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Biomedical subjects

G S Firestein

Publications and source records attributed to G S Firestein.

104 records · Page 6Linked to original sources
PubMed1989

Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions.

A liquid culture technique was used to study 23 synovial fluids (SF) (21 from inflammatory joint diseases and 2 noninflammatory SF) and supernatants of two cultured rheumatoid arthritis (RA) synovial tissues for colony-stimulating factor (CSF). The proliferative responses of human peripheral blood macrophage-depleted non-T cells treated with synovial fluids, supernatants of synovial tissue explants, and recombinant granulocyte-macrophage (rGM)-CSF were compared. Aggregates of cells that formed in long-term cultures (15 d) were similar for each applied agent and consisted of macrophages, eosinophils, and large blasts. Tritiated thymidine incorporation was proportional to the concentration of rGM-CSF and was accompanied by an increase in number and size of cellular aggregates formed in the cultures. CSF activity was observed in inflammatory SF, with tritiated thymidine uptake of 3,501 +/- 1,140 cpm in the presence of RA samples (n = 15) compared to 1,985 +/- 628 for non-RA inflammatory SF (n = 7) (P less than 0.05) and 583 +/- 525 for medium (n = 6) (P less than 0.01). The proliferative response to RA SF was often more apparent when the samples were diluted, because at higher concentrations the RA SF was inhibitory. Two RA SF were fractionated by Sephadex G100 column chromatography; low levels of CSF activity were detected in fractions corresponding to Mr of 70-100 kD, but the major CSF activity was found in the 20-24-kD fractions. A polyclonal rabbit anti-GM-CSF antibody eliminated the stimulating activity from both rGM-CSF and RA SF. Finally, a specific RIA identified significant levels of GM-CSF (40-140 U/ml) in the culture supernatants of 3 additional RA synovial tissues. These data document the local production of GM-CSF in rheumatoid synovitis and are the first description of this cytokine at a site of disease activity.

Arthritis↗
PubMed1988

Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis.

Because previous studies showed low levels of IFN-gamma in rheumatoid arthritis (RA) synovial fluid (SF) and synovial tissue (ST) explant supernatants, we assayed RA SF and ST for IL-2 and IL-3-like activity. Using an IL-2 dependent murine CTLL line, 6 of 14 RA SF caused increased thymidine uptake (greater than three times control). The activity was distinct from IL-2 because it was not blocked by antibody to IL-2-R. In addition, IL-2 was not detected (less than 50 pg/ml) in 16 joint samples using an ELISA. Multi-colony-stimulating factor (CSF) activity was measured using two assays that can detect murine IL-3 (mast cell proliferation, and bone marrow CSF). In the mast cell assay, [3H]TdR uptake was 493 +/- 67 cpm for medium, 2,910 +/- 329 cpm in the presence of RA SF (p less than 0.001), 1,246 +/- 156 cpm in the presence of SF from patients with seronegative spondyloarthropathies (p less than 0.001), and 736 +/- 100 cpm in the presence of osteoarthritis SF (p greater than 0.1). In the CSF assay, four of five RA SF and five of five RA ST induced colony formation from bone marrow nonadherent cells. Macrophage colonies were most common, although mixed colonies and granulocytes were occasionally observed. The multi-CSF activity in RA is not due to IL-3 since human rIL-3 was not active in either murine assay, and IL-3 mRNA was not detected in RA synovium. Sephadex column chromatography of RA SF revealed that the mast cell growth factor (approximately 6 x 10(3) mol wt) and the CSF (approximately 40 and 100 x 10(3) mol wt) are distinct. The colony-stimulating aspect of the "IL-3-like" activity in RA SF is likely due to CSF-1 because it is the appropriate mol wt and because the activity was neutralized by specific anti-CSF-1 antibody. Finally, an RIA detected 1.6-25 ng/ml of CSF-1 in RA SF and ST and CSF-1 mRNA was detected in four of five RA synovial tissue samples tested.

Arthritis, Rheumatoid↗
PubMed1988

Rapid and reversible modulation of T4 (CD4) on monocytoid cells by phorbol myristate acetate: effect on HIV susceptibility.

