Aspects of the clinical trials of slow-acting anti-rheumatic drugs.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
S N Breit
Publications and source records attributed to S N Breit.
Modulation of endothelial cell synthesis of von Willebrand factor by mononuclear cell products.
Von Willebrand factor (vWf:Ag) is an important product of endothelial cells whose major known functions are coagulation and platelet adhesion. It appears to behave as an acute-phase reactant, levels being elevated in the plasma in a wide variety of inflammatory disorders and in the extravascular compartment in at least some of them. To determine if products of mononuclear cells, activated as part of these disease processes, may directly influence the synthesis and or release of this substance, confluent human umbilical vein endothelial cells were cultured in the presence of supernatants of mononuclear cells undergoing a mixed lymphocyte reaction, and a variety of other purified or recombinant mediators including interleukin-1 (IL-1), interleukin-2, gamma-interferon and prostaglandin E2. The endothelial cell supernatants were then assayed for vWf:Ag levels using a sensitive enzyme-linked immunoassay. The results of this study demonstrate that supernatants of a mixed lymphocyte reaction increase the synthesis and or release of vWf:Ag from endothelial cells in culture by about 100-150%. As these supernatants did not cause any increase in the release of radioisotope from 51Cr-labeled endothelial cells, it appears very unlikely that this increase was simply due to the passive release of this material from dead and dying cells. Increased vWf:Ag release was also demonstrable with purified IL-1 but not with any of the other mediators tested. These results suggest that IL-1 is able to increase the release of vWf:Ag from endothelial cells largely by an increase in synthesis and indicate at least one mechanism whereby mononuclear cells, activated during the course of an inflammatory response, may be able to influence coagulation and platelet function.
Cells, Cultured↗
Flow cytometry with crystal violet to detect intracytoplasmic fluorescence in viable human lymphocytes. Demonstration of antibody entering living cells.
A new method is described for the detection of intracytoplasmic fluorescence and its differentiation from surface staining of viable human lymphocytes using flow cytometry after addition of crystal violet which quenches surface but not internal fluorescence. This has then been used to study antibody penetration of viable human lymphocytes, using FITC-conjugated IgG from normal serum or serum containing anti-RNP antibody. The results showed that 54 +/- 1% normal lymphocytes were penetrated by anti-RNP antibody and 23 +/- 3% by normal IgG respectively. The lymphocyte population analysed by flow cytometry has been directly demonstrated to be viable by FDA staining. These results provide unequivocal evidence that antibody can penetrate viable human lymphocytes.
Antibodies↗
Hypothesis: lymphocyte trafficking in inflammatory rheumatic disease. A role for receptor mediated homing.
The entry of lymphocytes into normal lymph nodes occurs principally after their passage across postcapillary high endothelial venules. Nonlymphoidal tissues do not normally express high endothelial venules; however, in inflammatory rheumatic diseases associated with prominent lymphocyte accumulation (e.g., rheumatoid synovium), high endothelial venule-like structures are found and may facilitate local lymphocyte traffic. In mouse and man there are lymphocyte surface membrane homing receptors which determine lymphocyte binding to acceptor sites on lymph node high endothelial venules. The migration of lymphocytes from the circulation into inflamed nonlymphoidal tissues may be controlled by similar homing receptor mediated mechanisms.
Adrenal Cortex Hormones↗
The role of alpha 1-antitrypsin deficiency in the pathogenesis of immune disorders.
The association between alpha 1-antitrypsin (alpha 1-AT) deficiency and a number of immune mediated diseases including rheumatoid arthritis, anterior uveitis, systemic lupus erythematosus, and asthma suggests that alpha 1-AT may be important not only as an anti-inflammatory protein but also as an immune regulator. That the relationship between decreased amounts of this inhibitor and these diseases is causal is suggested by both some of its physical properties and evidence indicating it is able to modulate immune function. alpha 1-Antitrypsin has a high plasma concentration, very broad range of inhibitory activity and is an acute phase reactant. Among other things, it is able to modulate lymphocyte proliferation and cytotoxicity, and monocyte and neutrophil function. Additionally, some of these changes are demonstrable in vivo in patients with severe alpha 1-antitrypsin deficiency. This paper reviews the important physicochemical characteristics of this protein, the association of its presence in decreased amounts with immune disorders, and finally the important mechanism that may underlie this disease association.
