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PubMed1983

Role of the capsule and the O antigen in resistance of O18:K1 Escherichia coli to complement-mediated killing.

Epidemiological data show that O18:K1 Escherichia coli is a common cause of neonatal bacteremia and meningitis. These bacteria were capable of multiplying in the bloodstream of newborn rats and were resistant to the bactericidal effects of complement in the absence of specific antibodies. The roles played by the O antigen and the K antigen in complement resistance were analyzed by comparing the bactericidal effects of normal sera and of sera deficient in various complement components or in immunoglobulins. These sera were tested on O18:K1 bacteria and on mutants lacking either the lipopolysaccharide O antigen or the K1 capsular polysaccharide. In addition, O1:K1 cells, which can cause pyelonephritis but which are rare in newborn meningitis and which do not multiply in the bloodstream of newborn rats, were also examined. Different mechanisms of protection against the alternative and classical pathways were recognized: K1-positive cells were resistant to the bactericidal activity of sera deficient in classical complement pathway components, whereas K1-negative cells were sensitive to these sera. Based on these results and on those from complement fixation assays, the K1 sialic acid polysaccharide impedes the activation of, and thus protects the bacteria against, the alternative complement pathway. Not only the K1-negative mutant cells but also O1:K1 bacteria and mutants lacking the O18 oligosaccharide repeating units of the lipopolysaccharide were sensitive to the classical complement pathway. These bactericidal effects were observed even in the absence of specific antibodies. It is proposed that both the K1 capsule and the O18 oligosaccharide restrict antibody-independent classical pathway activation by shielding deeper structures on the cell membrane that are capable of activating this pathway.

Animals↗
PubMed1984

Inhibition of immune precipitation by complement.

Normal human complement serum (NHS) inhibited precipitin reactions between tetanus toxoid and human or rabbit anti-tetanus toxoid IgG antibody, between bovine serum albumin (BSA) and rabbit anti-BSA IgG antibody, and between hen egg albumin and rabbit anti-egg albumin IgG antibody. Ethylene-diaminetetraacetic acid (EDTA) prevented this inhibition. Mg-ethyleneglycol-bis(aminoethyl)-tetra-acetic acid-(EGTA) also prevented the inhibition except with lower concentrations of antibody and antigen. Therefore, the inhibition of immune precipitation seemed to occur mainly through the classical pathway of complement activation. The alternative pathway was usually dispensable, but it augmented the inhibition. Guinea pig complement serum (NGS) was less effective than NHS in inhibiting immune precipitation. Guinea pig serum deficient in C4 (C4DGS) did not inhibit the immune precipitation. Mouse complement serum was effective for inhibiting precipitation, and C5-deficient serum was as effective as normal serum. Therefore, the inhibition of immune precipitation is considered to occur by activation of complement up to the step of C3. The size of the soluble immune complexes formed in the presence of NHS varied depending on the concentrations of antibody and antigen, even when the ratio of antigen to antibody was constant. On incubation at 37 degrees C immune precipitation was inhibited by 1/2 dilution of NHS for 2 to 3 hr and then gradually increased to the level in the absence of complement. When the immune complexes were formed in the presence of serum containing complement, fragments of C4 and C3 were incorporated into the soluble immune complexes. The C3 fragments incorporated into the soluble complexes were C3b, iC3b, C3c, and C3d, some of which were bound covalently with heavy chains of IgG antibody molecules. Some of the covalent linkages between C3 fragments and IgG seemed to be destroyed by alkali treatment, but not by hydroxylamine treatment. The formation of covalent bonds between IgG and C3 and probably C4 was essential for inhibition of immune precipitation, because inhibitors of their formation, such as putrescine, cadaverine, and salicylhydroxamic acid, effectively prevented the inhibition of precipitation. When antigen and antibody reacted in the presence of mixtures of various combinations of isolated complement components, C1, C4, C2, and C3 showed maximal inhibition of immune precipitation, whereas factors I and H had little effect.

