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ID PMID Title PublicationDate abstract
16362448 Clinical significance of IL-18, IL-15, IL-12 and TNF-alpha measurement in rheumatoid arthr 2006 Jul The aim of the study was to evaluate the clinical significance of serum (S) and synovial fluid (SF) interleukin (IL)-18, IL-15, IL-12 and the tumor necrosis factor alpha (TNF-alpha) measurements in relation to laboratory and clinical measures of disease activity of patients with active rheumatoid arthritis (RA). Sixty-four patients with RA and 25 patients with osteoarthritis (OA) were included in this study. RA activity was determined using the Disease Activity Score (DAS) 28 index. Concentrations of IL-18, IL-15, IL-12 and TNF-alpha were measured by ELISA. Serum C-reactive protein (CRP) levels were also determined. Cross-sectional correlations between S and SF levels of cytokines and values of DAS 28 index were calculated. The results have shown that IL-18, IL-15, IL-12 and TNF-alpha levels in S and SF of patients with RA were significantly higher than the levels obtain from patients with OA (p<0.01). Significantly higher levels of IL-18, IL-15 and TNF-alpha were found in the SF compared to the S of patients with RA (p<0.01). Significantly higher S and SF levels of all four cytokines and serum CRP values were found in RA patients with high disease activity (DAS 28>5.1) compared to those with mild (DAS 28>3.2) and low disease activity (DAS 28>2.6) (p<0.01). Serum and SF concentrations of all four cytokines positively correlated with DAS 28 index values, i.e., disease activity. A poor correlation was found for S and SF IL-12 whereas the highest coefficient of correlation was found for SF IL-18 (r=0.879, p<0.01), and SF TNF-alpha (r=0.827, p<0.01) and disease activity in this study. Strong correlation was found between SF TNF-alpha and SF IL-18 levels (r=0.732, p<0.01). In conclusion, SF IL-18 and TNF-alpha levels in RA patients are good indicators of disease activity. The results obtained support the use of the DAS in clinical practice as a reliable method in assessing disease activity in RA patients.
16127006 Rationale for T cell inhibition by cyclosporin A in major autoimmune diseases. 2005 Jun T cells exert a fundamental role in different autoimmune chronic inflammatory diseases. The low-affinity autoreactive T cell clones provide the first amplification loop after the antigen (AgX) presentation, and if not counterregulated by the T regulatory cells (Treg), they maintain the inflammation and predispose to organ damage. Interrupting the T cell amplification loop through calcineurin antagonists leads to maintenance of the whole process under the autoimmune threshold.
16114981 Sulfasalazine: a review of its use in the management of rheumatoid arthritis. 2005 Sulfasalazine (salazosulfapyridine) [Azulfidine, Salazopyrin] is a well established disease-modifying antirheumatic drug (DMARD) used in the treatment of patients with rheumatoid arthritis. Clinical trials with sulfasalazine have used an array of measures of disease activity, such as the number of tender and swollen joints, Ritchie articular index (RAI) and erythrocyte sedimentation rate (ESR). In randomised, double-blind, placebo-controlled trials, sulfasalazine was associated with statistically significant benefits for various measures of disease activity, according to results of individual trials and/or meta-analysis. Sulfasalazine was associated with broadly similar efficacy to that of various other DMARDs in several randomised, double-blind, comparative trials. Promising results have also been demonstrated with sulfasalazine in combination with other DMARDs (e.g. methotrexate and hydroxychloroquine) in patients with early rheumatoid arthritis and in those with more established disease. Sulfasalazine was generally well tolerated in clinical trials, the most frequently reported adverse effects being adverse gastrointestinal effects, headache, dizziness and rash; myelosuppression can also occur. Sulfasalazine has a relatively short lag time until its onset of action and is often considered to be among the more efficacious traditional DMARDs. Based on considerations of safety, convenience and cost, many rheumatologists (particularly outside of the US) select sulfasalazine as initial therapy, although preferred first-line treatment options vary between countries.
