Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
23087292 Sjogren's syndrome with distal renal tubular acidosis presenting as hypokalaemic paralysis 2012 Oct 19 A young lady with a history of repeated episodes of generalised weakness and fatigue presented to our hospital with similar symptoms and was found to have severe hypokalaemia. She had been previously diagnosed as hypokalaemic periodic paralysis but during this presentation she had also started complaining of the classic sicca-complex of Sjogren's syndrome, which was not present previously. On subsequent investigations she was found to have normal anion-gap metabolic acidosis with positive urine anion gap consistent with the diagnosis of distal renal tubular acidosis (RTA). It was thus concluded that the distal RTA secondary to Sjogren's syndrome was the cause of severe hypokalaemia in our patient. By presenting this case we aim to not only highlight one of the rare presentations of Sjogren's syndrome but also the favourable response of our patient to potassium replacement alone.
22174879 Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogre 2011 The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR9 inhibitors, and the in-house oligonucleotide BL-7040. We then measured salivation, inflammatory response markers, and expression of proteins downstream to NF-κB activation pathways. Finally, we labeled proteins of interest in salivary gland biopsies from Sjogren's syndrome patients, compared to Sicca syndrome controls. We show that in NOD mice BL-7040 activates TLR9 to induce an alternative NF-κB activation mode resulting in increased salivation, elevated anti-inflammatory response in salivary glands, and reduced peripheral AChE activity. These effects were more prominent and also suppressible by TLR9 inhibitors in NOD mice, but TLR9(-/-) mice were resistant to the salivation-promoting effects of CpG oligonucleotides and BL-7040. Last, salivary glands from Sjogren's disease patients showed increased inflammatory and decreased anti-inflammatory biomarkers, in addition to decreased levels of alternative NF-κB pathway proteins. In summary, we have demonstrated that activation of TLR9 by BL-7040 leads to non-canonical activation of NF-κB, promoting salivary functioning and down-regulating inflammation. We propose that BL-7040 could be beneficial in treating Sjogren's syndrome and may be applicable to additional autoimmune syndromes.
22208656 Current and future challenges in primary Sjögren's syndrome. 2012 Aug Sjögren's syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands. SS particularly affects the lacrimal and salivary glands. Dry mouth and dry eyes are frequently proffered as presenting symptoms, but nonspecific symptoms such as malaise and fatigue, and extraglandular manifestations like purpura, polyneuropathy and arthritis are also often present. Moreover, lymphomas develop in about 7.5% of SS patients, mostly marginal zone B-cell lymhomas. Futhermore, SS has a very substantial impact on the patients' quality of life and their daily activities. Recently, many breakthroughs have been seen in salivary diagnostics, which not only can be used for diagnosis but also for monitoring of disease activity and disease progression as well as for objectively scoring the effect of intervention treatment with biologicals. In addition, salivary proteomics, genomics and system biology have been shown to be very promising tools in unravelling the pathophysiology of SS, thus providing in depth insight in its underlying mechanisms which could give clues for intervention therapies with biologicals. The latter is of particular interest as B cell depletion therapy has been shown a very promising therapy for a subgroup of SS patients. When applying salivary diagnostics in combination with instruments to rate disease activity and progression in SS, one might be able to select those SS patients who respond to a particular type of biological. These topics are addressed in this review and promises for the near future are described.
21870104 Vasculitis in Sjögren's Syndrome. 2011 Dec Sjögren's syndrome is a chronic autoimmune disease that is commonly manifested by immune attack on the exocrine glands with resultant dry eyes and dry mouth. Sjögren's syndrome patients also have disease in other organs. One of the most common extraglandular manifestations is vasculitis. Skin vasculitis, with palpable purpura clinically and leukocytoclastic vasculitis on pathological examination, is common. Although half of those individuals with subcutaneous vasculitis have only a single episode, skin vasculitic involvement is associated with more severe disease. Necrotizing vasculitis of medium-sized vessels resembling polyarteritis nodosa can occur in Sjögren's syndrome patients. Experience in therapy for vasculitis is limited, but intravenous IgG may be effective. Recent data support a relationship between neuromyelitis optica (Devic disease) and Sjögren's syndrome. Sjögren's syndrome patients with optic neuritis or transverse myelitis have anti-aquaporin-4, which are characteristic of Devic disease. Devic disease patients have salivary lymphocytic infiltration similar to that found among Sjögren's syndrome patients.
