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Biomedical subjects

J P Atkinson

Publications and source records attributed to J P Atkinson.

At least 217 records · Page 12Linked to original sources
PubMed1975

Humoral immunostimulation. IV. Role of complement.

When L cells were treated with anti-L-cell antibody in medium containing heat-inactivated fetal calf serum, nucleoside uptake and cell growth were stimulated. The response was markedly increased when fresh, unheated sera from calves, guinea pigs, humans, mice, or rabbits were also present. The factors in unheated serum responsible for the enhancement of immunostimulation were studied. Using low concentrations of sera deficient in various complement (C) components and low concentrations of antibody no augmentation of immunostimulation was seen with Clr-deficient human serum, C2-deficient human serum, C2,4-deficient human serum, C4-deficient guinea pig serum, C3-C9-depleted guinea pig serum (by administration of cobra venom factor to animals), but stimulation was observed with C5-deficient human serum, C5-deficient mouse serum, and C6-deficient rabbit serum. When the concentration of anti-serum was raised, however, augmentation was observed with C4-deficient guinea pig serum. Thus, at low concentrations of antiserum enhancement appeared to occur through the classical C pathway, whereas at high concentrations of antibody either the classical or alternate C pathways appeared to be involved. Stimulation was specifically restored by purified C2 in C2-deficient serum and by C3 in C3-C9-deficient serum. Under the usual reaction conditions consumption of guinea pig C component C4 could be demonstrated which provided direct evidence for activation of the classical C pathway under conditions leading to immunostimulation. By immunofluorescence, cells treated with antibody and normal human serum had human C3 deposited at the cell surface. Taken together these observations suggest that C activated through C3 by either the classical or alternate pathways has the potential to enhance nucleoside incorporation into DNA and cell growth of cells exposed to limiting amounts of antibody. Although the mechanism of stimulation is unknown, it is likely to involve a direct effect of C3 at the level of the cell membrane.

Animals↗
PubMed1975

Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery.

Six patients with hereditary anagioedema (HAE) undergoing 7 episodes of dental surgery received transfusions with fresh frozen plasma one day before surgery. Although the morbidity observed in these patients following similar procedures had been high, no significant complications of surgery were noted with this therapy. Thus, fresh frozen plasma infusion appears to provide a safe and effective method of prophylaxis in patients with HAE. Following infusion of fresh frozen plasma, serum levels of C4 esterase inhibitor (C1EI) rose transiently, and then fell to preinfusion levels within 1 to 12 days. In all but one patient the rise in C4 was greater than could be accounted for by the amount of C4 infused. In no patient did the level of C1EI or C4 rise to within the normal range. The data raise the question of the role of C1EI in the pathogenesis of angioedema in these patients.

Aminocaproates↗
PubMed1975

Serum complement and immunity in experimental simian malaria. I. Cyclical alterations in C4 related to schizont rupture.

Previous studies indicated that the level of whole serum complement (C') falls during malaria, and that the fall in C' is linked to schizont rupture and the appearance of humoral antibody. For a more detailed study of the role of C' in malaria, levels of C4 were monitored in rhesus monkeys infected with Plasmodium coatneyi. After one to two weeks of infection, significant and abrupt declines in C4 levels occurred, and these were temporally related to the process of schizont rupture. The level of C4 began to fall within a few hours after the onset of schizont rupture and fell to values as low as 2% of prerupture levels. Over the next 24-36 hr, C4 returned to normal levels, and fell again during the next cycle of schizont rupture. In general, the decline in C4 levels was positively correlated with the onset of immune response (functional and serologic) and degree of parasitemia. This marked cyclincal depletion of C4 indicates tremendous turnover of C' in primates with malaria.

Animals↗
PubMed1975

Serum complement and immunity in experimental simian malaria. II. Preferential activation of early components and failure of depletion of late components to inhibit protective immunity.

The role of complement in the control of parasitemia was examined. Depletion of late components (3-9) by cobra venom factor did not alter either the degree or course of parasitemia during the pre-immune or immune stages of infection. The pattern of consumption of complement components was therefore examined. Concomitant with schizont rupture there was depletion of early-acting components (C1, C4, and C2) of the clasical complement pathway. The magnitude and remporal relationships of the fall were similar for these three components. Serum levels returned to prerupture values over 36-48 hr, and then the cycle was repeated. There was no simultaneous change in the levels of C3, C3 proactivator, or C6. These results delineate a new pattern of cyclical consumption of early components of the classical complement pathway associated temporally with schizont rupture and suggest that the late-acting components are not required for protective host immunity in malaria.

Acute Disease↗
PubMed1975

Receptors for immunoglobulin and complement on human alveolar macrophages.