16257361 Rheumatoid arthritis among women in the Agricultural Health Study: risk associated with fa 2005 Nov PURPOSE: Farming has been associated with increased risk of rheumatoid arthritis (RA) in some studies, but specific causes have not been identified. We studied risk factors for RA in the Agricultural Health Study, a cohort of over 57,000 licensed pesticide applicators and their spouses. METHODS: We used a nested case-control design, limited to female participants. Physician-confirmed cases (n = 135) were matched to five controls each (n = 675) by birth date. We used logistic regression, adjusting for birth date and state to examine associations, as estimated by odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Risk of RA was not associated with mixing or applying pesticides overall or with any pesticide class, nor did it vary by number of days or years of use. Certain pesticides were associated with small nonsignificantly increased risks, including lindane (OR = 1.8, 95% CI: 0.6-5.0). RA risk was associated with welding (OR = 2.1, 95% CI: 0.8-5.4), albeit imprecisely, but not with solvents or sunlight. CONCLUSIONS: We did not identify any strong risk factors for RA. Because of the severe disability associated with this relatively common disease, further investigation into causes is warranted both in the Agricultural Health Study and elsewhere.
15645233 Influence of serum folic acid levels on plasma homocysteine concentrations in patients wit 2006 Jan The purpose of this study was to investigate whether negative effects of methotrexate (mtx) on blood homocysteine (hmc) levels can be prevented with the replacement of folic acid. 42 female patients with rheumatoid arthritis (RA) were studied. Patients were separated into two groups according to their treatment status with mtx (group I: 27 patients taking mtx and folic acid; group II: 15 patients not using mtx). The level of hmc was found to be 6.3+/-2.4 micromol/l in group I and 7.87+/-3.2 micromol/l in group II (p>0.05). Folic acid levels of group I and II were found to be 21.3+/-15.9 ng/ml and 8.41+/-2.86 ng/ml respectively (p<0.001). There was a statistically-significant correlation between age and hmc levels (r=0.386, p=0.012). Negative statistically-significant correlations were observed between folic acid and hmc levels. The effects of mtx on hmc can be prevented with the replacement of folic acid.
16421645 Urticaria and angiedema-like skin reactions in a patient treated with adalimumab. 2007 May Specific inhibition of the cytokine tumor necrosis factor alpha has resulted in significant clinical and laboratory improvement of patients with chronic inflammatory diseases of Th1 phenotype. Etanercept is a recombinant fusion protein of two p75 soluble receptors, while infliximab is a chimeric monoclonal antibody. Both have been considered to be immunogenic and cause various immune-mediated skin reactions. On the other hand, adalimumab, a human monoclonal antibody, was expected to cause little or no immune-mediated skin reactions. Herein, we report a patient with rheumatoid arthritis treated with adalimumab, who after the seventh injection, developed angiedema affecting the lips and face, as well as an urticaria-like skin reaction affecting the trunk. These reactions were followed by hypotension. The patient was treated appropriately and after 2 h, the rashes and the edema disappeared and the patient gradually recovered completely. Adalimumab was discontinued.
16239377 The 2005 International Symposium on Advances in Targeted Therapies: what have we learned i 2005 Nov This essay summarises a personal perspective on where we have got to in the five years since the turn of the last century. The focus is on advances in knowledge of antitumour necrosis factor (anti-TNF) therapy of rheumatoid arthritis and other chronic immune-inflammatory rheumatic diseases. The accumulating knowledge is clarifying the scope and limitations of efficacy, safety, and durability of these agents. It is defining the unmet needs of patients and communities worldwide for the future. The call is for progress in providing more cost-effective advances in therapeutics that not only interrupt the disease process long term but also reverse the anatomical and functional consequences of disease and the impairment in quality of life.
15789881 HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated 2005 Jan OBJECTIVE: Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be 1 in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated in a rheumatology clinic population. METHODS: Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs. RESULTS: The C282Y and H63D allele frequencies were 4.5 and 12.8 in patients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01). CONCLUSIONS: Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.
16437199 Temporomandibular disorders seen in rheumatology practices: A review. 2006 Jul Temporomandibular disorders are recognized as the most common nontooth-related chronic orofacial pain conditions. This article reviews the recent temporomandibular disorders literature and summarizes the temporomandibular disorders seen in rheumatology practices. Arthritis is a common condition affecting the temporomandibular joint. Although degenerative and rheumatoid arthritis are the most frequently encountered infectious arthritis, metabolic arthritis, spondyloarthropathies and the traumatic arthritis have also been reported. Distinguishing between different temporomandibular disorders is as important as the clinical course, long-term prognosis, and therapy. Diagnostic criteria are generally based on signs and symptoms of the patient. The American Academy of Orofacial Pain established the first well-defined diagnostic classification. In addition, Research Diagnostic Criteria for Temporomandibular Disorders have been developed using similar classification. In the treatment of temporomandibular disorders, conservative and noninvasive treatments are endorsed for the initial care of nearly all TMD patients because the majority of patients with TMD achieve good relief of symptoms with conservative treatment.
