. In contrast, no significant changes of OPG levels were found except for higher levels in RA. No differences were found in Dkk-1 levels of SLE patients with erosive arthritis subdivided according to presence or absence of anti-CCP antibodies. Moreover, higher levels of Dkk-1 were identified in anti-CCP positive SLE patients with erosive arthritis compared to those with non-erosive arthritis or without arthritis. However, no significant correlations between Dkk-1 and OPG levels or between Dkk-1 levels and other laboratory and clinical manifestations were observed. CONCLUSIONS: High levels of circulating Dkk-1 were associated with bone erosion in patients with SLE, even when anti-CCP antibodies were absent. | |
21123321 | High titers of autoantibodies in patients with sickle-cell disease. | 2011 Feb | OBJECTIVE: Frequency and titers of autoantibodies in patients with sickle-cell disease (SCD) have been reported as relatively high. In a prospective study of 88 patients, we examined this "hyper-autoreactivity" and its clinical consequences. METHODS: For 1 year, patients with SCD were screened for the presence in their serum of antinuclear, anti-double-stranded DNA, antiextractible nuclear antigens, anticardiolipin antibodies, and rheumatoid factors. A population of 85 sex-matched individuals of similar ethnic origin served as controls. RESULTS: Whereas prevalence of autoantibodies did not differ between the 2 groups, the type and rate of antinuclear antibodies were different. Autoantibodies from the SCD patients showed various immunofluorescence patterns, whereas only speckled patterns at low titers were present in controls. No antibody specificity was found in either group. SCD patients and controls displayed similar rates of anticardiolipin antibodies, but the SCD patients tended to be more frequently positive for rheumatoid factors. Six-year followup of the SCD patients did not provide any clinical evidence for onset of an autoimmune disease, except for 1 patient who developed rheumatoid arthritis, with increasing antinuclear antibodies followed by emergence of specific markers 5 years later. CONCLUSION: Patients with SCD displayed high titers of autoantibodies. This observation may be due only to immune activation and/or dysfunction in SCD, as neither pathogenic specificity of autoantibodies nor autoimmune clinical signs appeared in the majority of cases in our study. | |
21104102 | A case of rheumatoid pericarditis associated with a high IL-6 titer in the pericardial flu | 2011 Jun | We report a 60-year-old woman with rheumatoid arthritis complicated by pericarditis. Treatment with tocilizumab improved her polyarthritis, but the pericardial effusion increased so rapidly as to cause cardiac tamponade before the treatment could prove its efficacy. Pericardial effusion disappeared after pericardiocentesis. The pericardial fluid contained a remarkably high concentration of interleukin-6 (IL-6; 351,000 pg/mL), which tocilizumab appeared to have made yet higher compared to the reported IL-6 levels in rheumatoid pericarditis. No further exacerbation of pericarditis was observed after retreatment with tocilizumab. This case has important implications in that it suggests that the prominently elevated IL-6 level in pericardial fluid during tocilizumab treatment may be an indicator of its efficacy for pericarditis. | |
20615221 | Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression | 2010 | INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA). METHODS: We engineered an adenoviral vector to contain the CB11 portion of recombinant type II collagen and used PCR to introduce point mutations at three sites within (CII124-402, 260A, 261B, 263D), (rCB11-A9) so that the resulting molecule contained the A9 sequence at the exact site of the wild-type sequence. RESULTS: We used this construct to target intra-articular tissues of mice and utilized the collagen-induced arthritis model to show that this treatment strategy provided a sustained, local therapy for individual arthritic joints, effective whether given to prevent arthritis or as a treatment. We also developed a novel system for in vivo bioimaging, using the firefly luciferase reporter gene to allow serial bioluminescence imaging to show that luciferase can be detected as late as 18 days post injection into the joint. CONCLUSIONS: Our therapy is unique in that we target synovial cells to ultimately shut down T cell-mediated inflammation. Its effectiveness is based on its ability to transform potential inflammatory T cells and/or bystander T cells into therapeutic (regulatory-like) T cells which secrete interleukin (IL)-4. We believe this approach has potential to effectively suppress RA with minimal side effects. | |
