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PubMed1990

Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcal infections.

High incidence of hereditary complement (C) deficiencies was found among 101 patients who had a meningococcal disease. This study revealed 11 non-related patients with complete C deficiency: five deficient in C7, three in C8, two in properdin and one in C2. Additional C-deficient individuals, most of them with no history of severe bacterial infections, were detected in family studies. The C8-deficient patients were found to have a selective deficiency of the C8-beta subunit and a reduced expression of the alpha/gamma subunit. Only a few families with properdin deficiency have been described so far. However, it is likely that frequent analysis of the activity of the alternative C pathway in survivors of severe bacterial infections will disclose numerous properdin-deficient patients. All our C7-, C8- and properdin-deficient patients are Sephardic Jews whose families originated from Morocco, Yemen (C7 and C8 deficient) or Tunisia (properdin deficient). This and other findings indicate that the type of complement abnormality found in association with meningococcal infections varies with the ethnic origin of the patient.

Adolescent↗
PubMedDate not supplied

Serum complement profile in human leprosy and its comparison with immune complex diseases.

In the present study we have estimated the serum levels of early, middle, and distal complement components, e.g., Clq, C3, C4, C5, C8, and C9 along with C1-inactivator and CH50 in patients with tuberculoid and lepromatous leprosy and have compared these results with the levels in healthy subjects as well as with levels in patients with other immune complex diseases. We have also analyzed the cryoglobulins present in the sera of these patients; they consisted of either a single or mixed IgG, IgA, IgM or fibrinogen in most instances. The component C3 was found in only one sample. It appears that unlike lupus nephritis, in which complement is activated by direct path in which complement is activated by direct path in about 30% to 50% of leprosy patients, significant C3 complement consumption takes place primarily via the alternate pathway and is probably initiated by the aggregated immunoglobulins represented in cryoprecipitates. This is further supported by the study of serum factor B and its breakdown product (Ba) in these patients. The question of the role of the middle and distal complement components, such as C5, C8 and C9, during total hemolytic complement and C3 consumption in leprosy remains unanswered.

Complement C1 Inactivator Proteins↗
PubMed1984

On the cause and nature of C9-related heterogeneity of terminal complement complexes generated on target erythrocytes through the action of whole serum.

The binding of C8 and C9 from human serum to target erythrocytes was quantified, and the molecular stoichiometries of C9:C8 within terminal C5b-9(m) complexes were determined. Low doses of serum generated terminal complexes with mean C9:C8 ratios of 2 to 3:1, whereas complexes generated by highest serum doses harbored an average of six to eight C9/C8 molecules. From the collective biochemical and ultrastructural data, we concluded that heterogeneous populations of terminal complexes regularly form on target membranes; those containing high numbers of C9 molecules (greater than or equal to six to eight) exhibit the structure of the classical "lesion", whereas those containing low numbers of C9 do not exhibit this typical structure, although they probably still function as small pores. A major cause for this heterogeneity of the lesions derives from shortage of C9, which is naturally present in a 2 to 1 molar ratio relative to C8 in serum. Generation of terminal complexes harboring high numbers of C9 on erythrocyte membranes is possible in spite of this natural shortage because SC5b-9 does not form in the fluid phase to compete for C9 binding. If interrupted, the process of C9-C9 oligomerization cannot be recontinued, and "incomplete" C5b-9 complexes are unable to bind additional C9 upon reincubation with this component. The demonstrated heterogeneity of terminal complexes with respect to their C9 content may explain the functional heterogeneity of complement lesions observed previously by other investigators.

Animals↗
PubMed1990

Membrane attack complex of complement in Henoch-Schönlein purpura skin and nephritis.

The present study using direct immunofluorescence with monoclonal antibodies to C5b-9 complex-related antigens was undertaken to determine whether complement activation in Henoch-Schönlein purpura (HSP) causes assembly of the membrane attack complex of complement (MAC) in skin and nephritis lesions. The deposition of C5, C6, C7, C8, C9, and C5b-9 neoantigens was noted in the vascular walls of papillary dermis and/or subpapillary dermal plexus of the vessels in 11 out of 15 patients with HSP. Their presence in vessel walls indicates complement activation which leads to terminal complement activation. There were small deposits of S protein at the same sites in three of the 11 skin specimens. Thus, the majority of C5b-9 demonstrated in HSP skin was the cytolytically active C5b-9 complex, MAC. Granular deposits of C5b-9 related antigens without S protein were also found in the capillary walls and mesangium of the glomeruli of two out of four specimens from patients with HSP nephritis; in the other two S protein was colocalized with the deposition of C5b-9. The results of the present study indicate that complement activation leading to generation of MAC may possibly be involved in the pathogenesis of vascular injury in a significantly large number of skin lesions and of HSP nephritis.

