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PubMed1981

Complement activation in nonsystemic glomerular diseases in children.

All forms of glomerulonephritis (GN) in man seem to be immunologically mediated and the complement system appears as one of the most important mediators of renal injury. The study of complement activation is therefore of great help in the identification of the immunopathogenic process involved in the various types of glomerular diseases. After a review of the molecular events of complement activation and the methods used to study the complement system in man, we will attempt to summarize current knowledge concerning complement in nonsystemic glomerular diseases frequently encountered in children. The terms used are those descriptive of glomerular morphology as defined either by light microscopy and electron microscopy (endocapillary-proliferative GN with humps, extramembranous GN, membranoproliferative GN) or by immunofluorescent microscopy (mesangial IgA GN).

Basement Membrane↗
PubMedDate not supplied

[Genetics of complement: recent aspects (author's transl)].

Genetic deficiencies of complement proteins are now more often recognized and analysed more precisely because the structure of the different complement proteins is better known. Partial defects may be detected in some components by the combined utilization of titration techniques, polymorphism studies and linkage analyses. The partial deficiency in C4 seems to be the most frequent protein deficiency in the human. The complement markers on the short arm of the sixth chromosome in man (BF, C2, C4A and C4B) are located in close proximity to the HLA-D/DR region. The combined study of the complement and HLA markers will probably allow the fine structure of the HLA region to be better defined. The association of some diseases with HLA types will probably also be better specified by the definition of associations not only with HLA-B or HLA-D types but also with the BF, C2 and C4 types.

Animals↗
PubMed1982

Hemolytic and antigenic measurements of complement. A comparison of serum and plasma samples in normal individuals and patients.

Over a 2-year period we evaluated 10 patients with a discrepancy between functional and antigenic assays in the routinely employed clinical assays for measuring serum complement concentrations. These differences were shown to be secondary to cold-dependent activation of the classical complement pathway in vitro, in some cases by cryoglobulins and in others by unknown means. Plasma samples were procured with commonly used anticoagulants (EDTA, citrate, or heparin) that prevent in vitro complement activation. To assess whether plasma samples were suitable for complement determination, a comparison of serum vs. plasma samples for THC, C4, C2, C3, factor B, and C6 levels in normals and patient populations was undertaken. Only modest differences were found between serum and plasma samples for these functional and antigenic assays except for heparinized samples in which determinations by rate nephelometry produced falsely elevated C4, C3, and factor B antigenic levels. Thus plasma samples, especially EDTA or citrate, are suitable for complement determinations and could be used either routinely or, more selectively, in patients in whom there is a discrepancy between functional and antigenic determinations.

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↗
PubMed1978

Experimental bovine trypanosomiasis. Changes in serum immunoglobulins, complement and complement components in infected animals.

In three calves experimentally infected with Trypanosoma congolense the amounts of IgG1 and IgG2 were little changed and similar to those of normal animals. IgM increased in amount early in the infection and the amount of the increase appeared related to the parasite burden. The amounts of IgA and IgE were both much decreased and this also appeared related to the numbers of parasites in the blood. There was a decrease in the amounts of total haemolytic complement and complement components C1, C1q and C3 in the infected calves. Furthermore the amounts of properdin fluctuated with the cyclical changes in numbers of T. congolense parasites in the individual calves. No significant change in the amount of C8 was observed. It is considered that activation of both the alternative and the classical complement pathways occurs in trypanosome infected animals but that neither pathway goes to its terminal stages.

Animals↗
PubMed1981

Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement.

We have examined the interaction of C-reactive protein (CRP) with model membranes and complement. Binding of CRP to multilamellar liposomes or unilamellar vesicles of egg-phosphatidylcholine required the presence of lysophosphatide in the bilayer. The binding was Ca++-dependent, could be inhibited by phosphocholine, and resulted in activation of the classical complement pathway. A weak interaction between CRP and agarose was observed, which was also CA++-dependent and could be inhibited by phosphocholine and galactose. In addition, incorporation of galactocyl cerebroside in phosphatidylcholine:lysophosphatidylcholine liposomes enhanced the binding of CRP. Binding constants of 1.9 X 10(-5) M and 7.1 X 10(-5) M were calculated for liposomes containing and lacking the glycolipid, respectively. Furthermore, CRP bound to galactocyl cerebroside-containing liposomes bound approximately twice as much C1q as the same amount of CRP bound to liposomes lacking the glycolipid. We conclude that: 1) An alteration of the normal organization of phosphatidylcholine bilayers is necessary for binding of CRP. 2) The presence of galactosyl residues on the surface of the bilayer enhances the binding of CRP, perhaps through interaction with a putative secondary binding site on the protein.