The effect of phorbol myristate acetate (PMA) on T4 (CD4) expression by monocytoid cells was studied. Greater than 99% of untreated U937 and HL-60 cells expressed surface T4 as measured with a fluorescence-activated cell sorter. The percentage of T4 positive cells decreased to less than 20% after incubation with PMA (10(-8) M). A decrease was observed within 15 min of PMA exposure, was maximal within 1 hr, and persisted for at least 3 days in the continuous presence of PMA. The susceptibility of untreated and PMA-treated U937 cells to human immunodeficiency virus (HIV) was also studied. Pretreatment of cells with PMA for 18 hr decreased the production of viral RNA and p24 antigen 24 hr after infection. The dose of PMA resulted in a parallel reduction of both T4 expression and infection by HIV. When PMA was washed from cultures and replaced with fresh medium for 48 hr, then T4 expression and the production viral RNA and p24 antigen following infection were restored. These data suggest that pharmacologic manipulation of surface T4 expression may have a potential role in the prevention or treatment of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Cytokines in chronic inflammatory synovitis.

Cytokines likely play a role in the pathogenesis of rheumatoid arthritis and other chronic inflammatory arthritidies. Recent studies on the cytokine profile of inflammatory synovitis have provided insight into the mechanisms of cellular activation in the inflamed joint. Although gamma interferon has been proposed as a major macrophage activating factor and inducer of class II major histocompatibility antigens in the joint, studies using sensitive and specific immunoassays have shown that the concentration of this lymphokine in synovial fluid is probably not sufficient to account for the high level of HLA-DR expression on Type A synoviocytes and macrophages in the joint. In contrast, GM-CSF has recently been identified in synovial effusions of patients with rheumatoid arthritis and is produced by synovial tissue cells in vitro. Like gamma interferon, GM-CSF is a known macrophage activating factor and induces HLA-DR on cells of macrophage lineage. Furthermore, supernatants of cultured synovial tissue cells contain an HLA-DR inducing factor that is neutralized by specific antibodies to GM-CSF but not by antibodies to gamma interferon. These data suggest that GM-CSF plays a significant role in macrophage activation in the synovium.

Biological Factors↗
PubMed1987

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. I. A cytofluorographic study of monocyte differentiation antigens and class II antigens and their regulation by gamma-interferon.

Recent study of the expression of monocyte differentiation antigens (MAg) and HLA-DR on peripheral blood monocytes (PBM) has led to the recognition of resting and activated monocyte phenotypes. The former is identified by the expression of large amounts of MAg (i.e., Mo2 and 63D3) and small amounts of HLA-DR, while the latter is identified by the reverse. We studied the phenotypes of PBM and synovial fluid monocytes (SFM) of patients with chronic inflammatory arthritis and found that PBM were primarily resting and SFM were usually activated. In addition, we measured the degree of modulation of MAg and HLA-DR by gamma-interferon (gamma-IFN). Patient PBM reacted the same as PBM from normal individuals (i.e., MAg decreased and HLA-DR increased after exposure to gamma-IFN). However, in patient SFM, HLA-DR did not increase with exposure to gamma-IFN because expression was already maximal. Interestingly, MAg could still be down-regulated on gamma-IFN-treated SFM, even when expression began at a very low level (i.e., activated phenotype). This independent regulation of MAg and HLA-DR suggests that macrophage activating factors other than gamma-IFN may be responsible, in part, for the activated phenotypes observed.

Antigens, Differentiation↗
PubMed1987

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. II. Low levels of synovial fluid and synovial tissue interferon suggest that gamma-interferon is not the primary macrophage activating factor.

Because synovial fluid monocytes (SFM) in patients with inflammatory arthritis bear an activated phenotype (i.e., high expression of HLA-DR and low expression of the monocyte differentiation antigen Mo2), we assessed the role of gamma-interferon (gamma-IFN) in the activation of these cells. Sensitive and specific radioimmunoassays detected only 0.40 +/- 0.20 units/ml of gamma-IFN in the SF of patients with rheumatoid arthritis (RA) and 0.61 +/- 0.67 units/ml of gamma-IFN in the SF of patients with other forms of chronic inflammatory arthritis. There was no detectable alpha-IFN in any SF studied by radioimmunoassay. Bioassays failed to detect nonimmunoreactive IFN. Synovial tissue (ST) explants produced very little gamma-IFN (0.14 +/- 0.091 units/ml), and production was not increased by the presence of indomethacin in the cultures or by removal of adherent cells. However, gamma-IFN was produced if ST was cultivated in the presence of phytohemagglutinin. In SF and ST supernatants, gamma-IFN-mediated induction of HLA-DR on monocytes was inhibited, even though the amount of immunoreactive IFN was not affected. Prostaglandin E2 was shown to be one possible inhibitor. We demonstrated that a factor that induces HLA-DR on some individuals' peripheral blood monocytes, and cannot be neutralized by monoclonal anti-gamma-IFN antibody, is present in SF and ST supernatants. These data suggest that activation of SFM may occur by mechanisms other than gamma-IFN.