16263782 Touch-screen computer systems in the rheumatology clinic offer a reliable and user-friendl 2006 Jan OBJECTIVES: To investigate the feasibility of collecting rheumatoid arthritis (RA) patient self-administered outcome data using touch-screen computers in a routine out-patient clinic. METHODS: Forty patients with RA completed the touch-screen and paper Rheumatoid Arthritis Quality of Life Questionnaire (RAQol) in the clinic and rated ease of use and preference. Forty-five others completed the Stanford Health Assessment Questionnaire (HAQ) and visual analogue scales (VASs) for pain, fatigue and global arthritis activity on touch screen and paper and a joint assessment on touch screen. They rated ease of use and willingness to complete the assessment again. Joints were independently assessed, and completion times and technical problems recorded. RESULTS: No technical problems were encountered. The touch-screen RAQol took no longer to complete, was preferred by 64% (33% had no preference) and was rated significantly higher for ease of use (two-tailed P=0.003, n=40) even by computer naïve patients (two-tailed P=0.031, n=24). Intraclass correlation coefficients between methods were high for RAQol (0.986) and tender joint counts (0.918), and as high for the pain, fatigue and global activity (0.855, 0.741, 0.881) as for test-retest of the paper versions (0.865, 0.746, 0.863). Ninety-eight per cent rated the touch screen very/quite easy for HAQ and VAS, and 90% for joint assessment. Ninety-six per cent stated a willingness to complete the touch-screen assessment in clinic again. CONCLUSIONS: Touch-screen questionnaires in the clinic can produce comparable results to paper, eliminate the need for data entry and afford immediate access to results. It is an acceptable, and in many cases a preferable, option to paper, regardless of age and previous experience of computers.
16955275 Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like sy 2006 Oct Fibroblast-like synoviocytes (FLS) play a key role in the genesis of rheumatoid arthritis (RA). FLS are among the most versatile cells with the potential to activate an array of genes that are able to initiate and propagate inflammation in RA-affected joints. Controlling activation of FLS might hold the key to restraining inflammation in RA-affected joints. In this study, we investigate the effect and mechanisms of short-term hyperthermia on a series of proinflammatory genes in FLS. In vitro experiments demonstrate that exposure of FLS to elevated temperatures for the duration of 30 min prevents activation of a series of genes with proinflammatory properties. Exposure to hyperthermia reduces IL-1beta-induced prostaglandin E2 release, suppresses activation of the adhesion molecules VCAM-1, ICAM-1, the cytokines TNFalpha, IL-1alpha, IL-1beta, IL-8 as well as COX-2 protein synthesis. Real time reverse transcriptase-polymerase chain reaction showed that hyperthermia altered gene expression at the transcriptional level. The amount and the duration of inhibition is gene-specific and lasts for up to 25 h. As to the mechanism of inhibition, electrophoretic mobility shift assay experiments demonstrated that exposure of FLS to hyperthermia prevents IL-1beta-induced NF-kappaB translocation and subsequent DNA binding. Many mechanisms have been shown to be involved in hyperthermia-mediated effects on NF-kappaB-DNA interactions. We demonstrate by Western blot experiments that in FLS, hyperthermia prevents the phosphorylation and subsequent degradation of IkappaBalpha, therefore retaining the NF-kappaB complex in the cytoplasm. Carefully controlled in vivo tests are certainly needed before one can take full advantage of those phenomena; however, the ease by which the temperature in joints can be modulated might offer an opportunity for manipulating inflammatory processes in joints by simple balneological means.
16160208 Analytic choices in economic models of treatments for rheumatoid arthritis: What makes a d 2005 Sep OBJECTIVES: To compare the analytic judgments, data, and assumptions of different models used in the economic evaluation of infliximab, one of a new class of drugs for rheumatoid arthritis (RA). METHODS: A detailed assessment was made of 4 models, 1 submitted (in a reimbursement dossier) by the manufacturer, 1 produced by an independent academic group, and 2 recently published in the literature. Factors considered included the key data inputs, assumptions about the sequencing of treatments for RA, the methods used to calculate health utilities, and the estimation of cost offsets. RESULTS: Two of the 4 models, although embodying different methodological approaches, gave fairly similar results (approximately 25,000 pounds- 35,000 pounds cost per additional quality-adjusted life year [QALY] gained). The other 2 models, both by an independent academic group, gave much higher estimates, ranging from 50,000 pounds to 60,000 pounds to more than 100,000 pounds per additional QALY. The differences appeared to depend mainly on differences in model structure, the assumptions about the positioning of infliximab in the treatment sequence, and the relationship between Health Assessment Questionnaire (HAQ) states and QALYs. CONCLUSIONS: Economic models of treatments for RA incorporate different key data inputs and analytic judgments. However, convergence was observed in some of the estimates produced by the models, particularly when adjustments were made for some of the differences in input parameters. Nevertheless, differences in the choice of model structure and in key assumptions also had a major impact on results. Therefore, more discussion is needed to reach a consensus on some of these methodological issues.