19921588 | The effect of triptolide on CD4+ and CD8+ cells in the Peyer's patch of DA rats with colla | 2009 | Triptolide is a purified component from a traditional Chinese herb Tripterygium wilfordii Hook F. It has been shown to have anti-inflammatory and immunosuppressive activities by its inhibitory effect on T-cells. But the effect of triptolide on enteric mucosal immune responses is not well known. The enteric mucosal immune system, especially the Peyer's patch, is regarded as one of the sites for inducing immunity tolerance, and this intolerance effect has been used to induce oral tolerance, which can considerably reduce arthritis severity in several models of experimental polyarthritis and rheumatoid arthritis (RA) patients. In this study, we investigated the effect of triptolide on the CD4+ and CD8+ cell distribution in Peyer's patch cells and periphery lymphocytes and TGF-beta and IFN-gamma levels in periphery in collagen induced arthritis (CIA) in DA rats. CIA in the rat is a widely studied animal model of inflammatory polyarthritis, with similarities to RA, and the DA rat is one of most susceptible strains for CIA. Our data show that triptolide could lower the arthritic scores of CIA. The more CD8+ cells in the Peyer's patch, the more CD4+ cells in periphery. High level IFN-gamma and low level TGF-beta in periphery are observed in CIA rats, while the less CD4+ and CD8+ cells in the Peyer's patch, the less CD4+ cells in periphery. Low level IFN-gamma and high level TGF-beta in periphery are shown in triptolide-treated rats. The dose dependency of triptolide was observed in periphery CD4 cells and in the arthritic score. Therefore, the effect of triptolide on Peyer's patch immune cells might partially explain some of the immunosuppressive activities of triptolide. | |
21058934 | siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis. | 2011 Jan | IMPORTANCE OF THE FIELD: Gene silencing mediated by siRNA has been widely investigated as a potential therapeutic approach. The success of these therapies depends on effective systems capable of selectively and efficiently conveying siRNA to targeted cells/organs with minimal toxicity. AREAS COVERED IN THIS REVIEW: This review discusses current experimental approaches to siRNA delivery strategies available for arthritis treatment and the management of other musculoskeletal disorders. The review covers literature on the subject from 2000 to 2010. WHAT THE READER WILL GAIN: In the last decade, extensive improvements have been made to optimize siRNA-based gene therapy and have been tested on several arthritis and orthopedic conditions. However, except for Phase I - II DNA-based gene therapy trials on arthritis, no clinical studies have reported siRNA application in these domains. TAKE HOME MESSAGE: Most musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, fracture, aseptic loosening, cartilage and intervertebral disc degeneration are non-fatal and age-related chronic inflammatory conditions, but represent significant morbidity and a socio-economic burden. siRNA-based gene therapy offers treatment opportunities that are less invasive, more effective and less expensive than existing modalities. Future directions for siRNA therapy include the development of safe and more efficient delivery systems and the selection of optimal gene targets for disease control. | |
19525961 | A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and | 2009 Jul | The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders. | |
20482767 | Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts | 2010 | INTRODUCTION: Targeting joint destruction induced by osteoclasts (OCs) is critical for management of patients with rheumatoid arthritis (RA). Since phosphoinositide 3-kinase (PI3-K) plays a critical role in osteoclastogenesis and bone resorption, we examined the effects of ZSTK474, a novel phosphoinositide 3-kinase (PI3-K)-specific inhibitor, on murine OCs in vitro and in vivo. METHODS: The inhibitory effect of ZSTK474 on OC formation was determined and compared with other PI3-K inhibitors by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells after culturing murine bone marrow monocytic OC precursors, and RAW264.7 cells. Activation of Akt and expression of nuclear factor of activated T cells (NFAT) c1 in cultured RAW264.7 cells were examined. The suppressing effect of ZSTK474 on bone resorption was assessed by the pit formation assay. The in vivo effects of ZSTK474 were studied in collagen-induced arthritis (CIA) in the mouse. Oral daily administration of ZSTK474 was started either when more than half or when all mice developed arthritis. Effects of ZSTK474 were evaluated using the arthritis score and histological score of the hind paws. RESULTS: ZSTK474 inhibited the differentiation of bone marrow OC precursors and RAW264.7 cells in a dose-dependent manner. The inhibitory effect of ZSTK474 was much stronger than that of LY294002, the most commonly used PI3-K inhibitor. In addition, ZSTK474 suppressed the bone resorbing activity of mature OCs. Moreover, oral daily administration of ZSTK474, even when begun after the development of arthritis, ameliorated CIA in mice without apparent toxicity. Histological examination of the hind paw demonstrated noticeable reduction of inflammation and of cartilage destruction in ZSTK474-treated mice. ZSTK474 also significantly decreased OC formation adjacent to the tarsal bone of the hind paw. CONCLUSIONS: These findings suggest that inhibition of PI3-K with ZSTK474 may potentially suppress synovial inflammation and bone destruction in patients with RA. | |
