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Biomedical subjects

A Salama

Publications and source records attributed to A Salama.

At least 109 records · Page 6Linked to original sources
PubMed1989

Acute immune hemolysis induced by a degradation product of amphotericin B.

We report here on an eight-year-old boy who first developed acute intravascular hemolysis following therapy with amphotericin B (AmB) and subsequently a delayed hemolytic transfusion reaction due to alloantibodies. Although there is as yet no evidence for metabolism of AmB in vivo, the hemolysis appeared to be the result of sensitization against a degradation product of the drug. The patient's serum contained a hemagglutinating IgM antibody that reacted with all red blood cells (RBC) tested in the presence of plasma obtained from patients receiving AmB (ex vivo antigen), but not in the presence of their urine, AmB itself, or with AmB-pretreated RBC. These findings indicate that the antibody was directed against a degradation product of AmB, presumably a trace metabolite, that has not yet been identified.

Acute Disease↗
PubMed1989

Immune-mediated agranulocytosis related to drugs and their metabolites: mode of sensitization and heterogeneity of antibodies.

Two major unresolved problems in drug-related immune agranulocytosis are understanding the mechanism by which sensitization takes place in vivo, and verification of the diagnosis. Using a sensitive, competitive enzyme-linked immunoassay (ELISA) we were able to characterize the causative antibodies in 13 patients with drug-related agranulocytosis [metamizole (n = 5), penicillin (n = 5), dimethylaminophenazone (n = 1), propyphenazone (n = 1) and diclofenac (n = 1)]. Irrespective of the causative drug, the majority of patients appear to have developed autoantibodies (aab) in addition to drug-dependent antibodies (ddab) of the IgG and/or IgM classes. In all cases related to metamizole, and in the single case related to diclofenac, the ddab appeared to recognize only metabolites of the drug since they were reactive in the presence of ex vivo antigens (urine from individuals receiving therapeutic levels of the drugs), but not the native drugs. Only a few ddab were reactive with granulocytes pretreated with the drug (cell-drug complexes); the majority of ddab could not be detected unless the drug or ex vivo antigen was added to the incubation mixture as well as the solution used for subsequent washes. Our results indicate that drugs and/or their metabolites interact with target cells and thereby directly function as immunogenic haptens, even when the drugs do not bind tightly to the cells.

Adolescent↗
PubMed1989

[Drug-induced immunocytopenia].

Drugs are responsible for the causative antibodies in 10-20% of all cases with immunocytopenias (immune hemolytic anemias, immune thrombocytopenias or immune granulocytopenias). Usually only one cell type is affected in the same patient, but rarely two cell types can be simultaneously involved. The immunocytopenia can precipitously occur within minutes to hours, or it develops gradually throughout days and weeks. In the former case the reactions are usually due to complement-activating IgG- and/or IgM-antibodies, and in the latter case to non-complement-activating IgG-antibodies without complement activation. The corresponding antigens could be complexes of the drug (metabolites) and structures of the cell membrane (drug-dependent antibodies) as well as cell antigens alone (autoantibodies). These findings indicate that the immunogenicity of haptens (metabolites and less commonly the drug itself) can result not only from their stable conjugation on macromolecules, but also from a loose interaction between the drug (particularly its metabolites) and the cell surface.

Agranulocytosis↗
PubMed1988

Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass.

Hemolysis, leukopenia, a hemostatic deficit, and nonspecific systemic reactions collectively known as the postperfusion syndrome develop in patients who undergo cardiopulmonary bypass. We now report that terminal C5b-9 complement complexes are deposited on erythrocytes and polymorphonuclear neutrophilic leukocytes during cardiopulmonary bypass. Plasma samples taken from 48 unselected patients during and at the end of cardiopulmonary bypass contained raised levels of fluid-phase SC5b-9 complement complexes, indicating that the complement sequence had been activated to completion. Various degrees of overt intravascular hemolysis were observed in all the patients, and lysed erythrocyte membranes were recovered from the blood samples. Immunoassays performed with use of antibodies to C5b-9 neoantigens demonstrated the presence of C5b-9 on red-cell ghosts but not on intact erythrocytes. The appearance of ghosts carrying C5b-9 always coincided with hemolysis. Furthermore, granulocytes isolated from 20 patients during bypass were all found to carry C5b-9 complexes, whereas cells isolated before or 24 hours after surgery carried no C5b-9. The neoantigen-positive material present in detergent extracts of granulocytes sedimented in a broad peak (25 to 40 sedimentation coefficient [S]) in sucrose-density gradients, exactly as did pore-forming C5b-9 complexes. Deposition of C5b-9 on blood cells during cardiopulmonary bypass may be partly responsible for the hemolysis and may augment granulocyte activation by the stimulation of arachidonate metabolism in those cells.