Specific cell membrane surface receptors for immunoglobulin and complement components were identified by rosette formation on in vitro cultured alveolar macrophages obtained from 24 humans and from rabbits. Respiratory macrophages have easily identified receptors for IgG and the C3b fragment of the third component of complement. A macrophage receptor for the C3d fragment was detected only when purified human complement components were used to form erythrocyte-antibody-C3 immune complexes but was not detected when whole human serum was used as the source of complement. No IgM cell receptor was identified. Thus, with respect to membrane receptors, alveolar macrophages resemble peripheral blood monocytes. These studies in addition emphasize the importance of using a variety of immune reagents, especially the use of human reagents, to determine correctly these cell receptors.

Animals↗
PubMed1975

Two novel stimuli of cyclic adenosine 3',5'-monophosphate (cAMP) in human lymphocytes.

Polystyrene latex particles (PLP) and zymosan particles (ZP), two commonly employed phagocytic stimuli, were noted to bind to purified human peripheral blood lymphocytes. This interaction was not accompained by ingestion but did lead to a marked increase in intracellular cyclic AMP. The cAMP response to PLP was proportional to the particle cell ratio which, in turn, correlated with the number of membrane-associated particles. After the addition of PLP to lymphocytes, the cAMP response occurred within 2 min, peaked between 4 and 15 min, and returned to baseline by 30 to 60 min. The cAMP response to ZP was similar in onset and duration to that seen with PLP but was less marked (2- to 4-fold vs 25- to 50-fold) and more variable in magnitude. This is probably a reflection of the smaller number of cells interacting with ZP. At high PLP to cell ratios almost all of the lymphocytes bound PLP but only 10 to 28% of the mixed lymphocyte population bound ZP. Two lines of evidence established conclusively that the cAMP response was taking place in the lymphocytes themselves rather than in contaminating cells. 1) When lymphocytes were purified additionally by filtration through a nylon wool column (99 to 100% lymphocytes), they were found to undergo a similar cAMP response to PLP. Since the nylon filtration procedure also removes almost all of the B cells, this further indicates that T cells are capable of undergoing the response. 2) Immunofluorescence studies with anti-cAMP antibody revealed an increase in intralymphocytic cAMP which was primarily adjacent to the site of PLP or ZP attachment. The likely explanation of this data is that PLP and ZP perturb the lymphocyte surface leading to regional activation of membrane-bound adenylate cyclase and subsequent cAMP accumulation. Although the physiologic significance of these observations remains to be determined, the results: 1) provide histologic confirmation for the concept of cAMP compartmentablization, 2) clarify conflicting results regarding the localization of cAMP accumulation during the phagocytosis of PLP by mixed leukocyte populations, and 3) suggest that this experimental system may allow an analysis of the mechanism by which perturbations of the lymphocyte surface modulate cAMP.

Binding Sites↗
PubMed1974

The effect of Bacillus Calmette-Guerin-induced macrophage activation on the in vivo clearance of sensitized erythrocytes.

The clearance of (51)Cr-labeled guinea pig erythrocytes, sensitized with a known amount of IgM or IgG antibody, was examined in normal and BCG-infected guinea pigs. In normal animals, IgM-coated cells were rapidly sequestered in the liver. Most of these cells were then slowly released into the circulation where they survived normally as Coombs-positive erythrocytes. Neither the site nor extent of initial clearance showed major alterations in BCG-infected animals; however, there was no return of the sequestered erythrocytes into the circulation. This pattern of clearance was only seen in normals at very high levels of sensitization. In contrast to the IgM studies, the pattern of clearance of IgG-sensitized erythrocytes was not altered, but the rate and magnitude was markedly increased at all levels of sensitization. In addition, complement-independent clearance of IgG-sensitized erythrocytes was augmented in BCG-infected guinea pigs lacking classical complement pathway function. The spleen remained the organ primarily responsible for this increased clearance of IgG-sensitized erythrocytes. Sensitized cells in BCG-infected animals were removed from the circulation as if they were coated with several times the amount of antibody. Serum factors were shown not to be responsible for the increased clearance. These data suggest that increased macrophage activation in BCG-infected animals plays a critical role in determining the consequences of cell sensitization in vivo. These studies may help to explain exacerbations of hemolytic anemias and related states after intercurrent infections.

Animals↗
PubMed1974

Studies on the in vivo effects of antibody. Interaction of IgM antibody and complement in the immune clearance and destruction of erythrocytes in man.