Animals↗
PubMed1987

Effect of differences in antibody and complement requirements on phagocytic uptake and intracellular killing of "c" protein-positive and -negative strains of type II group B streptococci.

The influence of antibody and complement on the polymorphonuclear leukocytic uptake and killing of type II group B streptococci (GBS) was examined with 11 adult sera and three type II strains possessing the trypsin-resistant and trypsin-sensitive components (II/TR+TS) of the "c" (formerly Ibc) protein or two type II strains lacking both components (II/no c) of the c protein. All tested sera mediated a greater than 1 log10 reduction in colony-forming units (CFUR) of a type II/no c strain, even in the absence of measurable type-specific antibody (less than 1.08 micrograms/ml), but only 5 of 11 mediated a greater than 1 log10 CFUR of any type II/TR/TS strain, even in the presence of moderate levels of type-specific antibody. The classical pathway of complement activation appeared to be more important than the alternative pathway, and even absorbed or immunoglobulin G (IgG)-depleted serum (IgG, 10 mg/dl) mediated a greater than 1 log10 CFUR without magnesium ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (magnesium EGTA) chelation. Chelation with magnesium EGTA reduced the CFUR in 4 of 11 test sera and greatly reduced the CFUR in absorbed or IgG-depleted sera for type II/no c strains. Despite variation in the phagocytic killing of two representative strains of type II GBS, both strains were well phagocytized, as measured by radiolabeled bacterial uptake or electron microscopy. This study suggested that poorly killed type II/TR+TS GBS were easily phagocytized but apparently resisted intracellular killing.

Antibodies, Bacterial↗
PubMed1986

Immunoregulatory disorders associated with hereditary angioedema. II. Serologic and cellular abnormalities.

Hereditary angioedema is defined biochemically by a deficiency in the functional activity of the inhibitor of Cl, Cl esterase inhibitor (Cl INH). Deficiency of this regulator of the early classic pathway of complement results in chronic activation of this cascade with a resultant deficiency of C4 and C2. Ninety-seven patients with either complicated (associated with autoimmune disorders) or uncomplicated hereditary angioedema were evaluated for laboratory evidence of immunoregulatory defects. Specific cellular and humoral abnormalities were found and included increased mean total lymphocyte counts, increased mean Leu 4+ (total) and Leu 3+ (helper) T cells, an increased mean Leu 3/Leu 2 (helper/suppressor T cell) ratio, polyclonal B cell activation, and evidence of circulating immune complexes. C4 functional titers were negatively correlated with percent Leu 3+ cells and absolute Leu 3+ cell numbers. We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group. Thus, early classic complement pathway activation and/or partial complement component deficiency may effect T cell subpopulations and B cell activation. However, additional predisposing factors (e.g., genetic or viral) appear necessary for the development of a particular autoimmune disease in hypocomplementemic patients.

Adolescent↗
PubMed1986

Hemolytic activity of leukemic sera: the role of complement and sucrose.

In sera of patients with acute myeloblastic leukemia (AML), hemolytic activity can be demonstrated in vitro in the presence of sucrose. To investigate the nature and the mode of action of this hemolytic activity, serum samples from 24 patients with AML were studied by incubation of normal human erythrocytes together with patient serum in the presence of sucrose at low ionic strength (inverse sucrose hemolysis test, ISHT). Fifty-five percent of the serum samples collected during the active stage of the disease gave a hemolysis rate of greater than 4%, whereas in remission only 15% of the samples lysed erythrocytes. Substitution of raffinose, lactose, or polyethylene glycol 400 for sucrose resulted in an almost complete failure of hemolysis under standard conditions, indicating a minor role of the low ionic strength in the ISHT. Heat inactivation, preincubation with inulin, and addition of EDTA, Mg2+-EGTA, or heparin completely abolished hemolytic activities of AML sera when the incubation was carried out for 30 minutes (standard conditions of the ISHT). A prolongation of the incubation time resulted in delayed hemolysis only with the Mg2+-EGTA-treated AML sera. The kinetics of this hemolysis by Mg2+-EGTA-treated AML sera were similar to those of normal human serum in the presence or absence of Mg2+-EGTA. Hemolysis was also obtained by performing the ISHT with normal sera and erythrocytes preincubated with AML sera. These observations suggest a mediation of membrane modification of normal human erythrocytes by AML sera in the presence of sucrose, resulting in an activation of the classical pathway of complement.

