Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis.
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OBJECTIVE: To determine how in vivo modulation of CD44 function by antibodies influences disease severity in a murine model of rheumatoid arthritis. METHODS: Mice with proteoglycan (PG)-induced arthritis were subjected to systemic treatment with 3 different monoclonal antibodies against CD44. Joint swelling and serum levels of hyaluronan (HA) and soluble CD44 (sCD44) were monitored. Inflammatory leukocyte infiltration in the joints, cell surface CD44 expression, and leukocyte adhesion to HA were compared. The effects of anti-CD44 treatment on the immune status of arthritic animals were also determined. RESULTS: Antibody IRAWB14, which enhances HA binding, aggravated the inflammatory symptoms, while KM201, which blocks ligand binding, reduced the severity of arthritis. The most effective suppression of inflammation was noted upon treatment with antibody IM7, whose epitope lies outside the HA binding domain of CD44. Serum levels of sCD44 increased, and HA levels decreased, in response to IM7. KM201 and IM7 treatment reduced, but IRAWB14 treatment enhanced, the adhesion of leukocytes to HA. However, these antibodies had little effect on PG-specific immune responses. CONCLUSION: Each antibody acted in vivo by virtue of its combined effects on CD44-HA binding and CD44 shedding. The dramatic reduction in arthritis severity effected by IM7 treatment was associated with extensive shedding of cell surface CD44 molecules. Loss of CD44 appears to be a major factor in preventing CD44- and HA-dependent cell-matrix interactions at the inflammatory site. Our study indicates a critical role for CD44 in the pathology of joint inflammation and reveals a unique mechanism of receptor down-regulation, which can be used therapeutically. (+info)
Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis: the role of telomerase activity in synovial proliferation.
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OBJECTIVE: To elucidate the involvement of telomerase activity in the pathogenesis of rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVS). METHODS: Peripheral blood lymphocytes (PBL), synovial infiltrating lymphocytes, and synoviocytes were isolated from peripheral blood samples and synovial tissue obtained from 18 patients with RA, 9 with PVS, 12 with osteoarthritis (OA), and 10 with knee joint trauma. Cellular telomerase activity was measured by the telomeric repeat amplification protocol assay. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was assessed for correlations with histologic features in rheumatoid synovium. RESULTS: A high level of telomerase activity was detected in the PBL and synovial infiltrating lymphocytes from RA patients and in the synoviocytes from PVS patients, whereas the enzyme activity was expressed at a low-to-borderline level in the PBL and synovial lymphocytes from OA, PVS, and trauma patients and was absent in the synoviocytes from RA as well as OA and trauma patients. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was significantly correlated with the intensity of synovial lining hyperplasia, microvessel proliferation, lymphocyte infiltration, and percentage of synovial cells positive for proliferating cell nuclear antigen in rheumatoid synovium. CONCLUSION: Telomerase activation in lymphocytes may provide insights into the progression of synovitis and synovial proliferation in RA. Moreover, the enzyme may be implicated in the proliferation of synoviocytes in PVS. (+info)
Expression of murine HOXD9 during embryonic joint patterning and in human T lymphotropic virus type I tax transgenic mice with arthropathy resembling rheumatoid arthritis.
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OBJECTIVE: To characterize the expression of murine HOXD9 during normal joint development and in arthritic joints of human T lymphotropic virus type I (HTLV-I) tax transgenic mice and the role of HTLV-I tax in HOXD9 expression. METHODS: Expression of HOXD9, HOXD1O, HOXD11, HOXD12, and HOXD13 genes in joint tissues at the ankle/foot regions of mouse embryos at day 10 to day 18 of gestation (E10-E18) and neonates within 10 days after birth was determined by reverse transcriptase-polymerase chain reaction and in situ reverse transcription methods. Adult synovial tissues from 5 HTLV-I tax transgenic mice with chronic polyarthritis and 4 nontransgenic (normal) mice were also examined for expression of these HOXD genes. The effect of HTLV-I on HOXD9 expression in cultured synoviocytes was studied by in vitro infection and transfection experiments. RESULTS: Expression of HOXD9 was detected in embryonic joints, preferentially on articular cartilage, only during the early stages of joint development (up to E15), whereas other HOXD genes were expressed throughout the embryonic and neonatal stages. In adult mice, transcripts of HOXD9 were specifically detected in synovial tissues from 4 of 5 arthritic mice, especially in the lining and sublining synovial cells, but not in synovial tissues of normal mice. Activation of HOXD9 was observed in cultured synoviocytes infected with HTLV-I in vitro as well as in those transfected with HTLV-I tax. CONCLUSION: Our findings suggest that HOXD9 is involved not only in the early stages of normal joint development, but may also be involved in the pathologic process of arthritis. HTLV-I tax appeared as an activator of this HOX gene in cultured synoviocytes. (+info)
Wegener's granulomatosis associated with renal cell carcinoma.
