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Biomedical subjects

H Gewurz

Publications and source records attributed to H Gewurz.

At least 127 records · Page 7Linked to original sources
PubMed1977

Effects of C-reactive protein on platelet function. III. The role of cAMP, contractile elements, and prostaglandin metabolism in CRP-induced inhibition of platelet aggregation and secretion.

It was previously demonstrated that C-reactive protein (CRP) inhibits platelet aggregation and release reactions, activation of platelet factor 3, and platelet-dependent clot retraction. Multiple considerations including selective inhibition of secondary wave aggregation suggested that CRP exerted its inhibitory effects by interfering with the release of endogenous ADP. In the present investigation, CRP was found by direct assay to inhibit the release of endogenous ADP and/or serotonin concomitant with inhibition of platelet aggregation stimulated by ADP, epinephrine, thrombin, and AHGG. CRP did not induce an increase in the basal level of platelet cAMP, suggesting independence of a direct effect upon this mediator system. Furthermore, CRP did not inhibit the aggregation and secretion induced by the antibiotic ionophore A23187, suggesting the absence of a direct effect upon the activation of platelet contractile elements. By contrast, CRP did inhibit both thrombin-induced release of malondialdehyde, a prostaglandin endoperoxide nonprostanoate endproduct, and platelet aggregation induced by the prostaglandin endoperoxide precursor arachidonic acid. These data, therefore, raise the possibility that CRP inhibits platelet reactivities by interfering with an aspect of porstaglandin metabolism, and that this occurs subsequent to the hydrolytic accumulation of arachidonic acid and prior to the movement of calcium from the platelet dense tubules. These studies support the concept that CRP serves to modulate platelet reactivities during acute inflammatory reactions.

Adenosine Diphosphate↗
PubMed1977

C567-initiated cytolysis of lymphoid cells: description of the phenomenon and studies on its control by C567 inhibitors.

Cells of the Raji human lymphoblastoid line, when pretreated with the metabolic inhibitor puromycin were found to be susceptible to killing by the isolated proteins of the complement attack mechanism (C5-9). Incubation of 51Cr-labeled lymphoblastoid cells with purified C56 and C7 resulted in the formation of a lymphoblast-C567 (LC567) intermediate, and the addition of purified human C8 and C9 resulted in release of 51Cr from these cells. Serum C567 inhibitors (C567-INH), purified human lipoproteins, and dextran sulfate, each previously shown to inhibit the attachment of the C567 trimolecular complex to erythrocytes, also inhibited the formation of LC567, and as a consequence, C56-initiated cytotoxicity; the polycation protamine sulfate counteracted the inhibitory effect of dextran sulfate. Thus, the potential for damage of bystander nucleated cells exists when C56 is generated in solution, and is influenced by agents known to modulate the hemolytic activity of C567. It is suggested that these mechanisms may be involved in the control of the function as well as the viability of various nucleated cells.

Cell Line↗
PubMed1977

Complement activation by interaction of polyanions and polycations. III. Complement activation by interaction of multiple polyanious and polycations is the presence of C-reactive protein.

Interactions between heparin and protamine previously were found to result in activation of the complement (C) system. In the present investigation, this interaction was shown to result in the binding of purified C1, and this was markedly enhanced in the presence of C-reactive protein (CRP). CRP also enhanced C consumption during heparin-protamine interactions in whole serum, and in the presence of CRP depletion of C components C1-3 was observed. Similar C1 binding and C consumption in the presence of CRP were seen upon the interaction of multiple additional polyanions including DNA, ENA, hyaluronic acid, chondroitin sulfate, and dextran sulfate with the polycations protamine sulfate and poly-L-lysine. These effects were observed with CRP concentrations well within the range found in normal human sera and considerably less than those found in most acute phase sera. We suggest, therefore, C activation by polyanion-polycation interactions in the presence of CRP may be important to certain reactions of host defense and inflammation.

Anions↗
PubMed1977

Enhancement of C56-initiated lysis by cell-bound C3 fragments: evidence for a mechanism independent of the prior binding of C56 to C3b.