21660135 Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury 2011 Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity.
23083054 'The eyes see what the mind knows.' Adult-onset Still's disease, a case series and review 2012 Oct AIM: Adult-onset Still's disease (AOSD) is a rare disease. Very few cases have been reported from the South-Asian region so the aim of this study is to assess the clinical and laboratory aspects of 15 patients with AOSD in a tertiary referral hospital in Karachi. METHODS: Retrospective data was collected from all patients diagnosed using Yamaguchi criteria for AOSD between January 2004 and December 2010 at Jinnah Medical College Hospital, Karachi. RESULTS: Data of 15 patients with AOSD were analyzed. Their ages ranged from 17 to 55 years, the male-to-female ratio being 6:1. The most common clinical features were fever and articular symptoms (100%), sore throat (60%), rash (53.3%), weight loss (93.3%), lymphadenopathy (40%) and elevated erythrocyte sedimentation rate (86.7%). All patients had leukocytosis with counts>20,000/mm 3 were seen in 40%. Elevated liver enzymes were present in 80% of the case series and hyperferritinemia in 100% with a mean of 3,962 ng/mL (range 555-13,865). Ambiguity in presentation and lack of serologic markers make diagnosis of AOSD difficult as 40% of patients were receiving empirical anti-tuberculous therapy prior to final diagnosis. CONCLUSION: It is necessary for physicians to have a high index of suspicion for AOSD in patients with high-grade fever, arthralgia and leukocytosis.
22417709 TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in p 2012 Mar 14 INTRODUCTION: The study was undertaken to investigate the interrelation of toll-like receptor (TLR) and interleukin (IL)-17 in the salivary glands of patients with primary Sjogren's syndrome (pSS) and to determine the role of TLR and IL-17 in the pathophysiology of pSS. METHODS: The expressions of various TLRs, IL-17 and the cytokines involved in Th17 cell differentiation including IL-6, IL-23, tumor necrosis factor-alpha (TNF-α) and IL-1β were examined by immunohistochemistry in salivary glands of pSS patients. The IL-17 producing CD4+ T cells (Th17 cells) were examined by flow cytometry and confocal staining in peripheral mononuclear blood cells (PMBCs) and salivary glands of pSS patients. After PBMCs were treated with TLR specific ligands, the induction of IL-17 and IL-23 was determined using real-time PCR and ELISA. The signaling pathway that mediates the TLR2 stimulated production of IL-17 and IL-23 was investigated by using treatment with specific signaling inhibitors. RESULTS: We showed that TLR2, TLR4, TLR6, IL-17 and the cytokines associated with Th17 cells were highly expressed in salivary glands of pSS patients but not in controls. The expressions of TLR2, TLR4 and TLR6 were observed in the infiltrating mononuclear cells and ductal epithelial cells, whereas IL-17 was mainly observed in infiltrating CD4+ T cells. The number of IL-17 producing CD4+ T cells was significantly higher in pSS patients both in PBMCs and minor salivary glands. The stimulation of TLR2, TLR4 and TLR6 additively induced the production of IL-17 and IL-23 from the PBMCs of pSS patients especially in the presence of TLR2 stimulation. IL-6, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-kB) pathways were implicated in the TLR2 stimulated IL-17 and IL-23. CONCLUSIONS: Our data demonstrate that TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in pSS. Therefore, therapeutic strategies that target TLR/IL-17 pathway might be strong candidates for treatment modalities of pSS.