Connective Tissue Diseases↗
Alpha 1 antitrypsin serum levels and phenotypes in patients with retinal vasculitis.
alpha 1 antitrypsin is an important immunoregulatory protein, the serum level of which is genetically determined. Deficient phenotypes of this ubiquitous protease inhibitor are associated with a variety of inflammatory diseases including anterior uveitis. In order to investigate the role of this protease inhibitor in the pathogenesis of retinal vasculitis (RV) 25 patients were investigated. Diseases associated with RV included Behcet's syndrome (8), SLE (2), and sarcoidosis (1). Deficient phenotypes of alpha 1 antitrypsin were not associated with RV. However, the serum alpha 1 antitrypsin level was significantly increased in patients with active RV and paralleled disease activity in patients studied prospectively.
Adolescent↗
Chemiluminescent response to pathogenic organisms: normal human polymorphonuclear leukocytes.
Chemiluminescence (CL) is a sensitive indicator of phagocytosis and intracellular killing; however, little is known of the normal CL response by human polymorphonuclear leukocytes to different pathogenic microorganisms. We investigated the luminol-enhanced CL response of normal polymorphonuclear leukocytes to a number of common bacterial pathogens and two yeasts. We analyzed the CL response to viable and heat-killed microorganisms at 25 and 37 degrees C. The CL response to all microorganisms was greater and more rapid at 37 degrees C. Variable responses were observed with viable and heat-killed microorganisms; some were unaffected, whereas other demonstrated reduced CL. Each microorganism caused a reproducible response pattern, which could be placed into two general categories. In the first category were those which caused a rapid exponential rise and decay in CL: Enterobacter cloacae, Salmonella typhimurium, Shigella flexneri, Staphylococcus aureus, Candida albicans, and zymosan. In the second category were those which rose slowly over a longer time course to a poorly defined peak: Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, and Streptococcus pyogenes. The CL response also reflected serum opsonic activity. The effect of inactivated complement, factor B, and removal of specific antibody were investigated. Increasing the concentration of zymosan gave a proportional rise in peak CL; however, a strain of E. coli caused a variation in peak time rather than peak height. Different CL kinetics were shown for three strains of K. pneumoniae, possibly a result of each having different membrane or cell wall characteristics. This study defines the nature and factors affecting the normal CL response to a variety of common pathogenic microorganisms.
Adsorption↗
The effect of purified alpha 1 antitrypsin on PWM driven IgG synthesis.
As part of a study investigating the mechanisms for the association of alpha 1 antitrypsin (alpha 1 AT) deficiency with immune disorders, the effect of purified alpha 1 AT on PWM driven IgG synthesis of peripheral blood lymphocytes was investigated. This demonstrated that alpha 1 AT in physiological doses enhanced IgG synthesis in stimulated but not resting cells. This effect is probably due to the known inhibition by alpha 1 AT of macrophage function. Increasing number of macrophages are known to inhibit IgG synthesis in the PWM system suggesting that this apparently paradoxical enhancement by alpha 1 AT is probably due to inhibition of these cells.
Animals↗
The effect of alpha 1 antitrypsin on the proliferative response of human peripheral blood lymphocytes.
In evaluating immune aberrations in patients with alpha 1 antitrypsin (alpha 1 AT) deficiency, we have previously shown that they exhibit enhanced lymphocyte responsiveness to PHA that is serum mediated. In this study, we demonstrate suppression of the PHA response by using purified alpha 1 AT, and also similar but less marked suppression of the Con A response. alpha 1 AT, however, has no effect whatsoever on PWM-induced proliferation. This effect is demonstrable provided alpha 1 AT is added within 4 hr of mitogen activation and is mediated by its action on adherent cells rather than on proliferating lymphocytes. Adherent cells still exhibit this effect if pulsed with alpha 1 AT, then thoroughly washed before their activation. This suggests that it may be inhibiting a membrane serine esterase already activated before the addition of PHA. Thus alpha 1 AT may modulate the activation of T cells through its effect on monocytes, leading to abnormalities in immunoregulation, and hence a predisposition to the development of a variety of immunologic disorders in alpha 1 AT-deficient subjects.
