Complement components on human lymphocytes.
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Animals↗
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Immunological evaluation of late complement component-deficient individuals.
The possible contribution of additional immunologic variables to the susceptibility of late complement component-deficient individuals to meningococcal disease has not been systematically examined in previous studies. Thus, we studied three groups of patients: (1) 24 healthy individuals, (2) 8 complement-sufficient individuals with a history of recurrent bacterial meningitis, and (3) 19 complement-deficient individuals with prior meningococcal infection. No statistical differences were noted among the three groups for the following parameters: the absolute number and the percentage of lymphocytes; CD3+, CD4+, CD8+, CD20+, and CD16+ cells; and the CD4+/CD8+ ratio. The concentration of C4 and circulating immune complexes was also similar among the groups. The concentrations of IgG, IgM, and IgA were slightly, but significantly, decreased in the complement-deficient individuals. Of interest, the coefficient of spontaneous and lipopolysaccharide-stimulated activation of neutrophils was significantly depressed in the deficient individuals. We hypothesize that the terminal complement components may participate in maximal neutrophil activation.
Adolescent↗
Biosynthesis of complement.
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Angioedema↗
Complement-fixing adrenal autoantibodies as a marker for predicting onset of idiopathic Addison's disease.
In a prospective investigation of the role of adrenal autoantibodies (AA) in predicting the onset of idiopathic Addison's disease, 9 initially non-addisonian AA-positive autoimmune subjects were followed for 42 months. In 4 of these subjects Addison's disease developed within 1-31 months. A fifth had reduced adrenocortical reserve at the start and at the end of the investigation. An AA capable of fixing the membrane attack complex of complement [(C5-C9) F-AA] was detected before onset of the disease in the sera of the 4 patients in whom Addison's disease developed. (C5-C9) F-AA may be involved in the pathogenesis of idiopathic Addison's disease and may be regarded as a marker for individuals in whom idiopathic adrenal insufficiency is likely to develop.
Addison Disease↗
Complement-induced decrease in membrane mobility: introducing a more sensitive index of spin-label motion.
We have used spin-labeling to investigate complement-induced changes in lipid organization of antibody-sensitized sheep erythrocyte membranes. The spectrum of methyl 5-doxylstearate incorporated into the lipid component of sheep erythrocyte membranes is typical of a membrane bilayer. The membranes from complement-lysed erythrocytes have a small, but statistically significant, reduction in fluidity when compared to membranes from osmotically-lysed erythrocytes, as indicated by a small increase in T'. In theory, measurements of the widths of the outer hyperfine extrema should be more sensitive to motion than the separation of the outer hyperfine extrema (2T'). Our results indicate that the half-width at half-height of the outer hyperfine extrema show a severalfold greater percentage change than T'. The sign and magnitude of these changes are in general agreement with previous predictions. Our results imply that motional corrections to the S formalism of Hubbell, Gaffney, and McConnell are necessary because spin-label motion appears to be explicitly represented in this type of electron spin resonance spectra.
Animals↗
Evidence suggesting the occurrence of C3-independent intravascular immune hemolysis. Reactive hemolysis in vivo.
The authors present circumstantial evidence for the involvement of reactive hemolysis, i.e., C3-independent binding of the cytolytic C5b-9 complement complex to bystander red cells (RBC), in a case of intravascular immune hemolysis. Fresh serum obtained from a 6-year-old patient during the hemolytic episode, but not obtained thereafter, induced C5b-9-dependent hemolysis of human RBCs but the indirect C3 antiglobulin test remained negative. Particles (presumably RBC ghosts) isolated from the patient's plasma anticoagulated with EDTA at the peak of hemolysis were coated with C5b-9 complexes, whereas the direct antiglobulin test was strongly positive for IgA, only weakly positive for IgG, and negative for C3. Moreover, neither the autoantibodies isolated by elution (IgG plus IgA), nor free serum autoantibodies (IgA alone) activated complement in vitro. Additionally, serum samples collected later during the 12-month period of observation contained normal levels of C3, C4, C8, and C9, but markedly reduced levels of C7. These serums all produced strong reactive lysis in agarose plates, but not in test tubes. These results appear compatible with the working hypothesis that the intravascular hemolytic episode in this patient might have arisen through a local initiation of complement activation with subsequent C3-independent binding of C5b-9 to and hemolysis of bystander RBCs.
Anemia, Hemolytic, Autoimmune↗
The complement abnormalities of lipodystrophy.