22337248 A clinical prediction rule for lymphoma development in primary Sjögren's syndrome. 2012 Apr OBJECTIVE: To develop and validate a practical prediction rule for the progression from primary Sjögren's syndrome (pSS) to B cell non-Hodgkin's lymphoma (B cell NHL) based on the combination of routinely available clinical and serological disease variables. METHODS: The case records of 563 patients with pSS were reviewed, and their demographic, clinical, and immunologic features were collected. Multivariate logistic regression analysis was performed to identify independent risk factors for lymphoma development and to create a propensity score for discrimination between patients at risk of B cell NHL and those patients not at risk. The model was internally validated by resampling procedures. RESULTS: Out of 563 patients with pSS, 387 fulfilling the American European Consensus Group criteria (12 with B cell NHL, 375 without B cell NHL) were included in our study. Salivary gland enlargement (p = 0.001), low C3 (p = 0.035) and/or C4 levels (p = 0.021), and disease duration (p = 0.001) were identified as independent risk factors for B cell NHL in pSS. The optimal threshold of the propensity score was determined at Y = 4.26, which allowed us to identify patients who develop B cell NHL with a sensitivity of 78% and specificity of 95%. The leave-one-out cross-validated prediction error was 6%, and the median bootstrapped sensitivity and specificity were 71% and 95%, respectively. CONCLUSION: We created a "bedside" prediction model for the identification of patients with pSS who are at risk for B cell NHL, which revealed an excellent discriminative ability and a good internal and external reproducibility.
22248244 Increased serum levels of high-mobility group box 1 (HMGB1) in primary Sjögren's syndrome 2012 Mar OBJECTIVE: To determine serum levels of high-mobility group box 1 (HMGB1) in patients with primary Sjögren's syndrome (pSS) as compared to healthy volunteers and patients with sicca symptoms, and to determine whether serum HMGB1 levels are correlated with disease activity in pSS. METHODS: Serum HMGB1 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 101 patients with pSS, 13 patients with sicca symptoms, and 40 healthy volunteers. Clinical and laboratory variables were also analysed and serum HMGB1 levels were correlated with the Sjögren's Syndrome Disease Activity Index (SSDAI). RESULTS: The serum levels of HMGB1 were significantly increased in pSS patients as compared to patients with sicca symptoms and healthy controls (p = 0.04 and p = 0.01, respectively). In the subgroups of patients with anti-SSA autoantibodies, the serum levels of HMGB1 were significantly higher than those in the subgroup of pSS patients who were anti-SSA negative and in healthy controls and patients with sicca symptoms (p < 0.001, p < 0.001, and p = 0.004, respectively). There was no significant correlation between serum HMGB1 levels (in pSS patients with anti-SSA autoantibodies) and SSDAI score (r = 0.03, p = 0.83). Patients with active disease had higher HMGB1 levels than patients with low disease activity (p = 0.04), but HMGB1 levels did not correlate with the SSDAI. CONCLUSION: Serum HMGB1 levels are increased in pSS patients and more specifically in patients with SSA autoantibodies. There was, however, no correlation of HMGB1 with the SSDAI.
21246358 The prevalence and the clinical relevance of anti-Ro52 in Korean patients with primary Sjà 2012 Feb So far, there was no report on the prevalence and clinical relevance of anti-Ro52 in primary Sjögren's syndrome (pSS) patients in Korea. In this study, we investigated the prevalence and the clinical relevance of anti-Ro52 in Korean patients with pSS. We retrospectively reviewed the medical records of 96 patients with pSS. On the first visit clinical manifestations, laboratory features and autoantibodies were assessed. We divided subjects into 4 groups according to the presence of anti-Ro60 or anti-Ro52 and investigated the association between those autoantibodies and clinical manifestations. Anti-Ro52 (66.7%) was the most frequently detected autoantibody, followed by anti-Ro60 (52.1%) and anti-La (49.0%). Patients with anti-Ro52 had higher frequency of liver and muscle involvements than those without, while anti-Ro60 exhibited negative association with liver involvement. Anti-Ro52 showed significant relative risk for liver involvement (OR = 5.987, P = 0.038, 95% CI = 1.109-32.326), while anti-Ro60 showed inverse relative risk for liver involvement (OR = 0.122, P = 0.003, 95% CI = 0.031-0.479). Anti-Ro52 also showed significant OR for muscle involvement (OR = 9.533, P = 0.044, 95% CI = 1.059-85.793). In conclusion, anti-Ro52 was the most frequently detected autoantibody except ANA in patients with pSS in Korea. Anti-Ro52 was significantly associated with liver and muscle involvements, while anti-Ro60 was inversely associated with liver involvement in Korean patients with pSS.