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OBJECTIVE: To determine the frequencies and types of malignant neoplasms occurring before or simultaneously with the diagnosis of Wegener's granulomatosis (WG), and to test for the presence of "Wegener's autoantigen," proteinase 3 (PR3), in malignant tissues from WG patients to ascertain whether an association exists between malignancy and WG. METHODS: A retrospective statistical analysis was performed on the medical records of 477 patients with WG as compared with a control group of 479 patients with rheumatoid arthritis (RA). A murine monoclonal antibody was used to test malignant tissues for the presence of PR3. RESULTS: A malignant neoplasm was found in 23 patients in the WG group and in 18 patients in the control group. The odds ratio for malignant neoplasm in the WG group was 1.79 (P = 0.0876, 95% confidence interval [95% CI] 0.92-3.48). Seven patients with renal cell carcinoma were found in the WG group compared with 1 patient in the control group, for an odds ratio of 8.73 (P = 0.0464, 95% CI 1.04-73.69). Simultaneous occurrence of cancer and WG was observed in 14 patients with WG compared with 1 control patient, for an odds ratio of 18.00 (P = 0.0059, 95% CI 230-140.67). Furthermore, the diseases occurred simultaneously in 5 of the 7 patients with both WG and renal cell carcinoma, but not in the single patient in the control group with RA and renal cell carcinoma. PR3 could not be detected in any of the 8 malignant tissue samples (4 renal cell carcinomas) investigated in the patients from the WG group. CONCLUSION: The close temporal association between renal cell carcinoma and WG suggests that malignancy is, in some cases, a trigger for the development of WG. However, since PR3 was not found in malignant tissues from the WG patients, the immunopathologic mechanisms leading to autoimmunity and vasculitis remain unclear. (+info)
Fertility and pregnancy outcome in women with systemic sclerosis.
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OBJECTIVE: To determine fertility and pregnancy outcome in women with systemic sclerosis (SSc; scleroderma) who had disease onset before age 45 years. METHODS: All living women with scleroderma who had first been evaluated at the University of Pittsburgh Scleroderma Clinic after January 1, 1972 were sent a detailed self-administered questionnaire in 1986 specifically concerning pregnancy outcomes and infertility. This group was compared with 2 race- and age-matched control groups, one comprising women with rheumatoid arthritis (RA) and one comprising healthy neighborhood women identified by random-digit dialing. We determined the number, history, treatment, and outcome of women who either had never been pregnant or had attempted to become pregnant unsuccessfully for more than 1 year. We also obtained data regarding pregnancy outcomes, including the frequency of miscarriage, premature births, small full-term infants, perinatal deaths, and births of live healthy infants. RESULTS: The study group comprised 214 women with SSc, 167 with RA, and 105 neighborhood controls. There were no significant differences in the overall rates of miscarriage, premature births, small full-term births, or neonatal deaths between the 3 groups. Women with SSc were more likely than those without SSc to have adverse outcomes of pregnancy after the onset of their rheumatic disease, particularly premature births (also seen in RA women after disease onset) and small full-term infants. Although a significantly greater number of women with SSc had never been pregnant, there were no significant differences in the frequency of never having been pregnant or of infertility in the 3 groups after adjustment for contributing factors. CONCLUSION: This study indicates that women with SSc have acceptable pregnancy outcomes compared with those of women with other rheumatic disease and healthy neighborhood controls. Infertility was not a frequent problem. We believe that there are no excessive pregnancy risks to women with SSc or their infants. However, a well-timed pregnancy with careful obstetric monitoring will maximize the likelihood of a successful outcome. (+info)
Pneumocystis carinii pneumonia in patients with connective tissue diseases: the role of hospital experience in diagnosis and mortality.
