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Biomedical subjects

H Gewurz

Publications and source records attributed to H Gewurz.

At least 73 records · Page 4Linked to original sources
PubMed1983

C3 nephritic factor and hypocomplementaemia in a clinically healthy individual.

Nephritic factor was detected in an individual whose serum showed a selective decrease in the third component of complement (C3) during and subsequent to an illness resembling disseminated gonococcal infection (DGI). As is characteristic of C3 nephritic factor (C3NeF), its activity was heat stable, was associated with IgG, and enhanced cleavage of normal human serum C3 via the alternative pathway. However, unlike previously reported cases of C3NeF detection in association with glomerulonephritis and/or lipodystrophy, this patient has had no significant disease before or more than 2 years after the apparent DGI. The significance of C3NeF in a healthy individual is unexplained, but this study suggests its occurrence may be more ubiquitous than previously suspected.

Adult↗
PubMed1983

The role of the spleen in the protective effect of C-reactive protein in Streptococcus pneumoniae infection.

C-reactive protein (CRP) is an acute phase serum protein in man which activates complement and has opsonic activity. We have reported that prior injection of CRP into mice can increase their survival following intravenous challenge with Streptococcus pneumoniae type 3 or 4. In this study the conditions required for protection, and the role of hepatic and splenic clearance of bacteria have been examined. Protection against lethal infection was observed with a minimum dose of 25-50 micrograms CRP per mouse. CRP was most effective when administered between 6 h before and 2 h after challenge. CRP treated mice were not protected against infection with Salmonella typhimurium, LT-2, an organism which does not bind CRP. Mice depleted of C3 by treatment with cobra venom factor were protected against S. pneumoniae infection by CRP. Pre-treatment of mice with CRP did not increase the rate of clearance of viable S. pneumoniae from the bloodstream but did increase splenic and decrease hepatic clearance of radiolabelled bacteria in both normal and complement depleted mice. Although these findings suggest a role for the spleen in CRP protection, mice which had been splenectomized were also protected against lethal pneumococcal infection by CRP treatment.

Animals↗
PubMed1983

Inflammation-induced changes in rabbit CRP and plasma lipoproteins.

Inflammation is accompanied by changes in the plasma concentrations of "acute phase reactants" including the C-reactive proteins of man and other species. Previous results in our laboratory showed that CRP in rabbit acute phase serum may circulate in association with very low density lipoproteins (VLDL), which influence both the apparent m.w. and electrophoretic mobility of CRP. We now show that the ability of VLDL to interact with CRP varies with time during the acute phase response. Before the induction of inflammation, the factor(s) responsible for the beta-mobility of CRP is present at low levels in the VLDL. During the first 24 hr of the acute phase response, the activity can no longer be demonstrated in the VLDL fraction. By 36 to 48 hr after inflammatory stimulation, a significantly increased level of this factor(s) is measurable in VLDL. Furthermore, during the acute phase response, the alpha-lipoproteins decrease, and the beta- and pre-beta lipoproteins increase. The increase in beta- and pre-beta-lipoproteins is due to an accumulation of VLDL isolated at d less than 1.006 g/ml. These changes are accompanied by marked hypertriglyceridemia and a significant increase in phosphocholine-containing phospholipids. A non-CRP apoprotein present in low amounts in VLDL from normal rabbit plasma appears to increase in VLDL as inflammation progresses. This VLDL apoprotein increases in response to multiple acute phase stimuli and may be a newly recognized acute phase reactant in the rabbit.

Acute Disease↗
PubMed1983

Decreased C5b67-inhibitor activity in two families with hereditary functional deficiency of the eighth component of complement.

In addition to its role in hemolysis and host defense against Neisseria infection, the eighth component of human complement (C8) is one of several plasma proteins that are C5b67-inhibitors (C5b67-INH). The recent identification in our laboratory of two new families with hereditary deficiency of C8 provided an opportunity to study further the role of C8 as a C5b67-INH. Based on mixing and reconstitution experiments, the deficiency of C8 seemed to be due to a selective lack of the C8 beta-chain in one family and the C8 alpha-gamma subunit in the other family. Sera from individuals homozygous for the C8 abnormality were substantially deficient in C5b67-INH activity as well as totally deficient in hemolytic activity. Sera from control individuals possessed approximately 2500 C5b67-INH U/ml, whereas sera from the C8-deficient individuals had markedly depressed C5b67-INH activity, with a mean of only 428 U/ml. C5b67-INH activity was completely reconstituted in C8-deficient serum by the addition of purified human C8. We conclude that C8 constitutes the substantial majority of the C5b67-INH activity of normal human serum.

