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Biomedical subjects

D R Schultz

Publications and source records attributed to D R Schultz.

At least 37 records · Page 2Linked to original sources
PubMed1990

Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen.

Four plasma proteins, referred to as positive acute phase proteins because of increases in concentration following inflammatory stimuli, are reviewed: C-reactive protein (CRP), serum amyloid A protein (SAA), alpha 1-acid glycoprotein (AAG), and fibrinogen. The CRP and SAA may increase in concentration as much as 1000-fold, the AAG and fibrinogen approximately twofold to fourfold. All are synthesized mainly in the liver, but each may be produced in a number of extrahepatic sites. The role of cytokines in induction of the acute phase proteins is discussed, particularly the multiple functional capabilities of interleukin-6 (IL-6). Other cytokines that regulate acute phase gene expression and protein synthesis include IL-1, tumor necrosis factor alpha, interferon gamma, as well as other stimulatory factors and cofactors. The physicochemical characteristics of each protein are reviewed together with the molecular biology. For each protein, the known biological effects are detailed. The following functions for CRP have been described: reaction with cell surface receptors resulting in opsonization, enhanced phagocytosis, and passive protection; activation of the classical complement pathway; scavenger for chromatin fragments; inhibition of growth and/or metastases of tumor cells; modulation of polymorphonuclear function; and a few additional diverse activities. The role of plasma SAA is described as a precursor of protein AA in secondary amyloidosis; other functions are speculative. AAG may play an immunoregulatory role as well as a role in binding a number of diverse drugs. In addition to clot formation, new data are described for binding of fibrinogen and fibrin to complement receptor type 3. Finally, the concentration of each protein is discussed in a wide variety of noninfectious and infectious disease states, particularly in connective tissue diseases. The quantification of the proteins during the course of various acute and chronic inflammatory disorders is useful in diagnosis, therapy, and in some cases, prognosis.

Acute-Phase Proteins↗
PubMed1989

Role of C1q in phagocytosis of Salmonella minnesota by pulmonary endothelial cells.

The Re mutant of Salmonella minnesota adheres in much greater numbers than the wild type to endothelial cells derived from the bovine pulmonary artery. Since the Re mutant is distinguished from wild-type S. minnesota by its ability to bind C1q and since endothelial cells possess receptors for C1q, we examined the role of C1q in the phagocytosis of the S. minnesota Re mutant. First, preincubating endothelial cells with C1q-enriched medium resulted in increased adherence of the Re mutant (17.9 x 10(4) versus 6.6 x 10(4]. Second, preincubating the Re mutant with C1q-enriched medium resulted in increased numbers of adherent bacteria (62.1 x 10(4) versus 6.6 x 10(4]. Preincubation of both endothelial cells and bacteria with C1q-enriched medium resulted in increased adherence above control levels but less adherence than when either cells or bacteria were preincubated separately in C1q-enriched medium. If serum depleted of C1q was used for preincubation of endothelial cells or bacteria, adherence was reduced below control levels. Thus, C1q plays an important role in the initial steps (recognition, binding, and ingestion) of phagocytosis. Next, the role of C1q was investigated in the respiratory burst response. Levels of superoxide anion released from endothelial cells 15 min after phagocytosis of the Re mutant (100 bacteria per endothelial cell) were assayed by measurement of the superoxide dismutase-inhibitable reduction of ferricytochrome c. Superoxide anion release was increased during phagocytosis of the Re mutant (35 nmol of O2- per 3 x 10(6) endothelial cells) and was also elevated above control values by incubation with soluble C1q (10 nmol of O2- per 3 x 10(6) endothelial cells). These results indicate a role for C1q in both the ingestion and the response of endothelial cells to the S. minnesota Re mutant.

Animals↗
PubMed1989

Measurement of complement proteins C2 and B in systemic lupus erythematosus and septic shock.

We developed sensitive radioassays to quantitate the homologous complement proteins C2 and B, in intact form, in sera from patients with diseases associated with hypocomplementemia. In a study of systemic lupus erythematosus (SLE) patients, we found a subset of patients (6/40) with low C2 concentrations, though overall, C2 concentration was not related to disease activity. Protein B concentration was increased in 23/40 SLE patients, apparently not due to a generalized acute phase response. Among patients with both gram-negative and gram-positive septic shock, C2 and B concentrations were low in a subset of patients with pre-existing cirrhosis, suggesting hepatic hyposynthesis of these proteins may be important in their prognosis and predisposition to severe infections.

