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PubMedDate not supplied

The complement system in host defense and inflammation.

In this discussion I have reviewed the major role of complement in host defense and inflammation. In addition, I have discussed dificiency states. Although these are rare, their clinical signs and symptoms can be predicted, at least in part, on the basis of our current understanding of the biological activities of complement and the various pathways of complement activation. This is not to say that complement plays no role in a wide variety of other illnesses. However, when complement plays a role in an illness, often this is not because it is functioning in an aberrant fashion. The usual situation is that complement is being activated and is serving its normal function in causing inflammation and damage to tissues under abnormal circumstances. Thus, for example, circulating antigen complexes may be deposited in the kidney, activate complement, and mediate tissue inflammation. In this case, complement is functioning normally but is being activated under abnormal circumstances. The same type of analysis can be made for many diseases of many different organ systems. At present, we have no drugs that are effective in humans in controlling the activation of complement and complement-mediated inflammation. We have not yet even established whether local variations in the activity of complement may affect the course of a clinical infection, but there is certainly strongly suggestive evidence to support this idea. It should be clear that under certain circumstances complement may well be a major factor in controlling the course of an infection. The near future should bring a vast expansion in our understanding of how complement contributes to specific clinical illnesses and to the defense of the host against specific microorganisms.

Angioedema↗
PubMed1978

Participation of immunoglobulin and the alternative complement pathway in opsonization of Bacteroides fragilis and Bacteroides thetaiotaomicron.

Studies were conducted to determine the requirements for immunoglobulin and complement for opsonization of Bacteroides fragilis and Bacteroides thetaiotaomicron. The ability of human sera depleted of immunoglobulin or complement components to promote phagocytosis and intracellular killing of the strains of Bacteroides by human leukocytes was measured in vitro under anaerobic conditions. Neither hypogammaglobulinemic sera nor pooled normal human serum (PNHS) heated at 56 C for 30 min supported phagocytosis and killing of the strains of Bacteroides. Sera depleted of terminal complement components by treatment with inulin or cobra venom factor and C8-deficient human serum did not support phagocytosis of the test strains. PNHS depleted of C3, factor B, or factor D also did not support phagocytosis of either strain. Dose-dependent restoration of the opsonic activity of factor B-depleted serum was accomplished by purified human factor B but not by human C2. The results indicated that immunoglobulin and components of the alternative complement pathway participate in opsonization of the strains of Bacteroides tested in this study.

Agammaglobulinemia↗
PubMedDate not supplied

Clinical applications of complement measurements in rheumatic diseases.

There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.

Antigen-Antibody Reactions↗
PubMed1978

Complement lysis: the ultrastructure and orientation of the C5b-9 complex on target sheep erythrocyte membranes.

The C5b-9 complex derived from human serum and assembled on target sheep erythrocyte membranes is a thin-walled cylinder rimmed by an annulus at one end. The total height of the cylinder is 150 A, towards which the annulus contributes 30 A. The cylinder has an apparently uniform internal diameter of 100 A. The external diameter of the annulus is 200 A. The classical complement 'rings' visualized on membranes after complement lysis represent such C5b-9 cylinders perpendicularly oriented on the membranes. The thin-walled cylinder is anchored in the membrane matrix and the annulus located in the exterior membrane glycocalyx. At the sites of attachment of the C5b-9 complexes, the continuity of the membrane bilayer is disturbed and the presence of trans-membrane pores is indicated. The data essentially support the 'doughnut' theory of complement lysis.

Animals↗
PubMed1975

Genetics of the complement system.

The complement system, unlike the coagulation system, was largely characterized by in-vitro techniques which did not make use of genetically deficient plasmas. The existence of the genetically deficient plasmas. The existence of the genetically deficient subjects therefore has served largely to increase our knowledge of the in-vivo role of complement. At the present time its clearest role is in the resistance to infection; obviously in the case of C3 deficiency and bacterial infection and possibly more subtly in the case of deficiency of the early active complement components and low virulence organisms. There is so far no evidence that genetic complement deficiency interferes with antibody formation or with the generation of tolerance as has been suggested in the pas (Azar et al, 1968; Dukor and Hartmann, 1973).

Child↗
PubMed1975

Complement.

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Anaphylaxis↗
PubMed1975

Effects of anesthesia, surgery and inflammation upon host defense mechanisms. I. Effects upon the complement system.