22527134 IL-32 aggravates synovial inflammation and bone destruction and increases synovial natural 2013 Mar This study was performed to investigate the effects of IL-32 on joint inflammation, bone destruction, and synovial cytokine expressions, and on synovial natural killer (NK) cell expressions in collagen-induced arthritis (CIA). CIA was induced by type II collagen in DBA1 mice, and phosphate-buffered saline (PBS group) or IL-32 (IL-32 group) were injected into both knee joints at day 28 and 32, then mice were killed at day 35. Severity of synovial inflammation and bone destruction was determined by histological scoring method, and synovial cytokine expressions such as IL-1β, TNF-α, IL-17, IL-18, IFN-γ, IL-21, and IL-23 were measured by real-time RT-PCR and western blot. Synovial NK cell expressions were determined by real-time RT-PCR, western blot and immunohistochemistry, and chemokines and chemokine receptors expressions that are associated with NK cell migration were determined by real-time RT-PCR. Scores of synovial inflammation and bone destruction, synovial expressions of IL-1β, TNF-α, IL-18, and IFN-γ were significantly increased in IL-32 group compared with PBS group. Synovial expressions of NK cell, and chemokines (CCL2 and CXCL9) and chemokine receptors (CCR2 and CCR5) that are associated with NK cell migration were significantly increased in IL-32 group compared with PBS group. IL-32 aggravated joint inflammation and bone destruction and increased synovial expressions of inflammatory cytokine and NK cells in CIA. These results suggest that IL-32 play a role in joint inflammation and bone destruction, and IL-32 might be a new target for treatment of rheumatoid arthritis.
21469939 The prothrombinase activity of FGL2 contributes to the pathogenesis of experimental arthri 2011 OBJECTIVE: Fibrin deposition is integral to the pathogenesis of collagen-induced arthritis (CIA), an experimental model of rheumatoid arthritis (RA). Membrane-associated fibrinogen-like protein 2 (mFGL2), a novel inducible prothrombinase, generates fibrin by an alternate pathway and has been reported to be involved in the pathogenesis of a number of immune-mediated diseases. We hypothesized that expression of mFGL2 in inflamed synovium contributes to the fibrin deposition and subsequent inflammation in arthritis. METHODS: DBA/1 mice were immunized with 100 µg bovine collagen type II (CII) emulsified in complete Freund's adjuvant (CFA) followed by lipopolysaccharide (LPS) injection. Expression of mFGL2 prothrombinase in association with fibrin deposition was examined in mice with CIA and CD200-treated mice following induction of CIA. To directly assess the contribution of mFGL2, fgl2(-/-) mice were injected with antibody to CII (anti-CII). RESULTS: Levels of fgl2 mRNA transcripts and mFGL2 protein were markedly up-regulated in joints of mice that developed CIA. Fibrin deposition was prominent within the synovial lining and articular joint space associated with expression of mFGL2. Inhibition of CIA by the immunosuppressant CD200 was associated with decreased expression of fgl2 mRNA and mFGL2 protein and absence of fibrin deposition. Following injection of anti-CII, all fgl2(+/+) mice developed severe arthritis with clinical and histological manifestations characteristic of RA, whereas fgl2(-/-) mice failed to develop any clinical manifestation or histological evidence of arthritis. CONCLUSIONS: This study demonstrates that the prothrombinase activity of mFGL2 contributes to the pathogenesis of experimental arthritis. These studies may have therapeutic implications for patients with RA.