Investigation of the serum complement system in 25 patients with various forms of lipodystrophy showed no abnormality in three patients with total lipodystrophy; a single patient with limb lipodystrophy had evidence of activation of the classical complement pathway. However, of the 21 patients with partial lipodystrophy, 17 had low serum C3, with normal C4 and C2, concentrations, accompanied in 14 by a serum C3 splitting factor indistinguishable from nephritic factor, suggesting activation of the alternative pathway. These abnormalities occurred in 10 patients without clinically overt renal disease. Seven patients had overt nephritis; renal biopsies obtained in six showed mesangiocapillary (membranoproliferative) nephritis in all. Thus, the majority of patients with partial lipodystrophy have hypocomplementemia. Although nephritis may not invariably develop, the high rate of mesangiocapillary nephritis in these patients suggests that complement activation via the alternative pathway predisposes to the development of this form of glomerular disease.
Adolescent↗
Increased ion permeability of planar lipid bilayer membranes after treatment with the C5b-9 cytolytic attack mechanism of complement.
The ion permeability of planar lipid bilayers, as measured electrically, was found to increase modestly upon treatment with purified complement complex C5b,6 and complement components C7 and C8. The subsequent addition C9 greatly amplified this change. No permeability changes occurred when components were added individually to the membrane, or when they were used in paired combinations, or when C5b, C7, C8, and C9 were admixed prior to addition. Thus, there is a significant parallel between the permeability changes induced in the model membrane and damage produced in biological membranes by the C5b-9 complement attack sequence. The efficiency of membrane action by C5b-9 was critically dependent on the order in whcih components were added to the membrane. There were also differences in the electrical properties of membranes treated with C5b-8 and C5b-9, though in both cases the enhanced bilayer permeability is best attributed to the formation of trans-membrane channels. Collectively, the data are consistent with the hypothesis that the mechanism of membrane action by complement involves the production of a stable channel across the lipid bilayer, resulting in cell death by colloid-osmotic lysis.
Cell Membrane Permeability↗
Steady-state analysis of tracer exchange across the C5b-9 complement lesion in a biological membrane.
Resealed erythrocyte ghosts have been used to define the kinetics of tracer exchange across the membrane-bound terminal complex of the complement cascade (C5b-9). Under steady-state conditions and at net chemical equilibrium, C5b-9 ghosts showed no significant lysis above control levels as measured by hemoglobin efflux. In 1 mM sucrose at 37 degrees C, [14C]sucrose isotopic exchange diffusion into C5b-9 ghosts occurred at 4.8 (+/- 0.5, SEM) X 10(-20) mol sec-1 per functional lesion, equivalent to an apparent permeability coefficient of 4.8 X 10(-14) cm3 sec-1 for the single C5b-9 lesion. No significant uptake of [14C]sucrose above control levels was observed in C5b67 ghosts. The apparent rate of tracer permeation through the complement lesion is one to two orders of magnitude slower than predicted by a model of a transmembrane channel of dimensions permitting free diffusion of sucrose. The data support earlier assertions from this laboratory that diffusion of small molecules across the complement lesion in biological membranes is significantly restricted.
Biological Transport↗
Membrane attack complex of complement: generation of high-affinity phospholipid binding sites by fusion of five hydrophilic plasma proteins.
The molecular basis of the membranolytic activity of the membrane attack complex (MAC) of complement was investigated. By using density gradient equilibrium ultracentrifugation, the binding of egg yolk lecithin to the isolated MAC and to its intermediate complexes and precursor proteins was measured. No stable phospholipid--protein complexes were formed with the MAC precursor components C5b--6, C7, C8, and C9. Stable complexes of phospholipid and protein were formed by C5b--7, C5b--8, C5b--9, and the MAC (C5b--9 dimer) and they exhibited densities of 1.2164, 1.184, 1.2055, and 1.2275 g/ml, respectively. The molar phospholipid/protein ratios for the four complexes were determined to be: C5b--7, 399:1, C5b--5, 841:1; C5b--9, 918:1; and C5b--9 dimer, 1460:1. Electron microscopy of the isolated phospholipid--protein complexes revealed no lipid bilayer structures. The magnitude of the phospholipid binding capacity of the MAC is consistent with the interpretation that the MAC forms phospholipid--protein mixed in micelles in lipid bilayers and biological membranes and thus causes formation of hydrophilic lipid channels.
Binding Sites↗
Chemistry and function of the complement system.
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Chemical Phenomena↗
Complement abnormalities in human disease.
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Angioedema↗
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↗
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↗
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↗
Complement deficiency states.
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Adolescent↗
Inherited complement deficiencies.
Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.
Blood Donors↗
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↗