Biomarkers↗
PubMed1989

Erythrocyte membrane protein deficiencies in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intermittent hemolytic anemia. Membrane abnormalities of blood cells from patients with PNH are the reason for the unusual sensitivity to lysis by autologous plasma complement. A patient with typical clinical disease consistent with PNH is described together with a few strategies and pitfalls for treatment. Commonly used in vitro assays are discussed that document the complement-mediated lysis of aberrant PNH erythrocytes. Membrane-associated proteins that are abnormal in PNH cells, the characteristics of these proteins, and their mechanism(s) of action are described; these include the decay accelerating factor that inhibits the C3/C5 convertases of both complement pathways on cell surfaces, the C8 binding protein that modulates a step in terminal complement lysis, and other proteins that regulate complement-mediated lysis at early or late steps of the complement cascade.

Adult↗
PubMed1988

The second component of human complement: detection of two hemolytic forms in plasma by pH variation.

The second component of human complement (C2) in pseudoglobulin prepared from normal plasma eluted as a single peak at high conductivity (30 mS) and pH 4.5 from the cationic exchangers S-Sepharose or Mono S in the Fast Protein Liquid Chromatography (FPLC) System. The C2 was stable at pH 4.5 and 0 degrees C if enzyme inhibitors were used and the pH was raised to 6.0 after elution from the columns. After rechromatography on Mono S in the FPLC System at the median isoelectric point of 5.5 or pH 6.0, the C2 eluted as two distinct hemolytic forms: the first peaked at 16 mS, the second at 30 mS. The two forms of C2 did not correlate with the allotypic variant of C2 in individual, normal human plasmas. After elution at pH 4.5 from S-Sepharose and rechromatography at pH 5.5 or 6.0 on Mono S, the hemolytic activities of the two forms in individual plasmas eluted in 3 patterns: 1) high activity at 16 mS, low activity at 30 mS; 2) low activity at 16 mS, high activity at 30 mS; 3) high activity at 16 mS, high activity at 30 mS. The specific activities of both forms were approximately the same; both eluted the same after gel filtration at pH 5.5, and both had the same pattern on SDS-PAGE and immunoblots. The pattern of elution was characteristic for each individual plasma, and the first hemolytic form appeared to elute independent of the second form. At pH 4.5, C2 was completely separated from Factor B, a functionally and structurally similar protein of the alternative complement pathway, whereas at pH 5.5 or 6.0, the two proteins eluted together. From these results, the two forms of hemolytic C2 can be purified for structural and functional analyses.

Chromatography, Ion Exchange↗
PubMed1988

The second component of human complement: use of glycosidases and glucosylation to distinguish the two forms.

The two forms of human plasma C2 that were described in the preceding report (1) were investigated for their functional and biochemical differences. Incubation with the neuraminidase (NAN'dase) of Clostridium perfringens at 37 degrees C resulted in a four- to fivefold increase in the hemolytic activity of both forms. The increase in activity was different than the increase caused by treatment with iodine. The mechanism of increased activity of NAN'dase-treated C2 was the generation of increased molecules of activated C3 (C3b), resulting in more molecules of C5 binding to (C4b, 2a, 3b)n. Removal of N-acetyl-neuraminate from C2 did not alter its binding to a cationic exchanger. Nonenzymatic glucosylation was used to distinguish the two forms of C2. Incubation of highly pure C2 with 14C-D-glucose resulted in the gradual accumulation of radioactivity in acid-precipitable material. The two forms of C2 were glucosylated in vitro for seven days with 14C-D-glucose in phosphate-buffered saline at 25 degrees C. Form 2 bound twice as much 14C-D-glucose as form 1. Glucosylated form 2, but not form 1, lost some of its affinity to bind to a cationic exchanger. Since the interaction between glucose and protein occurs at free amino groups, we conclude that form 2 of C2 has approximately twice as many free amino groups as form 1. This explains the reason for the existence of two forms of C2 in plasma independent of the allelic variant.

Complement C2↗
PubMed1986

Receptor-mediated binding of C1q on pulmonary endothelial cells.

Normal undamaged pulmonary endothelial cells appear to be immunologically privileged in that they do not express receptors for the Fc portion of IgG nor for C3b. However, these receptors become unmasked on endothelial cells injured by viral infection or exposure to white cell lysates. We now present evidence to indicate that C1q binds to specific receptors on the surface of normal healthy endothelial cells. The binding is dose-dependent, reversible and saturable. Furthermore our data show that binding of C1q to endothelial cells is via the collagenous portion of the molecule not via the globular head regions. Thus binding of C1q to endothelium would have the effect of exposing Fc receptors that could then bind to IgG of circulating immune complexes. That Fc receptors are in fact exposed is shown by rosette formation with antibody sensitized erythrocytes. With 2C1r-2C1s-associated C1q, no binding occurred using C1 fixation and transfer assays. Our results indicate that C1q binding to endothelium provides a means for localizing immune complexes on pulmonary vessels and may be important in the initiation and progression of the inflammatory response.