Autoantibodies↗
PubMed1988

Complement inhibitor S protein is associated with membranes of red blood cells from patients with paroxysmal nocturnal haemoglobinuria.

S protein is a plasma glycoprotein (Mr = 78,000) which binds to nascent C5b-7 complexes upon complement activation in the fluid phase in whole serum. It thereby protects innocent bystander cells from complement mediated lysis. It is unknown whether S protein also functions as complement inhibitor on cell surfaces. We here report that S protein is recognized on red blood cells (RBC) from patients with paroxysmal nocturnal haemoglobinuria (PNH), but not on normal RBC. RBC from eight PNH patients showed 12-48% haemolysis subsequent to complement activation in the fluid phase, while normal RBC did not respond. Preincubation of the PNH cells with affinity-purified antibodies against human S protein resulted in a three- to five-fold increase of haemolysis, while preincubation of these cells with S protein decreased haemolysis by 40%. In contrast, haemolysis remained unaffected by other unrelated antibodies, i.e. IgG anti-Rh(D) and anti-A. If PNH RBC, normal RBC pretreated with 2-amino-ethylisouronium bromide (AET), or untreated normal RBC, respectively, were incubated with purified S protein in vitro, the uptake of antibodies against S protein was significantly enhanced with PNH and with AET-treated, but not with untreated normal RBC. Additionally, while normal RBC did not respond to reactive lysis initiated by purified C5b-6 and C7, PNH as well as AET-RBC showed significant haemolysis that could be inhibited by S protein in a dose-dependent fashion. These findings strengthen the assumption that the increased sensitivity of PNH cells towards reactive complement lysis is either due to the lack of an inhibitor of the terminal complement sequence and/or enhanced insertion of the membrane attack complex. These defects of PNH RBC may partly be overcome by the fluid phase complement inhibitor S protein which binds to PNH RBC and may thereby suppress homologous cytolysis.

Complement Inactivator Proteins↗
PubMed1988

Carbimazole-induced immune haemolytic anaemia: role of drug-red blood cell complexes for immunization.

We report on a patient who developed acute intravascular immune haemolysis while receiving carbimazole. Serological studies revealed a strongly (3+) and a discretely positive (1+) direct antiglobulin test due to C3d and IgG respectively, and a very weak IgG autoantibody in the eluates. Serum from the patient contained specific carbimazole-dependent red blood cell (RBC) antibodies which reacted with all normal human RBC in the presence of free carbimazole as well as with RBC coated with the drug either in vitro or in vivo, although carbimazole itself is not detectable in plasma after oral administration. The results provide direct evidence for the sequence of the drug-RBC-antibody interaction and show that the RBC (and not plasma proteins) function as 'carrier-like' macromolecules in the immune response.

Aged↗
PubMed1988

Major histocompatibility complex markers in patients with nomifensine-induced immune hemolytic anemia.

To evaluate a possible role of major-histocompatibility-complex (MHC)-related immune-response genes for the selective production of drug-induced antibodies, HLA class I (ABC), class II (DR, DQ), class III (BF, C2, C4A, C4B) as well as glyoxalase-1 allotypes were investigated in 26 patients with nomifensine-induced immune hemolytic anemia. No statistically significant deviations of MHC antigen frequencies were noted. The possible implications of these findings are discussed.

Adult↗
PubMed1988

Complement-independent lysis of human red blood cells by cold hemagglutinins.