Animals↗
PubMed1980

Treatment of chronic urticaria with an inhibitor of complement activation (cinnarizine).

Twenty-three patients with chronic urticaria were treated with cinnarizine, dexchlorpheniramine and placebo in a double-blind, crossover trial. Compared to placebo treatment both cinnarizine and dexchlorpheniramine caused a statistically significant improvement in the clinical symptoms (p less than 0.01). The two active drugs were found to be equally effective; however, cinnarizine was better tolerated. Both drugs appear to be useful in the treatment of chronic urticaria.

Adult↗
PubMed1980

Sodium azide inhibition of complement-mediated functions.

Moderate concentrations of sodium azide (0.1-0.2%) significantly inhibited guinea-pig and human complement-mediated lysis of both IgM- and IgG-sensitized sheep erythrocytes. The reduction in cytolysis was not attributable to non-specific ionic effects, to inactivation of native complement components by azide, or to irreversible interactions of azide with sensitized erythrocytes. Mouse complement-dependent opsonization of sensitized erythrocytes, as judged by macrophage complement receptor-mediated attachment and phagocytosis of the erythrocytes, was comparably inhibited by sodium azide, suggesting that azide acted within the sequence of the first four components of the classical complement pathway.

Animals↗
PubMed1994

Mannan-binding protein levels in human amniotic fluid during gestation and its interaction with collectin receptor from amnion cells.

Collectins are a group of soluble proteins, each of which has collagenous and non-collagenous globular domains, and may be complement associated and/or have lectin activity. The complement protein C1q is structurally and functionally related to the collectins. Members of the collectin family are mannan-binding protein (MBP), lung surfactant protein A, CL-43, conglutinin and lung surfactant protein D. All except the last of these proteins have been shown to interact with a single, widely distributed receptor, named collectin receptor (also called C1q receptor). It has been proposed that collectins play an important role as opsonins in innate immunity. MBP is a serum protein and has been shown to activate the classical complement pathway. MBP has also been shown to opsonize bacteria and enhance clearance of bacteria by phagocytosis. In this article we demonstrate the presence of MBP in amniotic fluid and the localization of collectin receptor on the surface of amniotic epithelium. MBP levels in amniotic fluid were found to increase sharply from about 32 weeks of gestation. Collectin receptor was purified from a cell line, FL, derived from amniotic epithelium and was shown to interact with MBP. These results suggest that MBP may play a role in the antibody-independent recognition and clearance of pathogens in the amniotic cavity, towards term.

Amino Acid Sequence↗
PubMedDate not supplied

Studies of immune response in a patient with selective complete C1q deficiency.

Immune response in a six-year-old girl with a rare complement defect, namely selective complete C1q deficiency, was studied. Her cell-mediated immune response (delayed hypersensitivity skin tests, E, EAC rosettes, in vitro lymphocyte transformation with phytohemagglutinin), isohemagglutinin titers, serum immunoglobulin levels, antibody titers to tetanus, Epstein-Barr virus, keyhole limpet hemocyanin, pneumococcus and bacteriophage 0 x 174 were all normal. However, she had abnormal kinetics of the antibody response to bacteriophage following primary and secondary immunizations. Her antibody titers reached a peak four weeks after primary immunization and three weeks after secondary immunization, while the titers of controls peaked at two weeks and one week, respectively. In this study we could not prove the hypothesis that defective antibody response caused recurrent infections in this patient. An alternative hypothesis is the possible role of defective clearance of immune complexes in the development of severe infections. Patients with selective complete C1q deficiency form immune complexes with bacterial or viral antigens, thus activating the classical complement pathway. As a result, very low C1q levels decrease even further, leading to a severe immunodeficiency and recurrent infections. Future studies in this area may help to explain the mechanism(s) responsible for infections in this rare type of complement defect.

Antibody Formation↗
PubMed1993

Structure and function of collectins: humoral C-type lectins with collagenous regions.