Adult↗
PubMed1984

Complement in chronic secretory otitis media. C3 breakdown and C3 splitting activity.

Occurrence of in vivo C3 breakdown and in vitro C3 splitting activity was studied in serum and middle-ear effusion (MEE) samples from 30 children with chronic secretory otitis media (SOM). The MEE showed strongly elevated levels of both low- and high-molecular-weight C3 breakdown products, along with decreased factor B, C4, and C3 levels. Total hemolytic complement component activity was virtually absent from MEE. The MEE fluids were found to contain C3 splitting factors as demonstrated by their high capacity to convert C3 in vitro from fresh normal human serum. This activity was not inhibited by the classic complement pathway inhibitor, 0.01M ethylene glycol tetra-acetic acid with 0.005M magnesium chloride. The results suggest that a strong local complement activation has taken place and that the factors responsible are present in the MEE of patients with SOM.

Antigen-Antibody Complex↗
PubMed1985

Defective complement activity in chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) are at an increased risk for infections with bacteria which require complement for osponization. We explored the possibility that patients with CLL have a defect in binding the potent opsonin C3b to bacteria. Bacteria selected for these experiments included Streptococcus pneumoniae type 3, which binds C3 by activating the classical complement pathway (CCP), type 25, which can bind normal amounts of C3b by the alternative complement pathway (ACP), type 14, which can activate both the CCP and ACP, and Staphylococcus aureus and Escherichia coli, both of which activate the CCP. Bacteria were treated with normal serum or serum from 15 patients with CLL, and the bound C3b was quantified spectrophotofluorometrically. Despite normal serum concentrations of C3, C4, Factor B, C-reactive protein, and total hemolytic complement activity, all 15 CLL sera bound reduced amounts of C3b to at least one bacterial species; 9 to S pneumoniae type 3, 8 to types 14 and 25, 11 to S aureus, and 13 to E coli. Mixing normal serum with CLL serum restored C3b binding to all bacteria, suggesting a deficiency rather than an inhibitor of activity. Serum from ten hypogammaglobulinemic CLL patients bound less C3b (62.7 +/- 5% of normal) (means +/- SEM) than those with normal immunoglobulin levels (81.9 +/- 5%) (p less than .005). Nevertheless, the addition of specific antibacterial antibodies to CLL serum did not enhance C3b binding to any of the bacteria. Serum from patients with a history of a bacterial infection bound less C3b (62.3 +/- 5%) than those without a history of infections (76.1 +/- 6%) (p less than .05). Thus, there is a defect in either the activation or activity of C3 in CLL serum which may contribute to the increased incidence of infections in these patients.

Blood Bactericidal Activity↗
PubMed1982

A reinterpretation of the evidence for an interaction between Clq and pairs of immunoglobulin molecules in an immune lattice.

An error in a previous article [Cohen S. (1968) J. Immun. 100, 407-413] was discovered which invalidates it as evidence that IgG immune complexes activate the classical complement pathway by an interaction involving pairs of antibody molecules, so-called doublet formation. The error concerns the correction to be made for the observed 8% residual activity of the modified antibody preparation used. When appropriate correction factors are applied, the data are found not to be consistent with the hypothesis of doublet formation. The analysis presented here has no bearing on the original article's experimental techniques, nor on its demonstration of co-operation between IgG molecules during complement fixation.

Antigen-Antibody Complex↗
PubMed1983

Conditions which favor the C1-fixation by mouse IgG1.