16540554 A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patient 2006 Dec OBJECTIVE: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. METHODS: 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach. RESULTS: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period. CONCLUSION: After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.
16287922 Forefoot joint damage, pain and disability in rheumatoid arthritis patients with foot comp 2006 Apr OBJECTIVE: To assess (i) the relationship between forefoot joint damage and foot function (expressed as gait and pressure parameters), (ii) the relationship between foot function and pain, and (iii) the relationship between foot function and disability in patients with foot complaints secondary to rheumatoid arthritis (RA). METHODS: Sixty-two patients with RA-related foot complaints were included. Measurements of joint damage, gait characteristics, plantar pressure, pain and disability were obtained. Data were analysed using descriptive and correlational techniques. RESULT: s. Joint damage on radiographs of the forefoot correlated significantly with forefoot pressure (r = 0.296, P = 0.020). Further investigation of the metatarsophalangeal joints (MTPs) showed joint damage to correlate significantly with peak pressure and pressure-time integral (PTI) of MTP1 and MTP4. A significant correlation between PTI under the forefoot and barefoot pain was found (r = 0.290, P = 0.022). Gait parameters (total contact time and the duration of heel loading) and disability, measured with the Foot Function Index, were significantly correlated (r = 0.315, P = 0.013 and r = 0.266, P = 0.037, respectively). CONCLUSION: Forefoot joint damage in the rheumatoid foot is related to increased pressure under the forefoot, especially pressure under the first and fourth MTP joints. High forefoot pressure is associated with pain during barefoot walking. A prolonged stance phase and delayed heel lift are related to disability in daily activities.
16084814 Decreased muscle strength and mobility of the neck in patients with rheumatoid arthritis a 2005 Aug OBJECTIVE: To compare neck muscle strength and mobility of the cervical spine in rheumatoid arthritis (RA) patients with and without atlantoaxial (AA) disorders (anterior atlantoaxial subluxation [AAS], AA impaction). DESIGN: Clinical cross-sectional study. SETTING: Outpatient rheumatology and rehabilitation clinics in a Finnish hospital. PARTICIPANTS: Patients with RA (N=124; mean age +/- standard deviation, 62+/-12y [corrected]) on a waiting list for orthopedic surgery. Thirty (24%) patients presented with AA disorders (16 with anterior AAS, 8 with AA impaction, 6 with a combination of anterior AAS and AA impaction). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Neck function was measured by isometric neck strength and mobility tests, neck pain by a visual analog scale, erosion of the hands and feet by radiography, and the patients' function by the Health Assessment Questionnaire (HAQ). RESULTS: Maximal neck muscle strength against flexion, extension, and rotation was lower in patients with AA disorders compared with the other patients in both women (P=.012) and men (P=.017). Mobility was lowest in the AA impaction group in all measured directions (P<.001). Peripheral erosive disease was more frequent in the group with AA disorders. They also had longer disease duration and were more disabled (HAQ) than the other patients. CONCLUSIONS: Neck muscle strength is significantly decreased in patients with AA disorders. Mobility of the cervical spine is most limited in patients with AA impaction, but can be normal in cases with solitary anterior AAS.