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OBJECTIVE: Pneumonia due to Pneumocystis carinii has been increasingly reported in patients with connective tissue diseases, but the frequency of this complication is not known. We sought to determine the frequency of P carinii pneumonia (PCP) in patients with connective tissue diseases, and to determine the role that a hospital's acquired immunodeficiency syndrome (AIDS)-related experience may have in the diagnosis of PCP in these patients. METHODS: We used a state hospitalization registry to identify all patients with PCP and either rheumatoid arthritis, systemic lupus erythematosus, Wegener's granulomatosis, polymyositis, dermatomyositis, polyarteritis nodosa, or scleroderma who had an emergent or urgent hospitalization in California from 1983 to 1994. We compared patient and hospital characteristics between these patients and patients with connective tissue diseases hospitalized with other types of pneumonia. RESULTS: Two hundred twenty-three patients with connective tissue diseases were diagnosed with PCP in the 12-year study period. The frequency of PCP ranged from 89 cases/10,000 hospitalizations/year in patients with Wegener's granulomatosis to 2 cases/10,000 hospitalizations/year in patients with rheumatoid arthritis. Compared with 5,457 patients with connective tissue diseases and pneumonia due to other organisms, patients with PCP were more likely to be younger, to be male, to have private medical insurance, and to have systemic lupus erythematosus, Wegener's granulomatosis, inflammatory myopathy, or polyarteritis nodosa rather than rheumatoid arthritis, and were less likely to be African American. Hospital size, teaching status, urban/rural location, proportion of admissions due to AIDS or PCP, and proportion of patients with pneumonia undergoing bronchoscopy were each associated with the likelihood of diagnosis of PCP in univariate analyses, but only the number of patients with PCP being treated at a hospital (odds ratio [OR] 1.03 for each additional 10 cases/year, 95% confidence interval [95% CI] 1.01-1.05) was associated with the likelihood of diagnosis of PCP in multivariate analyses. Patients were also somewhat more likely to be diagnosed with PCP if there had previously been a case of PCP in a patient with a connective tissue disease at the same hospital (OR 135, 95% CI 0.98-1.85). In-hospital mortality was 45.7%, and was unrelated to hospital characteristics. CONCLUSION: PCP is an uncommon, but often fatal, occurrence in patients with connective tissue disease. A hospital's prior experience with patients with PCP is associated with the likelihood that this condition is diagnosed in patients with connective tissue diseases who present with pneumonia, suggesting that diagnostic suspicion is an important factor in the correct identification of affected patients. (+info)
Hydrolytic activity is essential for aceclofenac to inhibit cyclooxygenase in rheumatoid synovial cells.
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To investigate the mechanisms of action underlying the anti-inflammatory effects of the nonsteroidal anti-inflammatory drug aceclofenac in humans, we studied the metabolism of aceclofenac in detail in primary cultured synovial cells of 10 patients with rheumatoid arthritis. Aceclofenac and 4'-hydroxyaceclofenac are the major compounds in human blood after the administration of aceclofenac, but they had no inhibitory effects on cyclooxygenase (COX) activity or COX expression in the rheumatoid synovial cells. In contrast, aceclofenac and 4'-hydroxyaceclofenac reduced prostaglandin E2 (PGE2) production by the rheumatoid synovial cells. We also observed that aceclofenac and 4'-hydroxyaceclofenac were hydrolyzed into the COX inhibitors diclofenac and 4'-hydroxydiclofenac, respectively, by the rheumatoid synovial cells. However, the hydrolytic activity differed markedly among the cell preparations. Because the suppressive potency of aceclofenac and 4'-hydroxyaceclofenac against the PGE2 production was proportionally correlated with the hydrolytic activity in rheumatoid synovial cell preparations, we suggest that the suppressive effects of aceclofenac and 4'-hydroxy aceclofenac on PGE2 production are facilitated by the hydrolytic activity in rheumatoid synovial cells. (+info)
Nitrite determination in human plasma and synovial fluid using reactions of nitric oxide with 3, 5-dibromo-4-nitrosobenzenesulphonate (DBNBS).
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DBNBS (3,5-dibromo-4-nitrosobenzenesulphonate) reacts with nitric oxide (NO) produced from nitrite ions in acid solution to give a radical with a characteristic electron spin resonance spectrum, attributable to a 'DBNBS-NO' product, and comprising a triplet with alphaN=0.96 mT. This is identical with the spectrum obtained when NO, introduced from the gas phase, reacts with DBNBS. Under certain conditions, an additional signal is observed, attributable to oxidation of DBNBS to the radical cation, DBNBS*+ (a triplet with alphaN=1.32 mT). Conditions are described for the determination of nitrite, which avoid this DBNBS oxidation. The height of the low-field signal from the DBNBS-NO product is directly proportional to the nitrite concentration up to about 0.08 mM nitrite. The method has been applied to the measurement of nitrite concentrations in whole blood, plasma and synovial fluid taken from rheumatoid arthritis patients. In order to avoid the oxidation of DBNBS when analysing biological samples of this type, it is necessary to treat the specimen by ultrafiltration as soon as possible after collection and before addition of DBNBS. (+info)