Antibodies, Monoclonal↗
PubMed1977

Lytic activity of C5-9 complexes for erythrocytes from the species other than sheep: C9 rather than C8-dependent variation in lytic activity.

With the reactive lysis system, a form of hemolysis mediated solely by the late-acting complement components (C56, C7, C8, and C9), guinea pig C9 (C9gp) was found to be very inefficient in inducing the lysis of guinea pig and mouse erythrocytes bearing human C5-8. By contrast, C9gp could efficiently induce the lysis of sheep and goat erythrocytes bearing human C5-8. By contrast, C9gp could efficiently induce the lysis of sheep and goat erythrocytes bearing human C5-8. Human C9 was efficient in the lysis of erythrocytes from the species mentioned above. Further study showed: 1) the observed inefficiency in the lysis of guinea pig erythrocytes was not due to incompatibility between human C7 or C8 and C9gp; 2) C9gp could efficiently bind to guinea pig erythrocytes bearing human C5-8 but was inactive in the subsequent lytic process. The present finding emphasizes a role for C9 in complement-mediated membrane damage which may not be a simple effector function of C8 action.

Animals↗
PubMed1982

Recurrent pyogenic infections in individuals with absence of the second component of complement.

While deficiency of the terminal components of complement (C3-C8) has classically been associated with recurrent pyogenic infections, it has become apparent that C2 deficiency is also associated with recurrent infections in some individuals. The patient presented here had two major pyogenic infections prior to 1 year of age and was found to lack the second component of complement. Studies of alternative complement pathway and humoral and cellular immunity were found to be within normal limits. Family studies suggest an autosomal codominant pattern of inheritance for the C2 defect, which also corresponded to the inheritance of the HLA A10 B18 haplotype. A review of the literature revealed nine other cases of C2-deficient patients with well-documented recurrent infections. In these patients, Streptococcus pneumoniae is the organism most frequently implicated in infectious processes, whether or not their alternative complement pathway is intact.

Antibodies, Antinuclear↗
PubMed1999

Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation.

OBJECTIVE: Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. METHODS: In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. RESULTS: Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. CONCLUSIONS: The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit.

Antibodies, Monoclonal↗
PubMed1988

Human peritoneal macrophages. Production in vitro of the active terminal complement components C5 to C9 and a functional alternative pathway of complement. Brief report.

Endotoxin-stimulated human peritoneal macrophages were cultured in serum-free medium with agarose beads. Monospecific antibodies to human C3c, C3g, C5, C6, C7, C8, C9 and to C9-neoantigen bound to the beads. This shows that activated C3 and the terminal complement complex (TCC), made from complement components C5 to C9, were generated on the beads. De novo synthesis was confirmed by agarose binding of tritium-labelled protein. Moreover, C3-derivatives and C9-neoantigen were detected on normal serum-treated agarose beads but not on beads kept in factor B-depleted or heat-inactivated sera, implying that an intact alternative complement pathway was required for our findings. The macrophages thus synthesize the active complement components of the alternative and terminal pathways in vitro.

Ascitic Fluid↗
PubMed1977

Absence of the eighth component of complement in association with systemic lupus erythematosus-like disease.

A 56-yr-old black woman with absence of the eighth component of complement and a disease compatible with systemic lupus erythematosus is described. Her disease is characterized by the presence of photosensitive "malar" rash, alopecia, polyarthritis, and nephrotic syndrome. Hemolytic and immunochemical assays of the serum complement components were normal, except for C8 which was undetectable. Hemolytic activity could be restored to normal by the addition of functionally pure C8. In vitro tests to investigate the functional integrity of the classical and alternative pathways indicated that the functions mediated by activation of C3 and C5 were intact whereas heatlabile bactericidal activity was totally absent. Addition of C8 restored this function to normal levels. One of two brothers of the proband was shown to have serum C8 levels approaching 50% of normal indicating the hereditary nature of the defect. HLA typing studies showed that the normal brother had identical haplotypes to the proband while the proposed heterozygous brother only shared one haplotype with the patient, suggesting that the gene controlling the C8 defect was not closely linked to the major histocompatibility complex. If the association of a connective tissue disease and absence of a terminal component of complement is not coincidental, these results suggest that C8 deficiency may be associated with a subtle defect in the defense mechanisms to viral infection leading to viral persistance and perhaps to diseases such as systemic lupus erythematosus where chronic viral infections have been implicated.

