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PubMed1987

Hereditary complement deficiency in survivors of meningococcal disease: high prevalence of C7/C8 deficiency in Sephardic (Moroccan) Jews.

The prevalence of complement deficiency was studied among 111 survivors of sporadic meningococcal disease located through the medical records of 10 Israeli hospitals. There were 11 patients with CH50 = 0: one with systemic lupus erythematosus and 10 with hereditary terminal complement deficiency (four with homozygous C7 and six with C8 deficiency). There was no hereditary complement deficiency among 39 Ashkenazi subjects as against 18 per cent among 38 Sephardi subjects and 40 per cent among 15 of Moroccan ancestry (p less than 0.05). The age at first presentation of meningococcal disease in complement deficient patients was 14.7 +/- 7.6, years compared with 8.1 +/- 10.9 in the non-deficient patients (p less than 0.025). None of the complement deficient patients had meningitis below the age of 5 years vs. 49 per cent of non-deficient subjects. Recurrent meningitis was observed in 40 vs. 4 per cent (p less than 0.01) and meningitis in siblings in 40 vs. 2 per cent respectively (p less than 0.001). In addition to the 10 propositi, 11 non-propositus siblings were identified with severe complement deficiency (six with homozygous C7 and five with C8 deficiency). Seven of the non-propositi had no history at all of meningitis or any other serious systemic disease, underlining the relatively favourable prognosis of terminal complement deficiency. With increasing familiarity with the clinical features of this hereditary disease, it is possible now to identify on clinical grounds patients with meningococcal disease with a high likelihood of terminal complement deficiency.

Adolescent↗
PubMed1993

Genetic diversity of mitomycin C-hypersensitive Chinese hamster cell mutants: a new complementation group with chromosomal instability.

A Chinese hamster cell mutant (V-C8) isolated previously, which is approximately 100 fold more sensitive to mitomycin C (MMC) than its parental wild-type V79 cells (judged by D10 values), was further characterized. V-C8 cells exhibit an increased sensitivity towards other cross-linking agents, such as cis-DDP (approximately 40-fold), DEB (approximately 30-fold), and also to adriamycin (approximately 5-fold), and the monofunctional alkylating agents: MMS (approximately 5-fold) and EMS (approximately 6-fold). V-C8 cells show a higher level induction of chromosomal aberrations by cross-linking agents (MMC, cis-DDP, and DEB) and an increased level of spontaneous chromosomal aberrations in comparison to the wild-type V79 cells. To determine whether the V-C8 mutant represents a new complementation group among Chinese hamster cell mutants that also display the extreme sensitivity to MMC, V-C8 cells were fused with irs1, irs1SF, UV20, UV41, and V-H4 cells. In all cases, the derived hybrids regained the MMC sensitivity similar to wild-type cells, indicating that the V-C8 mutant belongs to a new sixth complementation group.

Animals↗
PubMed1991

Complement pore genesis observed in erythrocyte membranes by fluorescence microscopic single-channel recording.

The formation and opening of single complement pores could be directly observed in erythrocyte ghosts by confocal laser-scanning microscopy employing the recently introduced method of fluorescence microscopic single-channel recording. Resealed sheep erythrocyte ghosts were incubated with human complement. By limiting the concentration of C8, the eighth component of complement, the fraction of cells rendered permeable for the small polar fluorescent probe Lucifer Yellow was varied between 0.50 and 0.90. Under each condition the flux rate, k, of Lucifer Yellow was determined for a substantial number of ghosts. By analysing the sample population distribution of k the flux rate k1 of ghosts with a single pore was found to be (4.8 +/- 1.1) x 10(-3) s-1 consistent with a pore radius of about 3.5 nm (35 A). The genesis of single complement pores was studied by continuous influx measurements while triggering pore formation by a temperature shift. Pore genesis was found to be a very slow process, proceeding on a time scale of several minutes. During pore genesis the influx curves had a sigmoid shape, which excluded the possibility that the pore was preformed on the membrane surface and subsequently inserted. However, the influx curves could be well simulated by a model which assumed that pores grow stepwise by sequential incorporation of C9 monomers. The model predicts conditions under which the incorporation of single monomers can be directly revealed.

Animals↗
PubMed1992

Complement deficiency and antibody profile in survivors of meningococcal meningitis due to common serogroups in Italy.

A collaborative survey was carried out in Italy on a group of 59 subjects with a past history of meningococcal meningitis. The aim was to evaluate the prevalence of complement deficiencies, the serogroup of meningococci responsible for the disease and other possible immune abnormalities associated with the infection. Complement analysis allowed the detection of 10 cases (17%) with deficiencies of the terminal components, and in particular six cases of C8 beta, three of C7 and one of C6 defect. Half of the subjects with complement deficiencies had recurrences of meningitis and developed the infection at an older age in comparison with the control group with normal complement activity. The meningococcal C strain was the most diffuse (68%) and infected all the complement-deficient subjects. Evaluation of the antibody response to meningococcal capsular polysaccharides (PS) showed that only 42.5% of the individuals with group C had antibodies as opposed to 83% and 100% of the patients with meningitis due to group A and B, respectively. In all 59 subjects serum Ig as well as IgG subclasses were present, at normal levels for the age. Vaccination of seven out of the 24 subjects without detectable anti-meningococcal PS antibodies with the sole PS A+C induced a normal response in six of them, including a subject with complement defect. In the subject who did not respond to the antigen, the antibodies against the ubiquitous pneumococcal PS type 14 were also lacking, whereas anti-tetanus toxoid (TT) antibodies were normally present. From these data we may conclude the following: (1) the high prevalence (17%) of late complement components defect among survivors of meningococcal meningitis is also confirmed in the Italian population; (2) the serogroup C, responsible for the infections in all the cases with late complement components defect, is highly recirculating in Italy and apparently less immunogenic; (3) specific vaccination with meningococcal PS is a valid prophylaxis in subjects with lack of specific antibodies as well as in subjects with complement defect.

Adolescent↗
PubMed1995

Role of complement in renal tubular damage.

Deposition of immunoglobulins, complement proteins C1q, C3c, C3d, C4, C5, C6, C7, C8, C9, and terminal complement complex neoantigens in the renal tubulointerstitium was studied in serial sections by immunofluorescence microscopy. Renal tissue from 45 cases with various glomerular diseases, including 8 controls, was studied. The patients were divided into groups; one with tubulointerstitial lesions (24 cases) and the other without (13 cases). The immunoproteins were deposited mainly in the tubular basement membrane and blood vessels. Compared with controls there was a significantly increased staining score for C5 to C9 in the tubular basement membrane in both disease groups. However, the increase in terminal complement complex neoantigens score was significant only in the disease group with tubulo interstitial lesions. The changes in C3d score were not significant. Serial sections showed consistent and heavy ribbon-like deposits of complement proteins C3d, C5 to C9, and terminal complement complex neoantigens in corresponding locations of the segments of tubular basement membrane, mainly in the disease group with tubulointerstitial lesions and especially in the damaged tubules. These findings suggest that in situ activation of the complement cascade leads to the deposition of terminal complement complex neoantigens. Complement activation in the basal area of the tubules may, therefore, be an important pathogenetic mechanism in tubulointerstitial damage.

Basement Membrane↗
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↗
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↗