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PubMed1994

Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell.

The inactivation of type C retroviruses by human serum may be a considerable impediment to the use of retroviral vectors in vivo for gene therapy. Here we show that virus inactivation is dependent both on the virus and on the cell line used to produce the virus. All viruses produced from murine NIH 3T3 or dog Cf2ThS+L- cells are sensitive to human serum. In contrast, those produced from mink Mv-1-Lu and human HOS or TE671 cells are at least partially resistant, with the exception of murine leukemia viruses. In particular, the feline endogenous virus RD114 is completely resistant to a panel of eight human sera when produced from Mv-1-Lu or HOS cells. This differential resistance is controlled by the viral envelope proteins. Virus inactivation can be correlated with the ability of the producer cells to be lysed by human serum. Inactivation of sensitive viruses requires the classical pathway of complement but does not require virion lysis.

3T3 Cells↗
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↗
PubMed1998

Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock.

We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiologic and inflammatory response in baboons suffering from lethal Escherichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five controls receiving E. coli alone. Of the treatment group, one animal survived and another lived beyond 48 h, whereas all control animals died within 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not prevent the hemodynamic or hematologic changes observed upon E. coli infusion. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. However, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c, indicating substantial inhibition of activation of the contact system and the classical complement pathway, respectively. Furthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest that activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock through an augmentation of the cytokine response.

Animals↗
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↗
PubMed2002

Mechanisms of C1-inhibitor deficiency.

C1 inhibitor (C1-Inh) is a protease inhibitor of the serpin family. It interacts and forms complexes with several serine proteases although not all these interactions were proved to be relevant in vivo. Based on studies in deficient patients, C1-Inh appears pivotal in regulating the activation of complement classical pathway and of contact system. The best recognized consequence of defective C1-Inh function is predisposition to episodes of self-limited, increased vascular permeability (angioedema) that is restricted to three specific sites, which include the subcutaneous space, the gut and the upper airway. Candidate mediator of angioedema is bradykinin, a potent vasoactive peptide, released upon contact system activation. Mutations in C1-Inh structural gene are the most common cause of C1-Inh deficiency and lead to hereditary angioedema. Recurrent angioedema are also seen in the acquired defect of C1-Inh that is due to autoantibodies against this protein or to an associated disease causing accelerated catabolism of C1-Inh. Apart from the profound deficiency of C1-Inh characteristic of angioedema, it has been suggested that, in specific pathologic settings, C1-Inh levels in the low normal range could still represent a significant functional deficiency. Such conditions, as extensively investigated in sepsis, are of great relevance because they open the possibility of using C1-Inh as therapeutic agent in several different diseases.

Angioedema↗
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↗
PubMed1995

Coagulation inhibitor substitution during sepsis.

This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis. Activation of the contact system induces activation of the classical complement pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis. Physiologic inhibition depends on the C1-inhibitor (C1-Inh.). Septic patients exhibit a relative deficiency of biologically active C1-Inh. Substitution with concentrations of C1-Inh has been safely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septic shock. The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIC. Endothelial and monocyte generation of tissue factor (TF) is activated by bacterial products and endotoxin. Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPI). The potential for TFPI substitution to inhibit the activation of the coagulation cascade in sepsis requires further study. Thrombin generation is inhibited by antithrombin III (AT III) and the protein C-protein S system. During sepsis, AT III is consumed and degraded by elastase. Animal studies have shown that DIC and death were prevented by high doses of AT III concentrates. Although a significant reduction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of AT III substitution in human sepsis is still debated. None of the studies was able to document a statistically significant reduction in mortality. Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa. The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory protein. During sepsis, protein C activity is significantly reduced, either by acute consumption or by thrombomodulin down-regulation, and increased levels of plasma C4bBP inhibit protein S. Infusion of activated protein C and protein S substitution both protect animals from the lethal effects of bacteria. Combining these different coagulation inhibitors should be carefully studied before its use in septic patients is recommended.

Animals↗
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↗
PubMed2005

Complement-coated antibody-transfer (CCAT); serum IgA1 antibodies intercept and transport C4 and C3 fragments and preserve IgG1 deployment (PGD).

