Showing papers by "Richard J. Ulevitch published in 1978"

Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis.

Abstract: An acute phase of experimental autoimmune myasthenia gravis (EAMG) occurs transiently early in the immune response of Lewis rats to nicotinic acetylcholine receptors (AChR) when Bordetella pertussis is used as adjuvant. It is characterized by a destructive cellular attack directed at the postsynaptic membranes of muscle. Acute EAMG can be passively transferred to normal rats by IgG from serum of rats with chronic EAMG. In the present study, acute EAMG, induced either by passive transfer of syngeneic antibodies or by active immmunization, was inhibited in rats depleted of complement by treatment with cobra venom factor (CoF). Furthermore, passive transfer of antibodies in excess of the muscle's content of AChR was without any measurable effect in rats treated with CoF. Although 60% of the muscle's AChR was complexed with antibody, there was no reduction in the muscle's content of AChR, and neuromuscular transmission was not compromised as judged electromyographically by curare sensitivity. These data imply that redistribution, accelerated degradation, and impairment of the ionophore function of AChR, effects of antibodies described in vitro on extrajunctional AChR, do not play a significant role in vivo in impairing neuromuscular transmission in an intact neuromuscular junction. Complement appears to be a critical mediator of anti-AChR antibodies' pathogenicity in vivo.

The modification of biophysical and endotoxic properties of bacterial lipopolysaccharides by serum.

Abstract: Normal rabbit serum reduces the buoyant density of lipopolysaccharide (LPS) from Escherichia coli 0111:B4 (d = 1.44 g/cm3) and Salmonella minnesota R595 (d = 1.38 g/cm3) to a value less than g/cm3. This density shift is associated with the inhibition of a number of endotoxic activities of the LPS; namely, the pyrogenic activity, the ability to produce an immediate neutropenia in rabbits, lethality in adrenalectomized mice, and anticomplementary activity. A qualitatively similar change in buoyant density was observed to occur after intravenous injection of the LPS into rabbits. Preliminary evidence suggests that the density shift does not occur as a result of the degradation of the glycolipid backbone of the LPS. These data suggest that the interactions of LPS with plasma (or serum) components leading to reduction in buoyant density may account for a major pathway of LPS detoxification.

Role of complement in lethal bacterial lipopolysaccharide-induced hypotensive and coagulative changes.

Abstract: The effect of C3 depletion on the multiple pathophysiological changes produced by a lethal dose of Serratia marcescens lipopolysaccharide (LPS) was evaluated. The injection of this LPS into rabbits resulted in biphasic hypotensive changes and thrombocytopenia. These changes were characterized by an acute, transient decrease occurring within minutes after injection followed by a second more gradual decrease beginning 30 to 60 min post-LPS. Prior depletion of C3, with the anticomplementary protein from cobra venom (CoF), did not alter the extent of either the gradual hypotensive and platelet changes or the coagulative and metabolic changes when normal and C3-depleted rabbits were compared. Importantly, the lethal effects of S. marcescens LPS were not reduced by prior depletion of C3. Only the immediate, reversible thrombocytopenia and hypotension were abrogated by C3 depletion.

Phospholipase A2 contamination of cobra venom factor preparations. Biologic role in complement-dependent in vivo reactions and inactivation with p-bromophenacyl bromide.

Abstract: Cobra venom factor (CoF), the anticomplementary protein in Naja naja cobra venom, is usually purified by sequential ion exchange and gel filtration chromatography. CoF prepared in this manner contains small but significant quantities of phospholipase A2 activity. This acyl hydrolase activity can be simply and efficiently removed on a large scale by treatment of CoF with p-bromophenacyl bromide (BPB), an irreversible modifier of the histidine residue in the active site of phospholipase A2. BPB treatment does not alter the anticomplementary activity of CoF. In vivo experiments utilizing intratracheal injections of control and BPB-treated CoF, as well as pure phospholipase A2, revealed that contaminating phospholipase A2, and not the anticomplementary protein, was responsible for the observed acute neutrophil-associated lung injury. However, phospholipase A2 had no effect on the hypotensive and thrombocytopenic effects of CoF infected intravenously into rabbits. Depletion of circulating C3-C9 by intraperitoneal injections of CoF was not altered by removal of phospholipase A2 activity with BPB.

The Effect of Complement Depletion on Bacterial Lipopolysaccharide (LPS)-Induced Hemodynamic and Hematologic Changes in the Rhesus Monkey

Abstract: Lipopolysaccharide (LPS) isolated from Salmonella minnesota R595 or from Escherichia coli 0111:B4 induces hypotension in rhesus monkeys with normal complement levels. This hypotension is accompanied by decreased total peripheral resistance. The depletion of C3 and terminal complement components by prior intraperitoneal administration of the anticomplementary protein cobra factor did not alter the hemodynamic changes which occur following the rapid injection of 5 mg/kg of R595 LPS, the infusion of 500 μg/kg of R595 LPS, or the injection of 500 μg/kg of 0111:B4 LPS. We conclude that the LPS-induced hemodynamic changes in the subhuman primate are mediated by pathways which do not require the participation of C3. The kinetics and extent of the neutropenia and thrombocytopenia resulting from the injection of 0111:B4 or R595 LPS were not altered by prior depletion of greater than 95% of the plasma C3.

Two distinct mechanisms for the initiation of mast cell degranulation. II. A specific inhibition of amine release by serum proteins.

Abstract: Our experiments have provided additional data in support of the concept that different mast cell activators follow distinct biochemical path-ways in the initiation of secretion and degranulation. To do this we have taken advantage of the observation that some serum proteins, and albumins in particular, have the capacity to inhibit selectively the release of amines from rat peritoneal mast cells initiated by some, but not all, stimuli. We show that the relative inhibition of release obtained is independent of the concentration of activator but dependent upon the concentration of albumin, indicating that the inhibitory process does not involve a direct activator--inhibitor interaction. Finally, our data demonstrate that the inhibition does not interfere with the ability of the acitivator to interact with the mast cell. Thus, cells incubated with activator in the presence of inhibitor become increasingly unresponsive, or desensitized, to subsequent challenge with activator in the absence of inhibitor. These combined data therefore provide evidence, that, in addition to a selectivity in the activation/desensitization process initiated by different mast cell stimuli, at least one of the biochemical steps subsequent to the activation step is also not shared by all mast cell stimuli.