Hemolysis mediated by human antibodies is generally ascribed to the attack of red blood cells (RBC) by complement. We here extend earlier in vitro observations which indicate that potent cold agglutinins can directly cause lysis of RBC without the participation of complement. We have noted that EDTA plasma taken from patients with cold agglutinin disease is frequently reddish if the plasma is not immediately separated from the cells at 37 degrees C. Moreover, eluates prepared in such cases from plasma or heat-inactivated serum (30 min at 56 degrees C) by absorption (at 4-20 degrees C) and elution (at 37 degrees C) are usually contaminated with hemoglobin, and a large number of RBC used for absorption is lost during the procedure. To characterize this phenomenon further, we examined the effect of different hemagglutinating antibodies in vitro on normal RBC in the absence of complement. Hemolysis (5-17%) of RBC only occurred after treating the cells with potent antibodies at low temperatures (0-20 degrees C). This hemolysis increased 2- to 3-fold when the RBC were treated with an enzyme and decreased with rising temperature. Unlike cells hemolyzed by complement activation, no C5b-9 complexes could be detected on RBC damaged by this mechanism.

Cold Temperature↗
PubMed1988

The adrenergic responses of carp (Cyprinus carpio) red cells: effects of PO2 and pH.

Carp (Cyprinus carpio) red cells do not show beta-adrenergic responses when incubated with 10(-5) mol l-1 adrenaline at atmospheric oxygen tension and a pH value close to the in vivo resting pH (approx. 8.1). However, when either the pH or the oxygen tension of the incubation medium is decreased, the adrenergic responses appear, showing that oxygen or an oxygen-linked phenomenon has a direct influence on the response. Once present, the adrenergic red cell response is similar to that of trout: cellular water content, sodium content and intracellular pH all increase. Quantitatively the effect appears to be much smaller in carp than in trout. Adrenaline induces an increase in red cell oxygen content when the oxygen content is plotted as a function of extracellular pH. This effect coincides with the onset of the Root effect and is caused by the adrenaline-induced increase in intracellular pH, since it disappears when the oxygen content is plotted as a function of intracellular pH. The red cell ATP content decreases metabolically during adrenaline incubations. In contrast, cellular GTP content is not metabolically reduced in adrenaline-treated cells, showing that the rapid and selective decrease in red cell GTP concentration, observed in hypoxic cyprinids, is not adrenergically induced.

Adenosine Triphosphate↗
PubMed1987

Cianidanol and its metabolites bind tightly to red cells and are responsible for the production of auto- and/or drug-dependent antibodies against these cells.

Cianidanol ((+)-2-(3,4-dihydroxyphenyl)-3, 5, 7-chromantriol) is a flavonoid which has been associated with severe immune haemolysis by as yet unclear mechanisms. We report six patients who developed haemolysis while receiving the drug. The disorder was episodic in all patients and resolved after discontinuing the drug. The causative antibodies could be demonstrated in all six cases, even when the haemolytic episode was more than 1 year prior to this study. One patient had developed drug-independent IgG autoantibodies, another simultaneously developed autoantibodies and drug-dependent antibodies (ddab) of the IgG class, while the remaining four patients had only ddab of the IgM and/or the IgG classes. All ddab were reactive with red blood cells (RBC) in the presence of the drug and/or its metabolites (ex vivo antigens), and, quite unexpectedly, also with RBC coated with the drug (metabolites) in vitro or in vivo. This reactivity did not change either by preincubating the antibodies with the drug or by adding large amounts of the drug to the mixture of drug-coated cells plus antibody. It seems that the stable association of cianidanol with RBC generates antigenic sites against which a heterogeneous immune response is elicited giving rise to long-lasting drug-dependent antibodies as well as autoantibodies.

Adult↗
PubMed1987

Haemolytic 'efficiency' of C5b-9 complexes in drug-induced immune haemolysis: role of cellular C5b-9 distribution.

We report on quantitative analyses of C5b-9 binding to target red blood cells (RBC) lysed through the action of drug (nomifensine)-dependent antibodies (ddab) and anti-RBC antibodies (warm plus cold agglutinins). Immunoradiometric assays showed that, at any given degree of haemolysis, more C5b-9 was bound to cells sensitized with anti-RBC antibodies compared to cells lysed via ddab. Thus, C5b-9 complexes deposited through the action of ddab appeared to be haemolytically more 'efficient' than those deposited via anti-RBC antibodies. However, data obtained from flow-cytometric assays and immunoelectron microscopy demonstrated a major role for the distribution (total number) of C5b-9 lesions among the cells within a given cell population. Enhanced haemolysis with a given total amount of C5b-9 complexes appeared to be derived from a more even distribution of these complexes among the cells rather than from higher lytic efficiency of individual complexes. Since ddab bind with low affinity to cells, we suggest that these antibodies diffuse from cell to cell and cause extensive haemolysis through the deposition of relatively few C5b-9 complexes at each site. In contrast, high affinity antibodies remain largely bound to relatively restricted sites causing deposition of larger amounts of C5b-9 on, and hence lysis of, numerically fewer cells. With respect to the net intravascular haemolytic effect, our findings may explain why complement-activating antibodies of low affinity are often more detrimental than high affinity antibodies.