The capacity of mouse IgG1 to mediate activation of the classical complement pathway was reinvestigated with purified C1 and under various conditions. Monoclonal and polyclonal IgG1 antibodies to TNP, which failed to show a haemolytic activity on TNP-SRBC with low epitopic density at physiologic salt concentration, invariably restored their activity when reacted to TNP-SRBC with relatively higher epitopic density and at a reduced salt concentration. Unliganded, monomeric IgG1 too proved to possess an inherent C1-binding capacity, but the susceptibility to competing salt was extremely high. These results were seemingly in accordance with the reduced number of basic amino acids in the plausible C1-binding region of the molecule.

Animals↗
PubMedDate not supplied

Immunomodulatory activity of an aqueous extract of Azadirachta indica stem bark.

The interference of an aqueous extract of the stem bark of Azadirachta indica with different parts of the human immune system was investigated. The extract showed strong anticomplementary effects which were dose-and time-dependent and most pronounced in the classical complement pathway assay. Moreover, a dose-dependent decrease in the chemiluminescence of polymorphonuclear leukocytes was observed and a dose-dependent increase in the production of migration inhibition factor by lymphocytes.

Adjuvants, Immunologic↗
PubMed1985

Requirement for calcium ions in antibody-dependent complement-mediated cytolysis of Toxoplasma gondii.

The mechanism of antibody-dependent complement-mediated cytolysis of Toxoplasma organisms was studied by using a selective chelating agent for Ca++, ethyleneglycol-bis (beta-aminoethyl ether)-N,N-tetraacetic acid (EGTA). Toxoplasma organisms were lysed by treatment with human serum containing anti-Toxoplasma antibodies and with fresh human-plasma at 37 degrees C for 1 h. The reaction was prevented by heat treatment of the fresh plasma at 56 degrees C for 30 min, confirming that the cytolysis of Toxoplasma organisms had been mediated by an activation of complement. The lytic reaction was completely inhibited by an addition of EGTA at final concentrations of more than 2.5 mM. Addition of Ca++ cleared the inhibitory effect of EGTA on the reaction. These results demonstrate that the antibody-dependent complement-mediated cytolysis of Toxoplasma organisms requires the presence of Ca++, indicating that the reaction is mediated by an activation of the classical complement pathway.

Animals↗
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↗
PubMed1986

Susceptibility of phenotypic variants of Haemophilus influenzae type b to serum bactericidal activity: relation to surface lipopolysaccharide.

After three serial passages of Haemophilus influenzae type b strain Fuju in rats, we recovered a variant, which differed in colonial morphology, serum sensitivity, and lipopolysaccharide configuration from the parent strain. The parent organism (Fuju) appeared iridescent and transparent on Levinthal agar, and the rat-passaged variant (rat3 Fuju) appeared iridescent and opaque. The transparent, parent strain Fuju was sensitive to the complement-mediated bactericidal activity of normal rat serum, and the opaque, rat-passaged strain rat3 Fuju was serum resistant. Serum killing of the serum-sensitive strain appeared to be mediated by the classic complement pathway. Both serum-resistant and serum-sensitive strains were killed equally well by immune rat and human serum. These two strains did not differ in the amount of capsular polysaccharide that they elaborated nor in their major outer membrane protein patterns on SDS-PAGE. Lipopolysaccharide isolated from these two strains demonstrated different electrophoretic mobility patterns. Furthermore, the organisms showed different reactivities with two monoclonal antibodies directed against determinants of Hib lipopolysaccharide. Thus, the difference in susceptibility to complement-mediated bactericidal activity of normal rat serum displayed by these two strains is associated with their phenotypes, appears to be unrelated to differences in major outer membrane proteins or in the amounts of capsular polysaccharide elaborated, and is associated with differences in surface lipopolysaccharides.

Animals↗
PubMed1987

Bactericidal activity for Neisseria meningitidis in properdin-deficient sera.