Adolescent↗
PubMed1983

Selective inhibition of platelet activation by the amyloid P-component of serum.

One component of amyloid, protein AP, has a characteristic pentameric structure and is identical with a 9.5s serum alpha 1-globulin designated serum amyloid P-component or SAP. Another pentameric molecule, the acute-phase reactant C-reactive protein (CRP), shares major amino acid sequence homology with SAP although, in man, SAP is not an acute-phase reactant. Recently, we demonstrated that heat-aggregated CRP (H-CRP), like heat-aggregated IgG, activates platelets to reactions of aggregation, secretion, and generation of thromboxane A2. We report here that physiologic concentrations of SAP inhibit platelet aggregation stimulated by H-CRP. SAP must be present before platelet challenge with H-CRP to be effective. Native (unaggregated) CRP does not inhibit platelet activation induced by H-CRP, and the platelet inhibitory effect of SAP is restricted because platelet responses to each heat-aggregated IgG, acid-soluble collagen, DNA, ADP, and thrombin remain unaltered in the presence of SAP. Thus, human SAP seems to selectively modulate platelet reactivity to modified CRP, and as such to down-regulate at least one aspect of the biologic capacity of its acute-phase homologue.

Adenosine Diphosphate↗
PubMed1982

Antibody and complement in the stimulation of neutrophil chemiluminescence by Neisseria meningitidis: studies in a patient with complete deficiency of C7.

When an eight-year-old boy with a syndrome compatible with disseminated neisseria infection was found to lack C7, studies on the role of antibody and complement in the interaction of polymorphonuclear leukocytes (PMNLs) and Neisseria were initiated with use of a luminol-enhanced chemiluminescence assay. The chemiluminescent response to opsonized Neisseria meningitidis was markedly lower than the response to opsonized zymosan or Streptococcus pneumoniae but was similar to that obtained with Haemophilus influenzae type b. IgG antibody to N. meningitidis was shown to enhance the chemiluminescent response. The chemiluminescent response of PMNLs to N. meningitidis was normal when the bacteria were incubated with sera deficient in C5, C6, or C7 but was absent in serum lacking C2. Thus, both antibody and the early-acting proteins of the classical complement pathway appear to be essential for maximal stimulation of PMNL oxidative metabolism by N. meningitidis, although the late-acting components of complement are not.

Animals↗
PubMed1982

C-reactive protein reactivity with complement and effects on phagocytosis.

In the studies described here we have attempted to evaluate the hypothesis that CRP may function in host defense using two systems in which CRP in the presence of C appears to have opsonic properties. In the first, CRP and C were found to stimulate ingestion of erythrocytes by human monocyte or mouse macrophages in vitro, and to alter clearance patterns in vivo. In the second, we have studied opsonization of S. pneumoniae by CRP and C. Experiments with human neutrophils indicate that although CRP and C can enhance opsonization of S. pneumoniae, this effect is more pronounced in the absence of antibody. In vivo CRP was found to protect mice against intravenous infection with S. pneumoniae.

Animals↗
PubMed1982

Interactions of C-reactive protein with lymphoid cells.

The interactions between CRP and peripheral blood lymphocytes were investigated. CRP, in the presence of an appropriate ligand, bound saturably to a small percentage of normal PBL. The characteristics and optimal conditions for this binding were defined using several different assay systems. CRP was found to bind preferentially to cells with the IgG FcR. Binding was increased in the presence of acute phase sera, and higher numbers of cells binding CRP were observed in acute phase individuals. CRP and CRP-CPS had minimal effects upon lymphocyte responsiveness in vitro, although enhancing effects on MLC and CMC reactions, and a slight blastogenic effect, were observed. CRP antigenicity was detected on a small percentage of PBL, and treatment of PBL with anti-CRP and complement led to loss of NK reactivity, suggesting a possible association of CRP with this function. The functional expression of binding of CRP complexes, the relationship of the CRP-binding site to surface CRP antigenicity and the FcR, and the role of these factors in lymphocyte functions such as NK reactivity and recognition, are yet to be determined.

Animals↗
PubMed1982

Effect of C-reactive protein on the complement-mediated stimulated of human neutrophils by Streptococcus pneumoniae serotypes 3 and 6.