21188452 Therapeutic effect of D1-like dopamine receptor antagonist on collagen-induced arthritis o 2011 Jun Dopamine activates D1-like and D2-like receptors (D1R and D2R). While D1R antagonists have ameliorated the severity of disease in some experimental autoimmune models of mice by promoting interferon (IFN)-γ and inhibiting interleukin (IL)-17 production by T cells, dopamine effects in the immune system are reportedly diverse. To investigate the impact of D1R blockade on an animal model of rheumatoid arthritis (RA), DBA/1 mice with collagen-induced arthritis (CIA) were treated with a selective D1R antagonist, SCH23390, after the primary immunization. This treatment suppressed the severity of the CIA. Nevertheless, serum levels of antibodies to type II collagen were not affected by the treatment. Th1/Th17 differentiation of splenic T cells in the treated animals was not biased. In vitro, when bone marrow-derived macrophages were stimulated in the presence of the D1R antagonist SCH23390, alteration of inflammatory cytokine expression was not observed, but their in vitro differentiation to osteoclasts was inhibited. Co-administration of a selective D1R agonist, A68930, abrogated the in vivo anti-arthritic effect and the in vitro suppression of osteoclastogenesis by the D1R antagonist. Our results argue that D1R blockade is potentially a new approach to the treatment of RA. Its effect could be partly attributable to the inhibition of osteoclastogenesis.
22539421 Effect of triptolide on T-cell receptor beta variable gene mRNA expression in rats with co 2012 Jun Triptolide (TP) has been used in the treatment of rheumatoid arthritis (RA), but its mechanism of action is not understood. T-cell activation and associated release of cytokines appear to be major factors in the pathogenesis of RA. The overexpression of T-cell receptor (TCR) variable gene (V gene) fragments can cause the activation and infiltration of autoreactive T cells. This study examines the effects of TP on rats with collagen-induced arthritis (CIA). The levels of interleukin-10 (IL-10) in the serum were examined with ELISA. Compared to the CIA group, the levels of IL-10 were greater in the TP treatment group. Real-time quantitative polymerase chain reaction confirmed that the expression of TCR V beta (BV) 15 and TCR BV19 was increased in the CIA group, whereas in the TP treatment group, the expression was decreased. In this study, TP was found to enhance IL-10 levels and decrease the expression levels of TCR BV15 and TCR BV19. These changes might help explain the effectiveness of TP in the treatment of RA.
22354915 Intraarticular gene delivery of CTLA4-FasL suppresses experimental arthritis. 2012 Jun T lymphocytes are key inflammatory cells contributing significantly to the pathogenesis of Rheumatoid arthritis (RA). Biological treatments targeting T lymphocytes may provide an efficient approach for treatment of RA. CTLA4-FasL, a fusion product of extracellular domains of CTLA4 and FasL, integrating two inhibitory elements against T cells into one molecule, might be a desirable derivative of engineered soluble FasL or CTLA4 and have therapeutic potential in RA. The aim of this study was to investigate whether simultaneous induction of Fas-mediated apoptosis and blockade of co-stimulation signal by CTLA4-FasL gene delivery has a suppressive effect on adjuvant-induced arthritis (AIA) in Lewis rats. Recombinant adeno-associated virus (rAAV) vectors encoding rat CTLA4-FasL fusion gene (rAAV.CTLA4-FasL) or enhanced green fluorescent protein (rAAV.EGFP) were injected intraarticularly into both ankle joints after immunization. The ankles were monitored by measures of clinical, histological and inflammatory cytokines' changes. Treatment using rAAV.CTLA4-FasL resulted in a significant suppression of AIA compared with rAAV.EGFP control, as reflected in the mainly clinical signs including articular index, ankle joint thickness and paw swelling and typically histological characters of arthritic joints including synovial hyperplasia, inflammatory cells infiltration and cartilage degradation. Treatment with rAAV.CTLA4-FasL also significantly decreased the levels of key proinflammatory cytokines in AIA joints. Moreover, local productions of transgene mRNA and protein of CTLA4-FasL were found in injected joints without systemic distribution. Our results indicate that rAAV.CTLA4-FasL profoundly suppressed experimental model of RA, implicating the potential therapeutic applications for suppression of RA by local joint delivery of CTLA4-FasL.