15760931 Response criteria for rheumatoid arthritis in clinical practice: how useful are they? 2005 Aug OBJECTIVE: To compare the performance of the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and simple disease activity index (SDAI) response criteria for rheumatoid arthritis at the individual level in an observational cohort. METHODS: 184 outpatients were followed using a structured protocol. For each patient, the responses according to ACR 20% and 50%, EULAR moderate and good, and SDAI minor and major responses were calculated. For comparison, improvements in health assessment questionnaire (HAQ) score of 0.22 and 0.5 were calculated. The numbers of individuals fulfilling the criteria at each level were compared, and the numbers fulfilling any two sets of response criteria calculated. The EULAR "moderate" and "good" responses were grouped together as "overall," and SDAI "minor" and "major" were merged into SDAI "overall". RESULTS: All 94 ACR 20 responders were found in the EULAR and SDAI "overall" response groups, and 118 of 124 SDAI "overall" responders were found in the EULAR "overall" group. In contrast, of 53 ACR 50 responders, only 34 were found in the EULAR "good" or SDAI "major" group. Among the 56 patients in the EULAR "good" response group, only 26 met the SDAI "major" response. Improvement in HAQ score performed similarly to the other response criteria sets at the group levels. CONCLUSIONS: For individual patients, agreement is good at the level of ACR 20 response, when EULAR overall, SDAI overall, or HAQ 0.22 criteria are applied. Agreement between ACR 50, EULAR good, SDAI major, and HAQ 0.5 response is poor. This should be considered when response criteria are used for clinical decisions.
16712654 Dinucleotide repeat polymorphism in intron II of human Toll-like receptor 2 gene and susce 2006 Jun Human Toll-like receptors (TLRs) participate in innate immune response and signal the activation of adaptive immunity. The presence of a functional intronic polymorphism consisting of guanine-thymine repeats in TLR2 gene was recently reported. Here, we investigated a dinucleotide repeat polymorphism in intron II of TLR2 in Korean patients with rheumatoid arthritis (RA). The numbers of guanine-thymine [(GT)(n)] repeats in intron II of the TLR 2 gene were counted in 183 patients with RA and in 148 healthy controls, using the gene scanning technique. We classified alleles into two subclasses for further analysis, 12-16 GT repeats (S allele) and 17-28 repeats (L allele). By subgroup analysis, we also examined whether the S allele is associated with the presence of shared epitope (SE), rheumatoid factor (RF), joint erosion and extra-articular complications. S-allele frequency was significantly increased in patients with RA than in healthy controls [30.3% vs. 23.0%, P = 0.03, or 1.46, 95% confidence interval (CI) 1.03-2.07], and genotypes containing S alleles were more frequent in patients with RA than in healthy controls (54.4% vs. 46.5%. P = 0.04, or 1.57, 95% CI 1.01-2.42). A skewed S-allele distribution was not found to be related to the presence of SE. Subgroup analysis showed no genotypic or allele frequency differences between patients with/without RF, joint erosion, or extra-articular complications. Genotype containing shorter GT repeats in intron II of the TLR2 gene may confer susceptibility to RA in Koreans.
16704045 Tuberculosis and granuloma formation in patients receiving anti-TNF therapy. 2006 May In patients receiving anti-tumor necrosis factor (TNF) therapy, a probable exacerbation of latent tuberculosis (TB) is a major adverse event. The impairment of granuloma differentiation is considered a characteristic feature of TB in these patients. In this report we present three patients with rheumatic disease who developed TB under infliximab treatment. All of them had typical granulomas on the biopsy specimens, indicating that the expected impairment of granuloma formation is not always the case. The notion of granuloma-free TB in patients receiving anti-TNF therapy could shift a clinician's path away from performing a biopsy, thus delaying the establishment of a correct diagnosis.
16014635 Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared 2005 Aug 15 Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2) is an inhibitory receptor broadly expressed on leukocytes and recognizes HLA-class I and human cytomegalovirus UL18. LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE). In this study, we screened for polymorphisms of LILRB1 and examined their association with SLE and rheumatoid arthritis (RA). In the 5' portion of LILRB1, three haplotypes containing four non-synonymous substitutions within the ligand-binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03. In the 3' portion, two haplotypes (CY01, 02) containing a non-synonymous substitution of the cytoplasmic region were identified. CY01 and 02 did not co-segregate with PE01-03. Significant association with susceptibility to SLE or RA was not observed; however, among the subjects not carrying RA-associated HLA-DRB1 shared epitope (SE), LILRB1.PE01/01 diplotype was significantly associated with RA (odds ratio 2.05, P = 0.019 and Pc = 0.038). Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype. These findings demonstrated that LILRB1 is highly polymorphic and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes. In addition, these observations suggested that the polymorphisms of LILR family members may be substantially involved in the diversity of human immune responses.
16888026 Human mast cell-derived gelatinase B (matrix metalloproteinase-9) is regulated by inflamma 2006 Aug 15 Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-alpha significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-gamma inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-alpha significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-gamma, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.