C-reactive protein (CRP) has long been known to appear in the sera of individuals with inflammatory processes, but its role in host defense against bacterial infection is unclear. We have recently demonstrated that CRP in the presence of the classical complement pathway markedly enhances the opsonization of Streptococcus pneumoniae serotype 27 by polymorphonuclear leukocytes (Edwards et al., J. Immunol. 128:2493-2496). In this report we have extended these studies to characterize the role of CRP in the opsonization of other S. pneumoniae serotypes. Two clinically important serotypes, 3 and 6, were tested along with the nonpathogenic rough strain R36a. All strains were found to bind radiolabeled CRP in the presence of calcium and to activate the classical complement pathway in normal human serum. However, the opsonophagocytic response of polymorphonuclear leukocytes to the strains, measured by chemiluminescence, was quite different. In contrast to the marked enhancement by CRP of the chemiluminescent response to serotype 27 in normal human serum, CRP had no effect on the opsonization of serotype 6 or R36a and inhibited opsonization of serotype 3 in normal serum. In serum from a hypogammaglobulinemic patient, CRP enhanced the lowered chemiluminescent response to serotype 3 and 6 organisms but did not restore the response to normal. The greater opsonic effect of CRP on serotype 27 may be related to the ability of CRP to bind to the capsule as well as to the cell wall of this serotype or to differences in the amount of CRP bound to the different strains.

C-Reactive Protein↗
PubMed1982

Binding of human C-reactive protein to bacteria.

The binding of C-reactive protein to a variety of species of bacteria with potential clinical significance was studied to assess the potential function of C-reactive protein in nonimmune defense against infection. Purified, radioiodinated human C-reactive protein bound to all Streptococcus pneumoniae tested and to some viridans streptococci, but not to group A or group B streptococci or to any of eight different gram-negative rods and cocci.

Bacteria↗
PubMed1982

Interaction of very low density lipoproteins (VLDL) with rabbit C-reactive protein.

Rabbit CRP is similar to human CRP in structure, kinetics of appearance, and binding reactivities to phosphate esters and cationic polymers. CRP in rabbit acute-phase serum migrates either with gamma or with beta, pre-beta electrophoretic mobility, and distinct gamma- and beta-migrating species can be observed simultaneously in some sera. The present study shows that beta-CRP in serum is converted to gamma mobility during isolation and purification. Normal, acute-phase, or CRP-depleted acute-phase rabbit serum restores the beta mobility of purified gamma-CRP, a conversion that does not occur in the presence of EDTA. Serum CRP fails to adsorb to DEAE-cellulose but does adsorb to CM-cellulose, from which it elutes as gamma-mobility antigen. Chelation by EDTA or flotation and removal of lipoproteins from acute phase rabbit serum produces a gamma-mobility CRP that adsorbs to the anion-exchange resin. Lipid-containing fractions from ion-exchange columns as well as VLDL (but not LDL or HDL) isolated by ultracentrifugation change the mobility of purified CRP from gamma to beta, pre-beta. These changes in mobility are not observed in the presence of EDTA or phosphocholine. In acute-phase rabbit serum with CRP of both beta and gamma mobility, the beta form has a higher m.w. and is lipid-associated, whereas the gamma form is a lower m.w., lipid-poor molecule. These results suggest that in serum the association of CRP with lipoproteins, particularly VLDL, is responsible for its beta, pre-beta electrophoretic mobility. Further studies of the association of CRP with lipoprotein in relation to lipoprotein metabolism may provide insight into the biological role of CRP.

Animals↗
PubMed1982

C-reactive protein and the acute phase response.

Since its discovery approximately fifty years ago, CRP has been recognized as the prototype acute phase reactant. Now appreciated as a trace serum protein that elevates markedly in concentration in association with inflammation and tissue necrosis, CRP also has been found deposited at sites of cell injury. Together with its long appreciated ability to initiate precipitation, agglutination, and capsular swelling reactions, these considerations early led to the surmise that CRP may play a role in the host adaptive response. Studies of its binding specificities have indicated that CRP has reactivity with (a) phosphocholine and phosphate esters, and hence with lipids widely distributed in mammalian and microbial cells; and (b) with multiple widely distributed polycations, including those derived from leukocyte granules. Interaction with either of these ligands has been shown to alter CRP in such a way that it can bring about activation of the complement system with generation of all the known C-dependent reactivities, including component consumption, adherence, phagocytosis, and cytolysis. Similarly, modified CRP has been shown to react with the FcR or a closely related receptor of monocytes and lead to phagocytosis, to react with certain FcR-bearing lymphocytes, and to activate the platelet. Thus, CRP shares with immunoglobulins the ability to initiate multiple effector functions that have been associated with the inflammatory response, as well as to bring about primary recognition reactions. Obviously CRP-ligand reactions would be favored during intervals of acute inflammation and tissue necrosis, when larger amounts of CRP are available. Therefore, in addition to serving as a diagnostic aid for the presence of inflammatory and necrotic processes, elevated levels of CRP may well provide an important component of the nonspecific host mechanisms, particularly in the early stages following inflammatory stimuli. Inquiries into the structure and function of CRP indicated an unexpected relationship of this molecule to an amyloid-related protein. The amyloid P component shows remarkable structural similarity to CRP and also exhibits calcium-dependent reactivity with widely distributed ligands; those appreciated to date have mainly involved polysaccharides derived from fungi and natural products. While the only relationship of SAP to an immune-related effector system found to date is reactivity with altered C3, it nonetheless seems plausible that SAP, which like CRP recognizes certain microbial and altered host molecules and has the potential of activating a host effector system at the recognition site. Further inquiry into the structure and functional relationships of these molecules, which are broadly distributed through the vertebrates, should help to reveal the role that CRP and other acute phase proteins have in the body economy and provide additional insights to the understanding of body defense mechanisms in inflammatory, repair, and defense processes generally.