Adult↗
The effect of alpha 1 antitrypsin on phagocyte function.
alpha 1 antitrypsin (alpha 1AT) deficiency is a common genetic variant associated with many immunological and inflammatory disorders. Previous studies in alpha 1 AT deficient subjects have indicated possible monocyte (MN) and neutrophil (PMN) abnormalities with enhanced chemiluminescence (CL) and accelerated delayed hypersensitivity reactions. We have therefore extended these observations by investigating the effect of purified alpha 1 AT on MN and PMN motility and CL. These studies indicated that alpha 1 AT in physiological amounts inhibits PMN and MN chemokinesis by about 35% but chemotaxis by only 10%. It however has no direct effect on the zymosan induced CL of these cells. This study suggests that the increased incidence and severity of some inflammatory diseases in alpha 1 AT deficient subjects may in part be explained by increased motility and activation of MN and PMN, the former due to the absence of an inhibitor of PMN and MN locomotion and the latter due to secondary changes in serum resulting in enhanced chemiluminescence.
Chemotaxis↗
Genetic study of a family with two members with Weber Christian disease (panniculitis) and alpha 1 antitrypsin deficiency.
Alpha 1 antitrypsin phenotypes and serum levels are presented for a family in which two brothers have Weber Christian disease and alpha 1 antitrypsin (PI) Z phenotypes. Clinical histories are described for these two men. A younger brother has the PI Z phenotype but does not have the disease, indicating that additional genetic and/or environmental factors contribute to the pathogenesis of Weber Christian disease. However, the two cases described provide additional evidence for a relationship between alpha 1 antitrypsin deficiency and the development of symptoms.
Adult↗
Immunogenetic factors in inflammatory eye disease. Influence of HLA-B27 and alpha 1-antitrypsin phenotypes on disease expression.
The relationship between the nature and severity of inflammatory eye disease was analyzed with respect to HLA antigens and alpha 1-antitrypsin phenotypes. Using standard ophthalmologic criteria, we divided patients with anterior uveitis into acute, chronic (greater than 3-month duration), bilateral, or recurrent disease. There was a significantly increased incidence of alpha 1-antitrypsin-deficient phenotypes in anterior uveitis, especially in those patients with severe (chronic, bilateral, or recurrent) disease. HLA-B27 acts as an independent predisposing factor: it was present in 22% of patients with their first attack of acute uveitis compared with 51% of patients with recurrent disease. Together, these genetic factors are present in 63% of patients with severe anterior uveitis and represent the most significant predisposing and prognostic factors so far detected.
HLA Antigens↗
Immunoregulation by alpha 1 antitrypsin.
alpha 1 antitrypsin (alpha 1 AT) deficiency is a common genetic disorder seen in about 10% of the population. It predisposes to the development of a large number of inflammatory and immunologic disorders including rheumatoid arthritis, systemic lupus erythematosus, juvenile chronic arthritis, anterior uveitis, ankylosing spondylitis, fibrosing alveolitis and emphysema. We have investigated immunologic function in subjects with severe alpha 1 AT deficiency and demonstrated serum mediated enhancement of lymphocyte response to PHA and increased zymosan activation of mononuclear cells and neutrophils as measured by their chemiluminescence. These patients also have accelerated delayed hypersensitivity responses and increased levels of factor B, C3 and C5 but normal levels of immunoglobulin and other complement components. Such abnormalities in immunoregulation demonstrate a tendency to hyperreactivity that may contribute to disease predisposition.
Complement System Proteins↗
The role of alpha 1 protease inhibitor (alpha 1 antitrypsin) in the regulation of immunologic and inflammatory reactions.
Twenty-six different alleles have been identified for alpha 1 protease inhibitor (alpha 1 antitrypsin), each designated by a letter of the alphabet. In any individual two alleles codominantly determine the characteristics of alpha 1 protease inhibitor (Pi), including mobility on electrophoresis, serum concentration and acute phase response. Recent evidence has linked some mildly deficient phenotypes of Pi with a variety of chronic immunologic and inflammatory disorders, such as rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, asthma and fibrosing alveolitis, in addition to the well recognised association of severe deficiency with emphysema and chronic liver disease. This disease susceptibility in phenotypes associated with reduced serum levels may be due to alteration in lymphocyte responses, complement activation and leukocyte migration. Pi can also influence the autolytic effects of leukocytic enzymes on tissues and may inhibit some aspects of coagulation and fibrinolysis. Therefore patients with deficient Pi phenotypes are likely to have exaggerated immunologic and inflammatory responses.
Asthma↗
Comparison of direct and indirect arterial pressure measurements in hospitalized patients.
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Anthropometry↗
Lung involvement in scleroderma.
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Bronchiolitis↗