22057635 Prospective monitoring of Epstein-Barr virus and other herpesviruses in patients with juve 2012 Aug Methotrexate (MTX) is widely used for the treatment of articular-type juvenile idiopathic arthritis (JIA), but patients receiving MTX for rheumatoid arthritis have been reported to be at increased risk of reactivation of Epstein-Barr virus (EBV) and the development of lymphoproliferative disorder. The association between MTX and reactivation of herpesviruses in pediatric patients is not yet understood. We prospectively monitored the viral load of EBV, cytomegalovirus (CMV), and herpesvirus 6 (HHV-6) in four JIA patients treated with MTX for 12-24 months. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, was added to the therapeutic regimen in three patients during the observation period. Prior to the administration of MTX, EBV and HHV-6 were detected by PCR in two patients. Significant increases in EBV and HHV-6 load were not observed following the administration of MTX or tocilizumab. In one patient, a relatively high EBV load remained detectable during 21 months of observation in the absence of clinical symptoms. CMV was not detected throughout the observation period in any patient. This is the first report monitoring the longitudinal DNA loads of EBV and other herpesviruses in JIA patients. EBV and HHV-6 were often detectable, but treatment with MTX and tocilizumab did not appear to influence the viral load.
22513335 Obesity aggravates the joint inflammation in a collagen-induced arthritis model through de 2012 Jul 31 White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-α. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA.
21972327 Treatment of chronic inflammatory diseases with implantable medical devices. 2011 Aug Implantable medical devices are finding increasing use in the treatment of diseases traditionally targeted with drugs. It is well established that the cholinergic anti-inflammatory pathway serves as a physiological regulator of inflammatory responses, but stimulation of this pathway therapeutically by electrical stimulation of the vagus nerve can also diminish excessive or dysregulated states of inflammation. Recent data from a wide variety of animal models, as well as evidence of reduced vagal tone in rheumatoid arthritis and other inflammatory diseases, support the rationale for, and feasibility of, developing implantable vagal nerve stimulation devices to treat chronic inflammation in humans.
22127700 Early diagnosis of arthritis in mice with collagen-induced arthritis, using a fluorogenic 2011 Dec OBJECTIVE: Early treatment based on an early diagnosis of rheumatoid arthritis (RA) could halt progression of the disease, but early diagnosis is often difficult. Matrix metalloproteinase 3 (MMP-3) is thought to be particularly important in the pathogenesis of RA. The aim of this study was to investigate whether an MMP-3-specific polymeric probe could be used for early diagnosis and for visualizing the progression of arthritis, using a near-infrared fluorescence (NIRF) imaging system. METHODS: The MMP-3-specific polymeric probe was developed by conjugating NIRF dye, MMP substrate peptide, and dark quencher to self-assembled chitosan nanoparticles. One hour after intravenous administration of the probe, fluorescent images of mice with collagen-induced arthritis at different stages of disease development were obtained. The correlation between the fluorescence recovered in in vivo imaging when using an MMP-3-specific polymeric probe and up-regulated MMP-3 activity in the joint tissues was evaluated by Western blotting and immunohistochemical staining. Histologic analysis and micro-computed tomography (micro-CT) were also used to assess arthritis progression. RESULTS: A significantly higher NIRF signal was recovered from arthritic joints compared with normal joints at 14 days after the first immunization, before any erythema or swelling could be observed with the naked eye or any erosion was detected by histologic analysis or micro-CT. The results of immunohistochemical analysis and Western blotting confirmed that the fluorescence recovered in the in vivo imaging was related to up-regulated MMP-3 activity in the joint tissues. CONCLUSION: An MMP-3-specific polymeric probe provided clear early diagnosis of arthritis and visualization of arthritis progression using an NIRF imaging system. This approach could be used for early diagnosis and for monitoring drug and surgical therapies in individual cases.
23234733 [B lymphocyte stimulator in systemic lupus erythematosus]. 2012 Jul The B lymphocyte stimulator (BLyS) is an essential protein for the growth and survival of B cells. BLyS is expressed on monocytes, macrophages, and dendritic cells. BLyS binds to three receptors on B cells: BAFF-R, BCMA, and TACI. BLyS overexpression in mice leads to lupus-like syndrome, but not in all, whereas BLyS deficient mice results in a block of B cell development. High serum levels of BLyS can be detected in patients with lupus and rheumatoid arthritis. BLyS antagonists are an attractive target for treating autoimmune diseases.