Complement C8↗
PubMed1995

Protection of retroviral vector particles in human blood through complement inhibition.

The rapid inactivation of murine-derived retroviral vectors in human or nonhuman primate sera is largely attributed to the activity of complement mediated through the classical pathway. In this study, we have further investigated the relationship between the human complement cascade and retrovirus inactivation. Preincubation in normal human serum effectively inactivated LXSN retroviral vector particles, whereas the vector maintained the ability to transduce cells following incubation in sera deficient in either the C1, C2, C3, C5, C6, C8, or C9 human complement proteins. Preincubation of serum with monoclonal antibodies (mAbs) that functionally block specific complement components, including C5, C6, C8, and C9, successfully protected the LXSN vector from complement-mediated inactivation. Treatment of serum with cobra venom factor, which consumes terminal complement, also effectively protected the vector from inactivation. LXSN vector survival in serum corresponded inversely to the level of complement activity following treatment of serum with anti-C5 mAb as assessed in an erythrocyte hemolytic assay. Additionally, pretreatment of human whole blood with anti-C5 mAb effectively inhibited inactivation of the LXSN vector. Taken together, these data demonstrate that formation of the membrane attack complex (MAC, C5b-9) is required for the inactivation of the murine-based LXSN retroviral vector in human blood and that this process can be abrogated with the use of soluble complement inhibitors.

3T3 Cells↗
PubMed1985

[Recurring meningococcal meningitis in hereditary C 5 deficiency].

Inherited deficiency of the 5th complement component (C5) was the cause of recurrent meningococcal meningitis in a woman aged 20 years. Familial investigations confirmed an autosomal co-dominant type of inheritance for the defect. Whereas additional loss of chemotaxis only exists with a genetic defect in C5 complement, bacteriolytic activity of serum is lacking in all genetic defects of the terminal complement components C5 to C8. An intact bacteriolysis, however, is necessary for resistance against Neisseria meningitidis and Neisseria gonorrhoeae. Neisseria infections, particularly recurrent meningococcal meningitis or disseminated gonococcal infections, suggest the presence of a congenital or acquired deficiency in one of the complement components C5 to C8.

Adult↗
PubMed1994

Alternative pathway activation of complement by cultured human proximal tubular epithelial cells.

Human proximal tubular epithelial cells (PTEC) incubated with normal human serum (NHS) were found to fix on their surface C3, properdin, terminal complement components and C5b-9 MAC neoantigen, but not C1q and C4, by immunofluorescence. Complement fixation was abrogated if PTEC were incubated with EDTA-treated NHS or C3-deficient human serum, but not with Mg EGTA-treated NHS or C1q-deficient human serum, showing the prevalent activation of the alternative pathway of complement. This event was followed by marked cytoskeleton alterations with disruption of the actin cortical network, redistribution of actin throughout the cytoplasm and formation of blebs, and by cell cytolysis. In addition, superoxide anion and hydrogen peroxide production and chemiluminescence response were detected in consequence of MAC insertion on PTEC plasma membrane. The dependency on MAC of the observed biological effects of complement fixation on PTEC surface was shown by using sera selectively deficient of terminal components of complement (C6 or C8), and therefore unable to form the C5b-9 MAC, and by restoring the ability to form MAC after addition of purified C6 or C8. The possible pathogenetic relevance of these observations in tubulointerstitial injury occurring in patients with complementuria due to non-selective proteinuria, is discussed.

Blood↗
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↗
PubMed1981

Homologous species restriction in lysis of erythrocytes by terminal complement proteins.

The cytolytic efficiency of the terminal complement protein complex, C5b-9, varies with the species of origin of C8 and C9. In the present study, we explored the susceptibility of erythrocytes from various species to lysis by C5b6,7 plus C8 and C9 from different species. EC5b6,7 intermediates were prepared on human, guinea pig, rabbit, mouse, and rat erythrocytes with human C5b6 and guinea pig C7. The degree of lysis of these intermediates by C8 and C9 was found to vary widely depending on the species of the proteins and the target cells. In all cases, lysis was least efficient when C8 and C9 were homologous with respect to the target cell species. This effect was mostly attributable to C9. The inefficient lysis in a homologous system is not due to a failure of C9 binding. Rather, the poor lysis in the homologous system may be attributable to inefficient insertion or channel formation.