19327410 | Scopolin isolated from Erycibe obtusifolia Benth stems suppresses adjuvant-induced rat art | 2009 Jul | Despite scopolin is a main coumarin constituent in the stems of Erycibe obtusifolia Benth, a herb drug that has long been utilized in traditional Chinese medicine for the treatment of rheumatoid arthritis, little information is available about the pharmacological activities of this compound. The present study was performed to investigate the anti-rheumatic effects of scopolin in adjuvant-induced arthritis (AIA) in rats, and explore the underlying mechanisms of action in views of anti-inflammatory and anti-angiogenic properties in the synovial tissues. Scopolin (50, 100 mg/kg), injected intraperitoneally for 10 days from the onset of secondary response, significantly inhibited both inoculated and non-inoculated paw swelling as well as articular index scores in AIA. Meanwhile, the mean body weight of rats treated with scopolin was higher than that of model group. Rats treated with high dose of scopolin (100 mg/kg) preserved a nearly normal histological architecture of the joints and showed a significant reduction of the new blood vessels in the synovial tissues. Additionally, scopolin could reduce IL-6, VEGF and FGF-2 expressions in rat synovial tissues. In conclusion, scopolin can reduce the clinical symptoms of rat AIA by inhibiting inflammation and angiogenesis, and this compound may be a potent agent for angiogenesis related diseases and can serve as a structural base for screening more potent synthetic analogs. | |
19232063 | Tissue engineering in the rheumatic diseases. | 2009 | Diseases such as degenerative or rheumatoid arthritis are accompanied by joint destruction. Clinically applied tissue engineering technologies like autologous chondrocyte implantation, matrix-assisted chondrocyte implantation, or in situ recruitment of bone marrow mesenchymal stem cells target the treatment of traumatic defects or of early osteoarthritis. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Here, most likely, cartilage formation is impaired and engineered neocartilage will be degraded. Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases. Tissue engineering also provides highly organized three-dimensional in vitro culture models of human cells and their extracellular matrix for arthritis research. | |
20711367 | Immunomodulatory activity of a Chinese herbal drug Yi Shen Juan Bi in adjuvant arthritis. | 2010 Apr | OBJECTIVE: To investigate the immunomodulating mechanisms of a Chinese herbal medicine Yi Shen Juan Bi (YJB) in treatment of adjuvant arthritis (AA) in rats. MATERIALS AND METHODS: Levels of serum tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured by the Enzyme-Linked Immunosorbent Assay (ELISA). Expression of TNF-alpha mRNA and IL-1beta mRNA in synovial cells was measured with the semi-quantitative technique of reverse transcription-polymerase chain reaction (RT-PCR), while caspase-3 was examined by western blot analysis. RESULTS: The administration of YJB significantly decreased the production of serum TNF-alpha and IL-1beta. It also decreased significantly the TNF-alpha mRNA, IL-1beta mRNA, and caspase-3 expression in synoviocytes. CONCLUSIONS: YJB produces the immunomodulatory effects by downregulating the over-activated cytokines, while it activates caspase-3, which is the key executioner of apoptosis in the immune system. This may be the one of the underlying mechanisms that explains how YJB treats the rheumatoid arthritis. | |
19657778 | Sensitive and robust luminescent profiling of anti-La and other autoantibodies in Sjogren' | 2009 Sep | Sjogren's syndrome (SjS) patients often have a variety of extraglandular manifestations including neurological and gastrointestinal involvement. In this study we evaluated the diagnostic performance of luciferase immunoprecipitation system (LIPS) that employs mammalian cell-produced recombinant antigens for analyzing SjS autoantibody responses. LIPS testing of mammalian cell-produced La, Ro60 and Ro52 recombinant antigens with defined commercial antibodies demonstrated highly specific immunoprecitation of each antigen without cross-reactivity. Next, sera from 57 SjS and 25 volunteers were evaluated by LIPS against a panel of human autoantigens. LIPS detected robust anti-La antibody levels in 43/57 SjS patients (75% sensitivity) and markedly outperformed an ELISA (46% sensitivity). Profiling of other SjS-associated autoantigens revealed the presence of anti-Ro60, anti-Ro52 in 63% and 61%, of SjS patients, respectively. Interestingly, a C-terminal fragment of Ro52 (Ro52-Delta2), a protein fragment not previously found to be antigenic by ELISA, also showed positive immunoreactivity in 42/57 SjS patients (65% sensitivity). Additional profiling of other autoantigens revealed that certain SjS patients also showed positive immunoreactivity with thyroid peroxidase (14%), AQP-4 (12%) and the H(+)/K(+) gastric ATPase (16%) suggesting potential autoantibody attack of thyroid, neuronal and gastric parietal cells, respectively. These heterogeneous autoantibody responses detected by LIPS in SjS will likely be useful for diagnosis and for evaluating extraglandular manifestations. | |