Cell-bound C3b can reversibly bind C56, the activated complex of the fifth (C5) and sixth (C6) components of complement, and in this way potentiate C56-initiated lysis by favoring the formation of C567 at the cell surface. We report here another way in which cell-bound C3 fragments can enhance C56-initiated lysis, which involves C567 generated in the fluid phase rather than at the cell surface. Evidence for the involvement of fluid phase C567 was obtained by use of dextran sulfate, which is known to inhibit the hemolysis of E mediated by fluid phase C567. Dextran sulfate strongly inhibited the formation of C567 sites on cells bearing C4b and C3b (EAC4b3b) as well as on unmodified E when C56 and C7 were added simultaneously to the cells. By contrast, dextran sulfate had virtually no effect on the reaction sequence involving the prior binding of C56 to C3b and subsequent formation of C567 at the cell surface. Treatment of EAC4b3b with either anti-C3 Fab' fragments or the C3b inactivator reduced but did not eliminate the enhancement of hemolysis, raising the possibilities that a C3 fragment(s) other than C3b also can enhance C56-initiated lysis and/or that the enhancement is indirect without a requirement for an interaction between C567 and the cell-bound C3 fragment itself.

Complement C3↗
PubMed1976

Binding of C-reactive protein to antigen-induced but not mitogen-induced T lymphoblasts.

The C-reactive protein (CRP), an acute phase reactant which binds selectively to T (thymus-derived) lymphocytes, was found to bind to lymphoblasts formed upon stimulation with antigens but not with mitogens. Binding of CRP thus serves as a marker for antigen-reactive (-reacted) as opposed to mitogen-reative (-reacted) T cells, suggesting that these represent separate subpopulations, and supports the developing concept that CRP play an important role in the regulation of responses critical to inflammation, host defense, and tissue repair.

Antigens↗
PubMed1976

C1q deficiency associated with urticarial-like lesions and cutaneous vasculitis.

We describe a 46 year old women with a seven year history of urticarial-like symptoms and cutaneous vasculitis with marked deficiency of C1q in the presence of normal levels of C1r and C1s and high titers of low molecular weight (7S) C1q precipitins. Hemolytic C1 activity, which was greatly reduced, was restored upon the addition of purified C1q. The other complement components were present in moderately reduced or normal levels. This patient bears resemblance to several other persons previously described with urticarial-like lesions in association with selective deficiency of C1q. The similarity of the clinical features, pathologic diagnosis, C1q levels disproportionately deficient in relation to other complement components and low molecular weight C1q precipitins support the conclusion that these are causally related in a symptom complex. The underlying basis is yet to be defined.

Complement C1↗
PubMed1976

IgE myeloma presenting with classical myeloma features.

A patient with IgE myeloma, presenting with bone lesions and modest anemia without plasma cell leukemia or hepatosplenomegaly, is described. The findings are compared with those of other patients with this and the more common forms of multiple myeloma.

Aged↗
PubMed1976

Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis.

A previously healthy 6-year-old boy who presented with meningococcal meningitis responded favorably to ampicillin, but suffered two and possibly three repeat attacks in the ensuing month. No abnormality of the otolarynx, skin, or neuroskeleton was found. The infecting strain, Neisseria meningitidis, Group Y, Type IV, was sensitive to the therapeutic agents used, and antibiotic levels were adequate. Serum bactericidal antibody titers against autologous meningococci were high. Serum complement hemolytic bactericidal activities, however, were entirely lacking, and this was attributable to a complete deficiency of C6. Measurements of the remaining complement components, C-dependent chemotaxis and opsonization, neutrophil function, specific immunity, and the coagulation system, were normal. The parents had half-normal C6 levels. Recurrence of meningitis in this patient supports the concept that complement plays a role in resistance to certain microorganisms and emphasizes the need for complete evaluation of the complement system in individuals with unexplained repeated infections.

Child↗
PubMed1976

Activation of the complement attack mechanism in the fluid phase and its control by C567-INH: lysis of normal erythrocytes initiated by zymosan, endotoxin, and immune complexes.

Addition of zymosan-serum complexes to guinea pig erythrocytes in guinea pig complement-EDTA was found to result in substantial lysis of the bystander cells in the presence of polycations such as poly-L-lysine of 178,000 daltons. Involvement of the alternative C pathway was shown, and the optimum time, temperature, and eruthrocyte and polycation concentrations were defined; a surprising efficiency was observed at low temperature and high cell concentrations. Several lines of evidence indicated that this hemolysis was mediated via the C567 complex of the C system and modulated by serum inhibitors of C567 (C567-INH): lysis was observed only with zymosan-serum complexes possessing C-consuming activity; it was not observed in C5-depleted guinea pig serum but was restored upon addition of purified C5; the addition of partially purified C567-INH insubstantially depressed hemolysis; and poly-L-lysine which is known to neutralize C567-INH in solution resulted in substantial enhancement of hemolysis. We also sought to determine whether the addition of complement activators directly to erythrocyte-serum mixtures could result in the hemolysis of bystander erythrocytes. It was found that zymosan, endotoxin, antigen-antibody complexes, and aggregated human gamma-globulin each could initiate such bystander lysis under appropriate conditions. Lysis again was favored by increased erythrocyte concentrations, low temperatures, and the presence of polycations such as poly-L-lysine, and was found to be mediated via the C system. C567-INH blocked cytolysis whereas poly-L-lysine potentiated hemolysis by neutralization of C567-INH. These experiments emphasize the propensity for C567 formation and lysis of bystander erythrocytes during C activation generally, the role of C567-INH in the control of this lysis, and the susceptibility of these interactions to modulation by highly charged macromolecules.