Animals↗
PubMed1991

Inhibition of homologous complement by CD59 is mediated by a species-selective recognition conferred through binding to C8 within C5b-8 or C9 within C5b-9.

The capacity of the human complement regulatory protein CD59 to interact with terminal complement proteins in a species-selective manner was examined. When incorporated into chicken E, CD59 (purified from human E membranes) inhibited the cytolytic activity of the C5b-9 complex in a manner dependent on the species of origin of C8 and C9. Inhibition of C5b-9-mediated hemolysis was maximal when C8 and C9 were derived from human (hu) or baboon serum. By contrast, CD59 showed reduced activity when C8 and C9 were derived from dog or sheep serum, and no activity when C8 and C9 were derived from either rabbit or guinea pig (gp) serum. Similar specificity on the basis of the species of origin of C8 and C9 was also observed for CD59 endogenous to the human E membrane, using functionally blocking antibody against this cell surface protein to selectively abrogate its C5b-9-inhibitory activity. When E bearing human CD59 were exposed to C5b-8hu, CD59 was found to inhibit C5b-9-mediated lysis, regardless of the species of origin of C9, suggesting that the inhibitory function of CD59 can be mediated through recognition of species-specific domains expressed by human C8. Consistent with this interpretation, CD59 was found to bind to C5b-8hu but not to C5b67hu or C5b67huC8gp. Although CD59 failed to inhibit hemolysis mediated by C5b67huC8gpC9gp, its inhibitory function was observed for C5b67huC8gpC9hu, suggesting that, in addition to its interaction with C5b-8hu, CD59 also interacts in a species-selective manner with C9hu incorporated into C5b-9. Consistent with this interpretation, CD59 was found to bind both C5b67huC8gpC9hu and C5b-8huC9gp, but not C5b67huC8gpC9gp. Taken together, these data suggest that the capacity of CD59 to restrict the hemolytic activity of human serum complement involves a species-selective interaction of CD59, which involves binding to both the C8 and C9 components of the membrane attack complex. Although CD59 expresses selectivity for C8 and C9 of human origin, this "homologous restriction" is not absolute, and this human complement regulatory protein retains functional activity toward C8 and C9 of some nonprimate species.

Antigens, Differentiation↗
PubMed1975

Neoantigens of the membrane attack complex of human complement.

The membrane attack complex of complement is a fusion product of five complement proteins: C5b, C6, C7, C8, and C9. The complex causes complement-dependent cell membrane damage. It is assembled following complement activation both on the target cell surface and in the fluid phase. The isolated soluble complex, which has a molecular weight of one million, exhibited reduced expression of the antigenic determinants of the native precursor proteins. Antisera produced to the intact complex contained antibodies to neoantigens which were not detectable on the five precursor proteins. Antisera were rendered neoantigen-specific by adsorption with fresh human serum. Since the adsorbed antisera precipitated the complex, the complex must contain multiple neoantigenic sites. The complex-specific antibodies not only reacted with the soluble complex, but also with the target cell-bound membrane attack complex.

Antigens↗
PubMed1989

Cloning, analysis, and expression of murine perforin 1 cDNA, a component of cytolytic T-cell granules with homology to complement component C9.

The nucleotide sequence coding for the cytotoxic T-lymphocyte (CTL) protein perforin 1 (P1) has been determined and the corresponding protein sequence has been derived. Murine CTL cDNA libraries contained in the vector lambda gt11 were screened by using a monospecific antiserum to purified P1. Three recombinant phages were isolated and their cDNA inserts were sequenced. The derived protein sequence contains 554 amino acids and displays, as expected, considerable homology with certain functional domains in the complement components C9, C8 alpha, C8 beta, and C7. The identity of P1 cDNA clones was verified by prokaryotic expression and the reactivities of antisera produced to the expressed proteins. In addition, antisera were produced to two synthetic peptides located in the center and C-terminal portions of P1. All antisera reacted with purified P1. In Northern blot analyses, P1 cDNA probes recognized a 2.9-kilobase mRNA only in CTL. Perforin mRNA was found in all cloned CTL and in all mixed lymphocyte reactions that gave rise to cytotoxic cells. Perforin mRNA was also detected in virus-specific CTL that had been generated in vivo and isolated from liver tissue of mice infected with lymphocytic choriomeningitis virus. The cell-specific expression of perforin is consistent with its postulated role in cytolysis.

Amino Acid Sequence↗