Complement protein levels and C7 hemolytic activity were measured in four individuals following anesthesia and surgery, and in a group of 20 patients with inflammatory diseases. Seven of the eight complement components studied characteristically were elevated, most dramatically C1s and C3PA. Elevation of C1s often was greater than elevation of C1q, displaying an independent variation of C1s and C1q in both postoperative and inflammatory disease patient groupds. The major increases of C components were seen subsequent to the peak C-reactive protein response, as was the occurrence of the 'reactor state', a propensity to formation of C56 which surprisingly was associated with increased levels of C7. Levels of properdin frequently were reduced postoperatively. It is concluded that multiple complement components, with the notable exception of properdin, respond as acute phase reactants which are elevated and changed in proportion postoperatively and during inflammatory disease.

Anesthesia, General↗
PubMed1976

Human platelet-initiated formation and uptake of the C5-9 complex of human complement.

We have studied the interaction of radiolabeled complement components with normal human platelets, platelets from a patient with paroxysmal nocturnal hemoglobinuria, and rabbit platelets in the absence of known complement activators or in the presence of cobra venom factor (CVF). When unwashed platelets in platelet-rich plasma, or washed platelets suspended in serum or autologous plasma, were incubated for 30 min, C3 and terminal components (C5, C8, and C9) were found to bind to them. The terminal components were shown to be bound as the C5-9 complex, rather than as individual proteins, by eluting them from the platelet membrane and examining their behavior on ultracentrifugation. They cosedimented at a rate characteristic of the stable C5-9 complex (22S). As many as 370-1,380 C5-9 complexes/platelet were calculated to have been bound during the incubation period. The complex so formed did not differ by ultracentrifugational criteria from that binding to rabbit platelets after CVF activation of complement. Though C3 was not included in the complex, it did not appear to be bound by nonspecific absorption. It could not be removed by washing but rather was eluted by the freeze-thaw technique used to elute the C5-9 complex. Incubation of radiolabeled components in platelet-free plasma did not result in C5-9 complex formation, indicating an initiating role for platelets in this reaction. In contrast to platelets, erythrocytes incubated in analogous plasma did not induce detectable C5-9 formation. Neither EDTA, phenylmethylsulfonylfluoride, nor epsilon-amino-N-caproic acid prevented platelet-initiated formation of C5-9, suggesting that the reaction may involve mechanisms of complement activation not previously described.

Aminocaproates↗
PubMed1978

Inherited deficiency of the seventh component of complement associated with nephritis. Propensity to formation of C56 and related C7-consuming activity.

A 46-yr-old female with chronic pyelonephritis was found to lack complement (C) activity by the use of hemolytic screen assays in agarose gels. These assays also revealed a propensity of patient serum to form an activated complex of the fifth and sixth components of C, C56. Each of the C component hemolytic activities was present in normal or elevated amounts with the exception of C7, which was undetectable; addition of purified C7 led to the restoration of hemolytic activity. C-dependent phagocytosis, immune adherence, and neutrophil chemotaxis were normal. Family studies demonstrated that the defect was transmitted as an autosomal codominant apparently not linked with alleles at the HLA-A or HLA-B loci. Persisting C56 was readily formed in this as compared to normal serum upon incubation with multiple C activators including zymosan, inulin, immune complexes, heat-aggregated human gamma globulin, endotoxin, and agarose. A heat-stable (56 degrees C, 30 min) activity which consumed C7 with time-and temperature-dependent kinetics was detected in plasma and serum, and seemed to be similar to a "C7 inactivator" previously described in another C7-deficient individual. However, this activity was found to have properties identical to those of C56 during low ionic strength precipitation and chromatography on Sephadex G-200, to be specifically removed upon passage through an anti-C5 immunoadsorbent column, and to be associated with a small amount of C56, suggesting that it represents an expression of small amounts of C56 rather than a new C-inhibitory activity. Thus, an individual with chronic nephritis lacking C7 is reported; the utility of a hemolytic screen assay in agarose plates for the detection of such patients is emphasized; persisting C56 is shown readily to be formed in this serum; and the presence of C7-consuming activity which is associated with and in all likelihood attributable to C56 is shown.

Complement C5↗
PubMed1979

Complement lysis of human erythrocytes. Differeing susceptibility of two types of paroxysmal nocturnal hemoglobinuria cells to C5b-9.