Animals↗
PubMed1986

Complement activation in septic shock patients.

To evaluate the status of the complement system and to determine the effects of corticosteroids on complement component levels in septic shock, C3, C4, and Factor B were measured in 42 patients with severe late septic shock. Serum levels of C4 and Factor B correlated with C3 levels (r = 0.48 and 0.64, respectively; p less than .01) in patients in shock for more than 4 h, but only Factor B correlated with C3 (r = 0.85; p less than .01) in patients in shock for 4 h or less. C3 and Factor B levels were significantly (p less than .05) lower in patients who died (12,174 +/- 1,524 CH50 U/ml and 14 +/- 1 mg/dl, respectively) than in patients who survived (18,418 +/- 2,833 CH50 U/ml and 21 +/- 2 mg/dl, respectively). Corticosteroids did not alter complement component levels. The alternative pathway appears to be activated early in septic shock, whereas the classical pathway is activated later. C3 and Factor B levels may predict survival of patients in septic shock. In this study, corticosteroids did not change the complement component levels of patients in late severe septic shock.

Complement Activation↗
PubMed1986

Elevated levels of immunoglobulins and immune complexes in the bile of patients with primary sclerosing cholangitis.

The concentration of immunoglobulins and immune complexes was determined in the serum and bile of four patients with primary sclerosing cholangitis, only one of whom had chronic ulcerative colitis, and in four postcholecystectomy control patients. The result of the immunoglobulin studies demonstrated increased serum levels of IgM in primary sclerosing cholangitis as compared to control patients. The IgG, IgA, and IgM in bile were all significantly elevated as compared to controls (p = 0.02). Immune complexes in bile and serum were also determined in both groups by the C1q and conglutinin binding assays. Immune complexes in bile were elevated in three of four of the patients with primary sclerosing cholangitis. These findings further characterize primary sclerosing cholangitis in terms of biliary immunoglobulins and immune complexes but do not resolve whether these changes are an epiphenomenon or reflect a primary role of immunoglobulins and immune complexes in the pathogenesis of this disorder.

Adult↗
PubMed1984

The effects of a partially purified fraction of an ant venom in rheumatoid arthritis.

A partially purified extract of an ant venom from the South American tree ant Pseudomyrmex sp. was tested in a double-blind, controlled study of patients with rheumatoid arthritis. Venom treated patients demonstrated an improvement in global efficacy and a decrease in the number of tender/painful joints and swollen joints. Swollen joint index improved in 60% of venom treated patients. Other parameters did not demonstrate significant change. Reduction of joint swelling was followed by symptomatic improvement that was sometimes delayed by weeks. Reactions were limited to erythema at the injection site (all patients), local pruritus (two-thirds of the patients), and fever with malaise (one-third of the patients). Further study of this venom in rheumatoid arthritis appears warranted in view of its apparent favorable efficacy-to-toxicity ratio.

Adult↗
PubMed1984

Specific antibodies directed against toxins of Ptychodiscus brevis (Florida's red tide dinoflagellate).

Specific antibodies directed against Ptychodiscus brevis 'brevetoxins' have been produced in a goat. The haptenic toxin T34 was chemically reduced to toxin T17, covalently-linked to succinic acid via anhydride coupling, and coupled to bovine serum albumin using standard carbodiimide condensation procedures. The hapten coupling efficiency ranged from 10.4 to 13.5 moles of toxin bound per mole of protein. Antibody titers were directly related to the frequency of immunization, and weekly intervals appeared optimum for maintaining adequate titers. [3H]Brevetoxin T17 is displaced in a competitive manner from the antibody-antigen complexes by unlabeled toxin, but the antibodies do not distinguish between T17 and T34. The sensitivity achieved, using purified brevetoxins as competitive inhibitors of [3H]T17 binding, was 600 picograms. The assay linearity ranged from 1.5 to 48 ng.

Animals↗
PubMed1984

Separation of functionally or highly pure C2 from human plasma with Sepharose and a lectin of Euonymus europeus.