In periodontal disease, IgG1 and IgA1 antibodies produced in situ deposit on antigens in the affected tissues. Thus, there is an interest in the effect of co-deposited IgA1 antibodies on complement activation by IgG1-immune complexes. In the present study, we first analyzed the effect of IgA1-immune complexes on complement using human IgA1 antibodies to dansyl (with dansylated human serum albumin serving as the immobilized antigen). It was observed that these IgA1-immune complexes when incubated for prolonged times with 33% human serum as a source of complement received C4b and C3b deposition. As C4b and C3b deposited on the IgA1 antibodies and on the antigenic surface, the complement-coated IgA1 antibodies departed. These fluid-phase complement-coated IgA1 antibodies were transferred to antigen-coated microtiter-ELISA plates, where they became bound to the antigens. Thus, the complement-coated IgA1 antibodies retained their antigen-binding function, especially as a proportion of their covalently bound C3b progressively degraded to iC3b and C3d. Genetically engineered carbohydrate-deficient mutant human IgA1 antibodies were used to assess the role of carbohydrate in accepting the C4b and C3b depositions, and these studies indicated that the carbohydrate on the Fc-region of IgA1 played a positive role. Another interesting finding generated by this study was that when IgA1 was co-deposited with IgG1 antibodies, and serum complement was added, the IgG1 antibodies tended to remain on the antigenic surface. The co-deposited IgA1 antibodies not only controlled (reduced) the rate of the consumption of the first component of complement (C1) and of classical complement pathway activation by IgG1-immune complexes (and therein reduced the rate of complement-mediated dissolution of the IgG1-immune complexes), but also the co-deposited IgA1 antibodies simultaneously intercepted/accepted C4b and C3b, then departed, as complement began to cover the antigenic surfaces. The process in which complement-coated IgA1 antibodies transferred to non-complement-coated antigens is termed complement-coated antibody-transfer/transport (CCAT). In this way, IgA1 antibodies extended the efficiency of the complement system by insuring the specific IgA1 antibody-mediated transport of the captured biologically active complement fragments to those antigens stimulating the IgA1 antibody response but not yet neutralized (completely coated) with complement. Simultaneously by impeding the rate of C1 consumption and by intercepting C4b and C3b, IgA1 antibodies slowed C4b and C3b deposition on the antigenic surface and on the co-deposited IgG1 antibodies. Thus, in the presence of ongoing complement activation, the deposition of serum IgA1 antibodies enabled the co-deposited IgG1 antibodies to better maintain their ability to interact with antigens. We termed this latter phenomenon, preservation of IgG antibody deployment (PGD). In summary, co-deposited IgA1 antibodies maximized the efficiency of the complement system, transported their covalently bound complement fragments to specific antigens and sustained the effective deployment of IgG1 antibodies directed to those same antigens.

Antigens↗
PubMed2004

Intravascular schistosomes and complement.

Schistosomes are exposed to a variety of immunological effectors, such as host complement, in the bloodstream of their definitive hosts. The parasites are reported to possess a plethora of regulatory proteins, including molecules acquired from the host, which impede the complement cascade. Evidence for the presence of a surface C2-binding protein, a C3-binding protein and a C8- and C9-binding protein has been reported. In addition, a surface Fc receptor might bind immunoglobulin and limit its ability to fix complement. However, the actual protective role of these proteins in vivo remains unresolved.

Animals↗
PubMed1998

Regulation of C1 inhibitor synthesis.

The primary biologic roles of C1 inhibitor (C1-INH) are the regulation of activation of the classical complement pathway and of the contact system of kinin formation. Heterozygosity for deficiency or dysfunction of C1-INH results in hereditary angioedema (HAE). This deficiency results in loss of homeostasis with unregulated complement and contact system activation. Due to the consequent C1-INH consumption, plasma levels of C1-INH in patients with HAE are decreased below 50% of normal. In addition, diminished synthesis contributes to the lowered levels in some patients. The hepatocyte is the primary source of C1-INH, although a number of other cell types, including peripheral blood monocytes, microglial cells, fibroblasts, endothelial cells, the placenta, and megakaryocytes also synthesize and secrete the protein both in vivo and in vitro. Interferon-gamma and alpha (IFN), colony stimulating factor-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) all induce C1-INH synthesis in a variety of cell types. The IFN-response elements in the 5'-flanking region and in the first intron have been partially characterized, as have several of the promoter elements that direct basal transcription of the gene. However, although androgen therapy, in vivo, results in an increase in C1-INH plasma levels, a direct effect of androgens on C1-INH synthesis has not been convincingly demonstrated. Although the C1-INH gene contains a potential glucocorticoid/androgen response element, this element does not appear to respond to androgen. Continued analysis of the transcriptional regulation of the C1-INH gene may lead to new approaches to therapy of HAE.

Acute-Phase Reaction↗
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↗
PubMed2001

Complement activation by neurofibrillary tangles in Alzheimer's disease.

Brain inflammation is widely documented to occur in Alzheimer's disease (AD), but its sources are still incompletely understood. Here, we present in vitro and in situ evidence that, like amyloid beta peptide (Abeta), tau, the major protein constituent of the neurofibrillary tangle, is a potent, antibody-independent activator of the classical complement pathway. Complement activation, in turn, is known to drive numerous inflammatory responses, including scavenger cell activation and cytokine production. Because Abeta deposits and extracellular tangles are present from early preclinical to terminal stages of AD, their ability to activate complement provides a ready mechanism for initiating and sustaining chronic, low-level inflammatory responses that may cumulate over the disease course.

Alzheimer Disease↗
PubMed2003

Early mechanisms of Leishmania infection in human blood.

In human blood, promastigotes bind natural antibodies and activate the classical complement pathway. C3-opsonized promastigotes immune-adhere within seconds to erythrocytes. Promastigote lysis by complement parallels C3 deposition kinetics, and ~90% of promastigotes are killed after 2.5 min. During infection, complement thus exerts strong selective pressure on Leishmania. Paradoxically, promastigote adaptation to the host immune adherence mechanism may provide the parasite a key to invasion.

Animals↗