Although enhanced sensitivity of erythrocytes to complement-mediated lysis is a hallmark of paroxysmal nocturnal hemoglobinuria (PNH), subpopulations of erythrocytes in such patients vary significantly in this respect. One PNH erythrocyte subpopulation (termed type III) comprises exquisitely sensitive cells, whereas type II PNH erythrocytes are intermediate in complement sensitivity between PNH type III and normal human erythrocytes. Differences in the action of the terminal complement components that would account for the differing lytic behavior of types II and III PNH erythrocytes have been proposed but not directly demonstrated. The present studies, making use of carefully selected cases with pure populations of type II or type III erythrocytes, confirm a prior observation that antibody-coated PNH erythrocytes of both types II and III display comparably supranormal C3 binding in whole human serum. However, when lysis was induced by the isolated C5b-9 membrane attack mechanism, bypassing the requirement for C3 binding, only type III PNH cells exhibited greater than normal lysis. This finding suggests that type III PNH erythrocytes have an additional membrane abnormality not present in type II cells. Thus, the differing lytic behavior of these two cell types in whole serum may reflect the additive effects on type III cells of both exaggerated C3 binding and enhanced sensitivity to C5b-9, whereas the more moderate lysis of type II PNH cells may be determined mainly or entirely by the earlier-acting mechanism producing augmented C3 binding. The failure of guinea pig C8 and C9, as opposed to human C8 and C9, to reveal the true lytic sensitivity of PNH-III E in our earlier study is illustrated, and its implications briefly discussed.

Animals↗
PubMed1979

Serum complement levels in infancy: age related changes.

Levels of eight complement components and two control proteins, were determined on cord serum from normal full term neonates and serum from healthy infants aged 1 and 6 months. For all proteins, the levels were below the adult normal at birth and rose toward the adult range by age 6 months. In a second group of 271 patients, ages 1-36 months, serum Clq and properdin levels were measured. For both proteins, the mean values in early infancy were more than two SD below the adult range and did not reach the adult range until 18-21 months of age. The Clq concentration was more variable than that for any other component studied. In infants from 11 months-3 yr of age, Clq levels correlated with serum IgG levels, but properdin levels did not.

Adult↗
PubMed1976

Membrane receptors on neutrophils.

Neutrophils recognise humoral immunologic reactants through 'receptors' on their surface membrane. Most widely studied and probably of greatest biologic significance are the immunoglobulin (Fc), and complement (primarily C3b and C5a) receptors which enable the cell to ract with, and be stimulated by, antigen-antibody, or antigen-antibody-complement complexes and their products. This interaction with the putative receptors and the consequent cell activation occurs most optimally on surfaces and plays a critical role in the mammalian host defense system.

Antibody Specificity↗
PubMed1976

Activation of the complement attack mechanism in the fluid phase and its control by C567-INH: lysis of normal erythrocytes initiated by zymosan, endotoxin, and immune complexes.

Addition of zymosan-serum complexes to guinea pig erythrocytes in guinea pig complement-EDTA was found to result in substantial lysis of the bystander cells in the presence of polycations such as poly-L-lysine of 178,000 daltons. Involvement of the alternative C pathway was shown, and the optimum time, temperature, and eruthrocyte and polycation concentrations were defined; a surprising efficiency was observed at low temperature and high cell concentrations. Several lines of evidence indicated that this hemolysis was mediated via the C567 complex of the C system and modulated by serum inhibitors of C567 (C567-INH): lysis was observed only with zymosan-serum complexes possessing C-consuming activity; it was not observed in C5-depleted guinea pig serum but was restored upon addition of purified C5; the addition of partially purified C567-INH insubstantially depressed hemolysis; and poly-L-lysine which is known to neutralize C567-INH in solution resulted in substantial enhancement of hemolysis. We also sought to determine whether the addition of complement activators directly to erythrocyte-serum mixtures could result in the hemolysis of bystander erythrocytes. It was found that zymosan, endotoxin, antigen-antibody complexes, and aggregated human gamma-globulin each could initiate such bystander lysis under appropriate conditions. Lysis again was favored by increased erythrocyte concentrations, low temperatures, and the presence of polycations such as poly-L-lysine, and was found to be mediated via the C system. C567-INH blocked cytolysis whereas poly-L-lysine potentiated hemolysis by neutralization of C567-INH. These experiments emphasize the propensity for C567 formation and lysis of bystander erythrocytes during C activation generally, the role of C567-INH in the control of this lysis, and the susceptibility of these interactions to modulation by highly charged macromolecules.

Animals↗