Absorption↗
PubMed1987

Quantitative molecular hybridization with unfractionated, solubilized cells using RNA probes and polyacrylamide gel electrophoresis.

Molecular hybridization with RNA probes was performed on unfractionated cells solubilized in guanidine thiocyanate solutions. Unhybridized probe was digested with ribonuclease, and protected probe fragments were resolved by polyacrylamide gel electrophoresis (PAGE). Since the same medium was used both for solubilization of the cells and as the hybridization buffer, RNA purification was not required and the analysis of large numbers of samples was facilitated. Using this method, specificity is superior to dot blot analysis because the size of hybridized fragments is determined and the signal of the probe hybridized to target RNA is separated from the background by PAGE.

Animals↗
PubMed1987

Down regulation of human monocyte differentiation antigens by interferon gamma.

The role of IFN-gamma in the activation and differentiation of human peripheral blood monocytes was investigated. Recombinant IFN-gamma induced a decrease in the expression of monocyte differentiation antigens (Mo2 and 63D3) and, to a lesser extent, the C3bi receptor. Conversely, class II histocompatibility antigen expression increased on monocytes exposed to IFN-gamma. The antigen modulating effect of IFN-gamma was maximal on freshly isolated monocytes, with diminished potency if added to monocytes that had been cultivated in vitro for 1 to 3 days. Experiments to determine the fate of the down-regulated antigens on interferon-treated cells failed to demonstrate intracellular antigen due to internalization. We suggest that Mo2 and 63D3 may be considered "inverse" activation antigens; i.e., their expression is decreased in monocytes activated by interferon.

Antibodies, Monoclonal↗
PubMed1987

Reactive arthritis.

Inflammatory arthritis occurring days to weeks after a localized infection is known as reactive arthritis. Epidemiologic, genetic, and immunologic features have established this disease as a distinct clinicopathologic entity. Although reactive arthritis is often a transient disease, many individuals suffer a chronic relapsing course. Treatment is usually conservative except in a minority of cases in which patients require remittive therapy.

Arthritis↗
PubMed1987

Cellular immunity in the joints of patients with rheumatoid arthritis and other forms of chronic synovitis.

Rheumatoid arthritis (RA), although a systemic illness, is primarily a synovial disease. Morphologic and functional studies of immune cells within the synovium strongly suggest that disordered cellular immunity is key to the pathogenesis of RA. This article describes in detail the various cells found within the rheumatoid joint and compares them with those found in nonrheumatoid synovitis and in normal peripheral blood.

Arthritis, Rheumatoid↗
PubMed1987

The pathogenesis of rheumatoid arthritis. A critical assessment of the role of autologous stimulation in the perpetuation of rheumatoid synovitis.

Current models for rheumatoid arthritis emphasize the role of activated T cells and their products in the pathogenesis of synovitis. The data supporting this view are critically reviewed in this article and inconsistencies are discussed. To resolve these contradictions, the authors propose that rheumatoid synovitis represents a localized autologous mixed lymphocyte reaction.

Animals↗
PubMed1986

Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis.

The effects of peripheral cold exposure on myocardial perfusion and function were studied in 13 patients with scleroderma without clinically evident myocardial disease. Ten patients had at least one transient, cold-induced, myocardial perfusion defect visualized by thallium-201 scintigraphy, and 12 had reversible, cold-induced, segmental left ventricular hypokinesis by two-dimensional echocardiography. The 10 patients with transient perfusion defects all had anatomically corresponding ventricular wall motion abnormalities. No one in either of two control groups (9 normal volunteers and 7 patients with chest pain and normal coronary arteriograms) had cold-induced abnormalities. This study is the first to show the simultaneous occurrence of cold-induced abnormalities in myocardial perfusion and function in patients with scleroderma. The results suggest that cold exposure in such patients may elicit transient reflex coronary vasoconstriction resulting in reversible myocardial ischemia and dysfunction. Chronic recurrent episodes of coronary spasm may lead to focal myocardial fibrosis.

Adult↗
PubMed1985

Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behçet's disease.

Five patients with features of coexistent relapsing polychondritis and Behçet's disease are described. Review of the literature supports the overlap of the clinical manifestations of these two conditions. A common immunologic abnormality is likely, and elastin is cited as a possible target antigen. The "mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome" is the proposed name for this entity.

Adult↗