Acute Disease↗
PubMed1982

Platelet inhibitory effects of CRP preparations are due to a co-isolating low molecular weight factor.

We previously reported that C-reactive protein (CRP), an acute phase reactant, inhibits platelet activation through an effect upon a factor(s) critical to ADP-mediated secondary wave platelet aggregation but independent of a direct effect upon platelet contractile elements. However, a role for an accessory factor in this inhibitory effect became of concern because of an inconsistency in the effects of CRP preparations upon the platelet: inhibition was lost upon storage and CRP preparations differed, on a weight basis, in inhibitory capacity and sensitivity to the presence of the CRP ligand C-polysaccharide (CPS(. The studies presented herein were thus intended to assess whether an accessory factor was involved in the inhibition of platelet activation observed with CRP. We report that the activity of the inhibitory CRP preparations resulted from association with a low molecular weight factor (LMF) with an apparent nominal molecular weight of 8300-12,500 and an A280:A260 ratio of approximately 0.4. Purified CRP did not inhibit platelet responsiveness but CRP with associated LMF (CRP-LMF) did. Moreover, the inhibitory capacity of CRP-LMF but not LMF was substantially reversed in the presence of CPS. These studies indicate that the platelet inhibitory properties of CRP preparations result from and are contingent upon the presence of a co-isolating low molecular weight factor.

C-Reactive Protein↗
PubMed1982

Activation of platelets by modified C-reactive protein.

The functional similarities between C-reactive protein (CRP) and immunoglobulin raised the possibility that modified CRP might resemble immunoglobulin in its activating effects upon the human platelet. Thermally-aggregated CRP (H-CRP), but not unmodified CRP, induced reactions of aggregation and secretion from isolated platelets; maximum responses occurred with less than 50 microgram/ml H-CRP and were similar to responses mediated by thermally-aggregated human IgG (AHGG). Platelet activation induced by H-CRP was sensitive to the presence of EDTA and dibucaine, required metabolic energy and was inhibited by increased levels of cAMP. Like AHGG, H-CRP acted synergistically with other platelet stimulators, although on a weight basis H-CRP appeared approximately ten- to twenty-fold more effective than AHGG. Complexes formed between CRP and certain of its polycationic ligands (PLL and protamine) shared platelet activating properties with H-CRP, whereas complexes of CRP and CPS did not. These data point to the ability of appropriately modified CRP to stimulate or enhance platelet responsiveness, and taken together with those reactivities described previously between modified CRP and certain lymphocytes, phagocytes, and the complement system, support the concept that CRP can initiate biological activities similar to those mediated by immunoglobulin.

C-Reactive Protein↗
PubMed1982

Opsonic properties of C-reactive protein in vivo.

The capacity of CRP to alter the clearance and site of sequestration of erythrocytes was examined. Mouse erythrocytes, coated with PnC to provide a binding site for CRP, were radiolabeled and injected into homologous mice. The liver, spleen, kidneys, and lungs were removed and counted to assess the site of erythrocyte clearance. In the presence of CRP, an increase in splenic sequestration of E-PnC was observed along with a slight decrease in hepatic sequestration. This altered clearance pattern was dependent on both C activation and on the continued presence of CRP. The clearance of cells coated with IgM or IgG antibody to PnC was compared. In both cases, antibody caused an increase in sequestration by the spleen. However, IgM-coated cells required C for splenic clearance, whereas IgG-coated cells did not. We have shown in these experiments that CRP can affect the in vivo pattern of organ sequestration of cells to which it is bound in a manner similar to antibody.

Animals↗