A method is described for isolating both functionally and highly pure C2 from normal human serum or plasma. Functionally pure C2 was obtained by a two-step method of ammonium sulfate (AS) fractionation of plasma or serum and chromatography on AH-Sepharose containing a bound lectin of Euonymus europeus. The functionally pure C2 can be isolated in 2 days, and is used routinely as a reagent for functional hemolytic titrations of C3 and C4 in the Clinical Immunology Laboratory. Highly pure C2 was isolated by the two-step fractionation with AS followed by chromatography on CM-cellulose, aged CNBr-activated Sepharose 4B, and AH-Sepharose-lectin. The major difficulty for isolating highly pure C2 was its separation from Factor B of the alternative complement pathway. The yield of C2 varied from 30 to 40 per cent. Following electrophoresis and staining on polyacrylamide gels, the single band was hemolytically active C2.

Chromatography, Agarose↗
PubMed1982

Effect of sequential glycolysis of the lectin of Euonymus europaeus on activation of the classical complement pathway in normal human serum.

The lectin of Euonymus europaeus at concentrations of 5-21 micrograms/ml causes activation of the classical complement (C) pathway (C1, C4, C2) when added to normal human serum at 37 degrees C. At higher concentrations, C3 is also consumed. The effect is dependent on a 'natural antibody' in serum of the IgM class which reacts with an epitope of the lectin. With physicochemical methods, the carbohydrate of the lectin was shown to be involved in the activation of C, but not involved in the agglutination of group B erythrocytes. Removal of N-acetyl-D-glucosamine from the lectin with an exoglycosidase greatly reduced the activation of C in serum, but it did not affect erythroagglutination. Using competitive binding studies with various sugars, it was confirmed that N-acetyl-D-glucosamine is the dominant specificity of a determinant for activation of the classical C pathway in serum.

Binding, Competitive↗
PubMed1981

Fc and C3b receptors on pulmonary endothelial cells: induction by injury.

Receptors for the activated third component of complement and for the Fc portion of immunoglobulin G are not expressed by apparently normal bovine pulmonary endothelial cells, but are expressed when the cells are exposed to white cell lysates or are infected with influenza or cytomegalovirus. The unmasking of these latent receptors may contribute to the pulmonary inflammatory response characteristic of, for example, anaphylaxis and to those lung diseases characterized by the deposition of immune complexes.

Animals↗
PubMed1981

Glomerular disease in two patients with urticaria-cutaneous vasculitis and hypocomplementemia.

We assessed the clinical, serologic, and renal abnormalities of two patients with the syndrome of hypocomplementemia, vasculitis, and urticaria. Both patients presented with recurrent urticaria and were found subsequently to have glomerulonephritis. Both manifested depletion of the early complement (C) components, and their Cl inhibitor levels were normal. Circulating immune complexes were detected by two of three assays in both patients. One patient had a high titer of Sm antibodies. The detectable immune complexes were of high molecular weight, and were more suggestive of classical lupus erythematosus than the low molecular weight (7S) Clq precipitins which characterize some cases of hypocomplementemia-vasculitis-urticaria syndrome. Biopsy of the skin lesions in both patients revealed leukocytoclastic vasculitis with immunoglobulin and C deposits at the dermal-epidermal junction. Renal biopsy specimens showed segmental or diffuse proliferative mesangial glomerulonephritis. The results suggest that patients with this syndrome do not conform to a discrete entity but rather exhibit a spectrum of diseases ranging from systemic lupus erythematosus to the syndrome of urticaria, hypocomplementemia, and low molecular weight Clq precipitins.

Adult↗
PubMed1981

Activation of first component of complement (C1) in guinea pig serum by a polysaccharide is prevented by C1 inhibitor.

A polysaccharide (PS) purified from venom of the ant Pseudomyrmex sp. causes the activation of the classical complement (C) pathway in normal serum, but not in guinea pig serum. To investigate why C was not activated in guinea pig serum, we partially purified guinea pig C1 in the presence of the protease inhibitor p-nitrophenyl, p'-guanidinobenzoate (NPGB). This C1 preparation was activated (mu = 0.15, pH 7.5) by the PS in a dose-dependent reaction after NPGB was eliminated by dilution. The PS decreased the action of the C1 inhibitor for C1 in diluted guinea pig serum, and it also inhibited the activity of highly purified guinea pig C1 inhibitor for C1. There was a direct correlation between the concentration of the guinea pig C1 inhibitor and the loss of ability of the PS to activate C1 in mixtures of constant concentrations of purified guinea pig C1 and purified venom PS, and increasing concentrations of purified guinea pig C1 inhibitor. The activity of the human C1 inhibitor, either in diluted serum or highly purified, was not decreased by the PS. These results show that the PS does not activate guinea pig C1 in serum because its action is blocked by the C1 inhibitor.

Animals↗