Animals↗
PubMed1976

Radioimmunoassay of human C-reactive protein and levels in normal sera.

C-reactive protein (CRP) has been considered an acute-phase protein which appears only during reactions of tissue injury or inflammation. We report here the quantitation of CRP levels in normal adults and neonates made possible by the development of a sensitive and precise radioimmunoassay for human CRP which enables the detection of 3 ng. per milliliter. Serum levels in 153 healthy blood donors ranged from 68 to 8,200 ng. per milliliter, with a median value of 580 ng. per milliliter (mean = 1,340 ng. per milliliter). CRP levels in 24 normal cord serum samples ranged from 10 to 370 ng. per milliliter, with a median value of 70 ng. per milliliter (mean = 109 ng. per milliliter). CRP levels in 246 individuals evaluated for autoimmune diseases ranged to 256,000 ng. per milliliter with a median value of 13,000 ng. per milliliter (mean = 38,000 ng. per milliliter). No individual lacking CRP was detected. Thus, CRP can be considered a component of normal serum which only increases dramatically in concentration during inflammation.

Adult↗
PubMed1976

Complement activation by interaction of polyanions and polycations.

Interactions between heparin and protamine in normal human serum previously were found to activate the primary complement pathway and deplete the early-acting complement components. In the present investigation, the role of heparin-protamine complexes, immunoglobulins, C1q and C1-INH in this interaction was studied. Heparin and protamine, like antibody and antigen, were found to combine in multiple proportions; those proportions which resulted in optimal precipitation also induced maximal C consumption. Complexes formed in serum contained C1q and IgG, but the amount of C1q was insufficient to account for the total depletion of C1 haemolytic activity, and immunoglobulins were not required for activation of complement to occur: maximal consumption was observed in immunoabsorbed hypogammaglobulinaemic sera in which IgG, IgM and IgA were undetectable (less than 5, less than 10 and less than 7 mug/ml, respectively). Purified C1q aggregated heparin-protamine complexes formed or forming in the presence or absence of serum. The ability to induce maximal C consumption was rapidly lost as heparin and protamine interacted, and complexes preformed either in serum or buffer, or supernates thereof, were relatively ineffective in complement consumption. Thus, the consumption of complement seems to occur via transient reactivity with C1,probably at the level of C1q. It seems to be limited by the ability of free heparin to potentiate the activity of C1-INH, and perhaps also by its direct effect upon the early acting C components. These experiments support the concept that complement activation by interactions between polyelectrolytes such as heparin and protamine, like interactions between the antibodies and antigens, may have a role in the initiation of inflammatory reactions by direct activation of the complement system.

Agammaglobulinemia↗
PubMed1976

Effects of C-reactive protein on the lymphoid system. II. Inhibition of mixed lymphocyte reactivity and generation of cytotoxic lymphocytes.

C-reactive protein (CRP), an acute phase reactant which increases in concentration during inflammation, has been found to bind to human T cells and to inhibit certain of their functions. In the present study CRP was found to display a binding specificity for theta-bearing cells from mouse peripheral lymphoid tissue but not for thymus cells. CRP inhibited the proliferative response in a similar manner in both murine and human mixed lymphocyte reactions. This inhibition was prevented by the addition of the CRP substrate, pneumococcal C-polysaccharide (CPS), and was not a result of toxicity of CRP for lymphocytes. By contrast the response of spleen lymphocytes to mitogenic Con A concentrations was not altered by CRP. CRP also exerted an inhibitory effect on the in vitro generation of cytolytic T lymphocytes (CL) in mixed lymphocyte reactions of mouse spleen cells. The expression of the cytolytic process by T cells sensitized either in vivo or in mixed lymphocyte cultures was not altered in the presence of CRP. Therefore, CRP appears to influence the inductive phase of the allograft response and perhaps exerts a regulatory effect on cellular immune responsiveness during inflammatory reactions.

Animals↗
PubMed1976

Effects of C-reactive protein on platelet function. I. Inhibition of platelet aggregation and release reactions.