Antibody Affinity↗
PubMed1987

Autoimmune haemolytic anaemia in childhood associated with non-complement binding IgM autoantibodies.

Red cell bound IgM autoantibodies free of associated IgG autoantibodies and unable to activate complement have not yet been considered as the cause of autoimmune haemolytic anaemia (AIHA). We report on warm type AIHA resulting from the action of IgM autoantibodies on circulating RBC. Twelve children (eight of whom were infants) with relatively severe haemolytic anaemia were studied. Whereas the clinical findings and courses of all children appeared to be compatible with warm type AIHA, the serological findings during the haemolytic phase were atypical in that the direct antiglobulin test (DAT) was negative in 11, and positive in one case due to C3d only. The use of radiolabelled antihuman globulin antibodies showed, however, that the RBC of all the patients were sensitized with warm IgM antibodies. Elevated values of IgA and/or IgG immunoglobulins on the patients' RBC were found to be present in only two cases. Complement activation by IgM autoantibodies could not be detected in all other cases neither in vivo nor in vitro. Thus, we conclude that non-complement binding IgM autoantibodies were responsible for the AIHA in the majority of these children possibly representing an as yet unrecognized variant of warm type AIHA.

Anemia, Hemolytic, Autoimmune↗
PubMed1987

Red cell function of carp (Cyprinus carpio) in acute hypoxia.

The red cell function of carp, subjected to acute hypoxia, was studied. During hypoxic exposure red cell water content, sodium and chloride concentration and pH increased, whereas plasma sodium and chloride concentrations decreased. Treatment of the animals with a beta-adrenergic antagonist, propranolol, before the onset of hypoxia, largely inhibited the increase in red cell water content, diminished the changes in red cell pH and prevented the changes in red cell and plasma sodium concentration. The red cell chloride concentration increased also in propranolol-treated animals thus illustrating the effect of the deoxygenation of haemoglobin on the ion concentrations of red cells. These data indicate that adrenergic activation of sodium/proton exchange across red cell membrane plays a role in the acute responses of carp to hypoxia.

Animals↗
PubMed1987

On the mechanisms of sensitization and attachment of antibodies to RBC in drug-induced immune hemolytic anemia.

The mechanisms of sensitization and attachment of drug-dependent antibodies to RBC in drug-induced immune hemolytic anemias are largely speculative. Nomifensine has been incriminated in causing immune hemolysis in a large number of patients. The hemolysis was usually of the so-called immune complex type, less commonly of the autoimmune type, and more surprisingly, few patients had developed both types of hemolysis. To determine whether nomifensine (metabolite)-dependent antibodies (ndab) exhibit specificity for antigenic structures of RBC membranes, 30 ndab were tested against large panels of RBC with common and rare antigens. We found that only 14 out of 30 ndab were invariably reactive with all cells tested. Nine antibodies were, similar to the majority of idiopathic or drug-induced autoantibodies, not or only weakly reactive with Rhnull RBC. Three antibodies did not react with cord RBC and could be inhibited by soluble I antigen. The remaining four antibodies gave inhomogeneous reaction patterns or were even negative with selected RBC; their specificity could not be identified. On a Scatchard plot analysis of one ndab, a maximum of 173,000 drug-dependent antibodies of the IgG class can specifically bind per RBC in the presence of the drug. Although nomifensine and its metabolites do not attach tightly onto RBC, our results clearly indicate that RBC do not act as "innocent bystanders," but rather serve as a surface for a loose attachment of drugs that possibly cause a subtle structural change in the cell antigens and, by this means, allow in vivo sensitization; and a specific binding of the resultant antibodies. This concept would explain why these antibodies can be directed against drug-cell complexes, against cell antigens alone (autoantibodies), or against both in the same patient.

Anemia, Hemolytic, Autoimmune↗