19367638 | Subacute inflammatory polyradiculopathy associated with Sjögren's syndrome. | 2009 Jun | Peripheral nervous system involvement is common in Sjögren's syndrome (SS); however, polyradiculopathy has been reported rarely in association with SS, and predominantly chronic forms have been described. We describe a patient with clinical, cerebrospinal fluid, neurophysiological, and neuroradiological evidence of subacute inflammatory polyradiculopathy in whom Sjögren's syndrome was diagnosed after the onset of neurological symptoms. Our case suggests that SS should be included in the differential diagnosis of subacute inflammatory polyradiculopathy. | |
19345210 | Altered expression of genes functioning in lipid homeostasis is associated with lipid depo | 2009 Sep | Functional atrophy and accompanying lymphocytic infiltration and destruction of the lacrimal gland (LG) are characteristics of Sjögren's Syndrome (SjS). The male NOD mouse is an experimental model for the autoimmune exocrinopathy that develops in the LG of SjS patients. Acinar cells in LG of male NOD mice aged 3-4 months were previously shown to accumulate lipid droplets. In the current study, analysis of lipid components revealed that the accumulated lipids were mostly cholesteryl esters (CE). Gene expression microarray analysis followed by real-time RT-PCR revealed alterations in the expression of several genes involved in lipid homeostasis in LG of 12-week-old male NOD mice relative to matched BALB/c controls. A series of upregulated genes including apolipoprotein E, apolipoprotein F, hepatic lipase, phosphomevalonate kinase, ATP-binding cassette D1 and ATP-binding cassette G1 were identified. Comparison of liver mRNAs to LG mRNAs in BALB/c and NOD mice revealed that the differential expressions were LG-specific. Gene expression profiles were also characterized in LGs of female mice, younger mice and immune-incompetent NOD SCID mice. Investigation of the cellular distribution of Apo-E and Apo-F proteins suggested that these proteins normally coordinate to mediate lipid efflux from the acinar cells but that dysfunction of these processes due to missorting of Apo-F may contribute to CE deposition. Finally, the initiation and extent of lipid deposition were correlated with lymphocytic infiltration in the LG of male NOD mice. We propose that impaired lipid efflux contributes to lipid deposition, an event that may contribute to the development and/or progression of dacryoadenitis in the male NOD mouse. | |
20177071 | Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD | 2010 Apr 16 | Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis. | |
20943291 | [Small fibre neuropathy in primary Sjögren syndrome]. | 2011 Mar | PURPOSE: About forty percent of the patients with primary Sjögren's syndrome (pSS) experience chronic neuropathic pain with normal electrodiagnostic studies. Two previous studies suggest that chronic neuropathic pain in pSS is due to small fiber neuropathy (SFN). Quantification of epidermal nerve fiber density after skin biopsy has been validated to diagnose small fiber neuropathy. METHODS: Skin biopsy was performed in 14 consecutive pSS patients (satisfying the american-european classification criteria) with chronic neuropathic pain and normal electrodiagnostic studies suggesting SFN. RESULTS: Fourteen female pSS patients exhibited chronic neuropathic pain [burning sensation (n=14), prickling (n=4), dysesthesia (n=8)] with paroxystic exacerbations (n=10) and allodynia (n=13), for a mean period of 18.4±12.4 months. Neuropathic pain involved mostly hands and feet (n=13), with a distal (n=9) and leg (n=4) predominant distribution. Neurological examination disclosed normal deep tendon responses and absence of motor weakness (n=14). Small fiber neuropathy was confirmed by skin biopsy in 13 cases. Epidermal nerve fiber density was decreased in distal [(n=12), mean 3.5±1.7 fibers/mm (N>6.9)] and proximal site of biopsy [(n=9), mean 7.04±2.63 fibers/mm (N>9.3)]. CONCLUSION: Small fiber neuropathy is commonly responsible of chronic neuropathic pain in pSS. Prevalence, physiopathology and neurological evolution of such neuropathies still remain unknown. | |
19376547 | [Central nervous system involvement in primary Sjögren syndrome]. | 2009 Sep 12 | Sjögren syndrome (SS) is a systemic autoimmune disease that affects the exocrine glands and presents with sicca symptoms of the main mucosa surfaces. The spectrum of the disease extends from sicca syndrome to systemic involvement (extraglandular manifestations). Although earlier studies described central nervous system (CNS) involvement as a frequent extraglandular manifestation of primary SS, symptomatic CNS involvement is rarely described in recent large series (<5%). A wide spectrum of neurological features has been described, including not only asymptomatic white matter lesions in MR examinations, but also severe focal or diffuse neurological processes. Differential diagnosis includes the coexistence of other systemic autoimmune diseases (lupus, antiphospholipid syndrome, vasculitis), cerebrovascular disease and multiple sclerosis. |