C-reactive protein (CRP) is an acute phase reactant which shares numerous functional characteristics with the immunoglobulins. In the present study CRP was found to inhibit the aggregation of human platelets stimulated by either modified human immunoglobulin or thrombin. This effect did not involve chelation of calcium or cytotoxicity, and was overcome by larger amounts of the aggregating agents. CRP also inhibited the activation but not the activity of platelet factor 3 and the release of beta-glucuronidase. Thus, CRP can inhibit multiple platelet reactivities. We suggest that this property of CRP may play an important role in the control of platelet responsiveness during reactions of inflammation, defense, and repair.

Blood Platelets↗
PubMed1976

Interaction of C-reactive protein with lymphocytes and monocytes: complement-dependent adherence and phagocytosis.

The serum constituent C-reactive protein (CRP), which activates the classical complement (C) pathway when reacting with its substrates, was examined for its ability to mediate reactions of opsonic adherence and phagocytosis. Erythrocytes coated with C-polysaccharide (CPS) and reacted with CRP (E. CPS-CRP) failed to adhere to B cells and displayed only minimal adherence to monocytes. However, upon the addition of absorbed C or purified C components these cells were found to possess the cleavage products C4b and C3b, which in turn resulted in attachment of these cells to both human B lymphocytes and peripheral blood monocytes. E. CPS-CRP treated with C in the absence of antibody were readily phagocytosized by glass-adherent human monocytes. The phagocytosis of E. CPS-CRP-C was not only mediated by CRP but also required the presence of CRP on the surface of the red cells. The extent of ingestion was proportional to the amount of CRP on the red cell intermediate and was reduced by blocking monocyte receptors with aggregated human gamma-globulin (HGG) at concentrations which did not impair the uptake of other particles. The mediation by CRP of reactions of opsonic adherence and phagocytosis as outlined in these studies points to a significant role for CRP in reactions of host defense and inflammation.

C-Reactive Protein↗
PubMed1976

Potentiation of C56-initiated lysis by leucocyte cationic proteins, myelin basic proteins and lysine-rich histones.

Synthetic polycations such as poly-L-lysine (PLL) have recently been shown to enhance C56-initiated lysis by neutralization of serum-derived inhibitors of the C567 complex, collectively designated C567-INH. In the present report we have examined the effect of several naturally occurring polycations on C56-initiated lysis. Lysosomal granule extracts from rabbit peritoneal exudate cells were found to potentiate C56-initiated lysis via counteraction of C567-INH in the fluid phase; this was dependent upon the amount of C567-INH present and independent of cell concentration. The basic proteins of guinea-pig, bovine, and monkey myelin as well as lysine-rich histones also potentiated EC567 formation, but this effect seemed to occur predominantly at the cell surface. The presence of biologically derived cationic proteins at sites of complement activation during inflammation thus might lead to enhanced tissue damage by favouring the formation of cell-C567 intermediates by either or both of these mechanisms.

Animals↗
PubMed1976

Effects of C-reactive protein on platelet function. II. Inhibition by CRP of platelet reactivities stimulated by poly-L-lysine, ADP, epinephrine, and collagen.

It was recently demonstrated that C-reactive protein (CRP)4 inhibits the response of human platelets to heataggregated human gamma-globulin and thrombin and that this inhibition is characterized by a dose-dependent reduction in aggregation, activation of platelet factor 3 (PF3), and release of beta-glucuronidase. In the present experiments, CRP was found also to inhibit the ability of washed human platelets to aggregate in response to poly-L-lysine (PLL); in these experiments, the magnitude of the inhibitory effect was dependent upon the m.w. of PLL used as the stimulating agent, and was more effective with low (15,000 daltons) than with high (400,000 daltons) m.w. polymers. CRP similarly inhibited ADP- and epinephrine-stimulated platelet aggregation in platelet-rich plasma (PRP), and this was characterized by relatively minimal suppression of the primary wave of aggregation. CRP also inhibited the platelet aggregation induced by collagen in PRP, although it had no effect upon the adherence of platelets to collagen. Finally, CRP inhibited the activation of PF3 and the release of serotonin during stimulation of platelets with ADP, and this inhibition was temporally related to the onset of the secondary wave of aggregation. These experiments extend the platelet reactivities inhibited by CRP, show that CRP expresses its inhibitory capacity in platelet-rich plasma as well as upon isolated platelets, raise the possibility that CRP exercises its effects by inhibiting or interfering with the release and/or utilization of endogenous platelet ADP, and support the concept that CRP plays an important role in the control of platelet responsiveness to a variety of stimuli during acute inflammatory reactions.

Adenosine Triphosphate↗