Collectins are a family of C-type lectins with collagenous regions. Five such lectins have now been described: Lung surfactant protein A and D (SP-A and SP-D), and the plasma proteins, conglutinin, mannan-binding protein (MBP), and CL-43. They are composed of trimeric subunits containing a collagenous section and a C-terminal globular carbohydrate-recognizing domain containing the 14 invariant amino acids characteristic of the C-type lectins. The complete molecules of MBP and SP-A are composed of up to six such subunits, while conglutinin, SP-D and CL-43 contain up to four subunits. The collectins bind to carbohydrates on yeast, bacteria and viruses. The collagenous section reacts with the C1q receptor (collectin receptor) found on many cells including phagocytes. One function of these lectins appears to be the enhancement of phagocytosis, i.e. opsonization. One of the collectins, mannan-binding protein, activates the C1r2C1s2 complex of the classical complement pathway independently of C1q. Collectins have been found in several mammalian species and in the chicken. It seems likely that the biological role of the collectins is to participate in the innate immune defense.

Amino Acid Sequence↗
PubMed1993

Functional aspects of the C1q receptors.

C1q, the recognition subunit of the classical complement pathway, has been shown to stimulate host defense mechanisms. It has become increasingly evident that C1q can bind to several different cell types resulting in a variety of functional consequences depending on the cell type. For example, the binding of C1q to monocytes enhances the ability of those cells to ingest pathogens, while interaction with neutrophils, eosinophils, endothelial cells and vascular smooth muscle cells triggers or enhances the generation of toxic oxygen species. While these latter oxygen products play a major role in the destruction of foreign pathogens, in some cases, such as immune-complex-induced vasculitis and myocardial infarction, these toxic oxygen molecules can cause excessive host tissue damage. The differential modulation of C1q-mediated activities by monoclonal antibodies suggest that there is more than one unique type of C1q receptor, which is not necessarily surprising given the diversity of responses reported. This review summarizes what is known about the functional consequences of the interaction of C1q with cells, and describes initial investigations of the biochemical mechanisms/signal transduction pathways involved in these C1q-induced responses. Further investigations of the C1q/C1q receptor system(s) should uncover basic mechanisms and modes of regulation of these defensive responses by the host, and potentially provide information useful for beneficial manipulation of these activities.

Animals↗
PubMed1976

The heterocytotoxicity of human serum. III. Studies of the serum levels and distribution of activity in human populations.

A metabolic inhibition assay has been employed to investigate the distribution of serum heterocytotoxicity mediated by natural antibody activating the classical complement pathway and by antibody-independent activation of the alternative complement pathway in human serum samples derived from various groups of individuals. Levels in female cancer patients and in women taking oral contraceptives were significantly elevated over normal controls. Newborn infants exhibited approximately half of the average adult levels. Levels were maximally elevated in patients with visceral cancer, particularly in individuals with adenocarcinomas, while patients with sarcomas exhibited reduced levels. These and other data derived from the literature suggest that the metabolic inhibition assay may provide a useful measure of natural antibody and activation of the alternate complement pathway representative of mechanisms of natural immunity vs tumours.

Adult↗
PubMed1977

Cholesterol-dependent human complement activation resulting in damage to liposomal model membranes.

Human (but not guinea pig) complement-mediated damage. It was concluded that human complement was activated spontaneously by liposomes containing a high concentration (71 mol %) of cholesterol. This occurred in the absence of any recognizable antigen or antibody, and did not occur at a low concentration (43 mol %) of cholesterol. Activation of complement resulted in membrane damage and release of trapped liposomal glucose. The complement activity was inhibited by preheating (56 degrees C, 30 min), 10 mM Mg2EDTA3 or EGTA, and by prior adsorption with insoluble immune complexes. Almost all human sera had some reactivity, but it ranged from very low levels (less than 7% liposomal glucose release) to very high levels (greater than 50% glucose release). Complement activation appeared to be mediated by a serum factor which could be removed by adsorption and which was partially heat labile. The factor was transferred by adding heated high reacting human serum to unheated low reacting human serum, or to guinea pig serum. The serum factor, although quantitatively diminished in potency due to heat lability, caused equal activation of each of these two latter complement sources in the presence of high cholesterol liposomes. It did not cause activation of C4-deficient guinea pig complement. These data suggested that the classical complement pathway was activated. The liposomal membrane composition had an influence on this phenomenon. Activities of about half of the human sera were enhanced when galactosyl ceramide, or ceramide alone, was present in the liposomes. Activity was enhanced by longer fatty acyl chain lengths of lecithin when dimyristoyl-, dipalmitoyl-, or distearoyllecithin was employed in the liposomes. Liposomes containing sphingomyelin as the only phospholipid were not sensitive to cholesterol-dependent complement-mediated damage. It was concluded that human complement was activated in the presence of high concentrations of membrane cholesterol and that this was caused by an uncharacterized serum factor and was influenced by the lipid composition of the membrane.

Ceramides↗