We investigated serum bactericidal reactions against Neisseria meningitidis (serogroups A, B, C, D, Y, W-135, 29E, X, and Z) in the sera of two healthy adults with properdin deficiency. Bactericidal reactions mediated via the classic complement pathway (unchelated system) were not impaired in properdin-deficient serum. The properdin-deficient sera supported alternative pathway-mediated killing (Mg++EGTA-chelated system) of some, but not all, of the strains investigated. Vaccination of the properdin-deficient individuals with serogroup A and C polysaccharide clearly increased the concentrations of antibody to meningococci. At least some of the antibodies induced by vaccination supported the bactericidal activity of properdin-deficient serum. Some antibodies to meningococci, probably of the IgM class, promoted alternative pathway-mediated bactericidal reactions in the absence of properdin. By contrast, presensitizing meningococci with IgG enhanced the alternative pathway-mediated reactions, but this was strictly a properdin-dependent effect.

Antibodies, Bacterial↗
PubMed1986

Determination of anaphylatoxin concentrations in suction blisters in patients with psoriasis.

Concentrations of C3a and C4a anaphylatoxins in suction blister fluids were determined by radioimmunoassay in patients with psoriasis and normal controls. Comparison of anaphylatoxin levels between serum samples and blister contents in the same subjects revealed that the levels of both C3a and C4a anaphylatoxins were significantly higher in the former than the latter even in those raised on normal skin, suggesting that the classic complement pathway is activated during suction procedure. Therefore we cannot regard suction blister fluid to be simply representative of undisturbed interstitial tissue fluid as far as the complement system is concerned. There was no difference in anaphylatoxin levels between those from uninvolved skin of psoriatic patients and those from normal controls. However, significantly high anaphylatoxin levels were noted in fluids of suction blisters raised on lesional skin as compared with those produced on uninvolved skin in psoriatic patients.

Adolescent↗
PubMed1986

Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura.

Many chronic ITP patients have increased amounts of platelet-associated IgG, C3, C4 and C9, suggesting in vivo complement activation. In this study, we assessed the ability of various antiplatelet antibodies (APA) to activate and deposit complement proteins and to cause platelet lysis in vitro. Platelet sensitization with rabbit APA, anti-P1A1 antibody (one patient), anti-HLA antibody (two patients) and ITP autoantibodies (four patients) resulted in the deposition of C4 and C3 onto platelets in an amount proportional to the quantity of antibody-containing sera used to sensitize the platelets. Although C9 deposition onto platelets could not be quantitatively demonstrated on platelets sensitized with ITP serum, platelet lysis (51Cr release) was noted after incubation with each of three ITP sera and complement. When compared, ITP autoantibodies, anti-HLA and anti-P1A1 antibodies activated complement to a similar degree. We conclude that some autoantibodies in chronic ITP activate the classical complement pathway. The demonstration of in vitro platelet lysis by autoantibodies and complement suggests that in vivo platelet lysis may occur in some chronic ITP patients.

Autoantibodies↗
PubMed1982

An analysis of the lymphocytotoxic activity found in sera from patients with hypogammaglobulinaemia.

Sera from 59 patients with hypogammaglobulinaemia (hypogamma) were assessed for lymphocytotoxic activity. The activity was compared with that found in sera from patients with systemic lupus erythematosus (SLE) in titre, class of antibody, target cell, and complement requirements. Sera from patients with hypogamma showed cytotoxic activity when compared with sera from normal donors; however, the activity was far less than that in sera from SLE patients, The cytotoxic titre of both hypogamma and SLE sera was greater against T cells than non-T cells. Sera showing activity could be used to sensitize lymphocytes and render them susceptible to subsequent lysis, but IgM was not detectable on the surface of the sensitized cells. Following sucrose density gradient fractionation of the sera the lymphocytotoxic activity was recovered in those fractions that contained IgM. Lymphocytotoxic activity was dependent on classical complement pathway activity. In all the experiments the hypogamma sera showed the same pattern of activity as the SLE sera, but the activity was always far weaker than that found in SLE sera. The evidence does not suggest that lymphocytotoxicity is likely to be more important in the pathogenesis of hypogamma.

Agammaglobulinemia↗