Purified human IgM isoagglutinins were utilized to sensitize (51)Cr-labeled erythrocytes so as to produce a known number of complement-fixing sites. These cells were then reinfused into the erythrocyte donor. A minimum of 20 C1-fixing sites/erythrocyte were required for decreased survival. As the amount of antibody coating the erythrocytes was increased, a larger percentage was sequestered. With 80 C1-fixing sites, more than 75% of the injected erythrocytes were removed from the circulation within 10 min. In each case, the clearance pattern consisted of rapid hepatic sequestration followed by a gradual return of a portion of the erythrocytes into the circulation where they survived normally. Clearance was shown to be dependent upon activation of the classical complement pathway, since sensitized cells survived normally in hereditary angioedema patients with low levels of C4 and no detectable C2. Exposure of sensitized cells to fresh serum for 15 min led to the deposition of 550-800 C3 molecules/C1-fixing site. Such cells were immune adherence positive, were agglutinated by anti-C3b, formed rosettes with human alveolar macrophages, and were sequestered in vivo, presumably because of the interaction of cell-bound C3b with the C3b receptor on hepatic macrophages. After exposure to heated serum as a source of the C3b inactivator, the cells were immune adherence negative, were agglutinated only by anti-C3d, did not form rosettes with macrophages, and survived normally in vivo despite, being Coombs positive. Cleavage of cell-bound C3b to C3d may explain the release phase of the IgM clearance pattern. Whereas erythrocytes coated with IgM antibody and complement were previously thought to be sequestered in the liver because of extensive membrane damage, these experiments suggest that clearance is determined by the interaction of erythrocyte-bound complement fragments with specific receptors on hepatic macrophages.

Adolescent↗
PubMed1974

Relationship of serum complement levels to events of the malarial paroxysm.

Malarial paroxysms due to Plasmodium vivax were studied for alterations in whole serum complement (C') and certain C' components. The objective was to relate C' values with events of the parasite cycle during schizogony and with the febrile pattern. Substantial decreases in C' were found in 9 of 18 paroxysms studied during relapse. In contrast, only one of 22 paroxysms occuring during the primary attack was associated with a striking depression in C', and this case exhibited certain characteristics of a relapse paroxysm. The mean change in C' levels during paroxysms in relapse (-23%) was significantly different from paroxysms of the primary attack (-2%). Depletion of C' was associated directly with degree of parasitemia and presence of complement-fixing (CF) antibody. Lowest levels of C' were found within a few hours after completion of schizont repture and peak fever. C4 levels reflected changes in whole serum C' and appeared to be a more sensitive indicator of C' alterations during malaria. While the alterations in C4 as well as C1 and C2 indicated that the classical C' pathway was involved, some preliminary results showed little or no depletion of late components, C3 and C6. Overall results are compatible with C' activation and depletion during or soon after schizont repture if parasite density is sufficiently high and if CF antibody is present.

Adult↗
PubMed1973

Effects of corticosteroids and splenectomy on the immune clearance and destruction of erythrocytes.

Corticosteroids and splenectomy constitute two important therapeutic modalities in the treatment of autoimmune hemolytic anemia. Each of these may affect both the rate of synthesis of autoantibody and the clearance of antibody sensitized cells. The latter possibility has been examined in an experimental model which allows evaluation of the role of antibody and complement in the immune clearance of erythrocytes in molecular terms. The in vivo clearance of (51)Cr-labeled guinea pig erythrocytes sensitized with purified rabbit IgG or IgM antibody to produce a known number of complement-fixing sites per cell was studied. Corticosteroid therapy increased the survival of both IgG and IgM sensitized erythrocytes by decreasing sequestration in the reticuloendothelial system (RES). 5 days of therapy prior to injection of antibody coated cells were required for a maximal effect. It appeared that the RES of cortisone-treated animals had a lowered sensitivity to erythrocytes coated with antibody and complement and the cells were removed as though they were coated with fewer complement sites/cell. The general pattern and kinetics of clearance and the localization of sequestered cells were not modified by corticosteroids. As the number of IgG C1-fixing sites was increased, the difference betwen cortisone treated and control animals was less marked. Splenectomy led to an increased survival of IgG-coated cells and a sixfold increase in IgG C1-fixing sites was necessary in order to obtain similar rates of clearance in splenectomized and control animals. The liver was responsible for this much less efficient clearance of cells in splenectomized animals: the clearance pattern was typical of that noted for IgG. No effect at all was noted on the clearance of IgM sensitized cells in splenectomized animals. These experiments clearly demonstrate that both corticosteroid therapy and splenectomy act to decrease the in vivo clearance of IgG-sensitized cells: only corticosteroids alter the clearance of IgM-sensitized erythrocytes. This effect may be of major importance in explaining the efficacy of these therapeutic modalities in autoimune hemolytic anemia.

Anemia, Hemolytic, Autoimmune↗