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PubMed1978

Complement activation during subsequent stages of canine endotoxin shock.

Changes in total haemolytic complement and levels of C3, C4 and C6 were studied during subsequent stages of lethal endotoxin shock in dogs. Substantial decreases of all parameters were observed. C4 and C6 decreases showed a very similar pattern, indicating activation of complement by the classical pathway in addition to the activation of the alternative pathway known to occur in this pathological condition. The findings emphasize the role of the complement system in the pathophysiology of endotoxin shock and are consistent with the concept that complement activation has prognostic value during endotoxaemia.

Animals↗
PubMedDate not supplied

The role of complement in anti-bacterial defence.

The complement system consists of several proteins present in human serum interacting among themselves and with the other compounds of the immune system in the host defence process. In particular, late complement component (C5, C6, C7, and C8) deficiencies (LCCD) are closely associated with Neisseria, mainly meningitidis, infections. The aim of our study was to verify this association in an Italian population by analyzing the complement profile in survivors of meningococcal meningitis. Ten out of the 59 (17%) subjects studied had homozygous LCCD (6 C8, 3 C7 and 1 C6). The meningococcal C strain was the most widely diffused (68%) and had infected all homozygous LCCD subjects. In addition meningococcal serogroup C seemed to be the least immunogenic when compared to serogroups A and B. These data confirm the close association between homozygous LCCD and meningococcal infections from common serogroups (A, B and C) in the Italian population. Anti-meningococcal vaccination is usually recommended for LCCD subjects because it increases, both quantitatively and qualitatively, the antibody component of anti-meningococcal immune defence. We therefore analyzed the levels of anti-polysaccharide (PS) A and PSC antibodies in the members of 4 families including normal subjects and subjects with homozygous and heterozygous C7, C8 or factor H defects, before and after vaccination with only PSA+C. Surprisingly, we found the highest levels of antibodies before vaccination in homozygous subjects, followed by heterozygous and normal controls, whereas, after vaccination, homozygous subjects showed the lowest increase of specific antibodies, indicating their relative incapacity to respond to meningococcal PS alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Inhibition of neutrophil adhesion and the membrane attack complex of complement synergistically prolongs cardiac xenograft survival.

BACKGROUND: Hyperacute xenograft rejection is affected by activation of the complement cascade. Split products of early complement components influence the localization, activation, and effector function of platelets, granulocytes, and lymphocytes, whereas the formation of the membrane attack complex (C5b-9) leads to direct cellular injury. In a unique strain of PVG rats deficient in the C6 component of complement, the terminal membrane attack complex is not formed. However, production of the chemotactic and vasoactive components C3a and C5a proceeds normally. Guinea pig cardiac xenografts in these C6-deficient rats have prolonged survival, and at the time of rejection the inflammatory infiltrate is composed primarily of neutrophils. NPC 15669, a member of a class of antiinflammatory agents called leumedins, is known to inhibit neutrophil adhesion. The purpose of this study was to determine whether inhibition of neutrophil recruitment in animals incapable of membrane attack complex formation would prolong cardiac xenograft survival. METHODS: Cardiac xenografts from male Hartley guinea pigs were heterotopically grafted into PVG (C-) and PVG (C+) male rats. Experimental animals received 20 mg/kg of NPC 15669 i.v. before cross-clamp release and 10 mg/kg of NPC 15669 intravenously on postoperative day 1. Control animals received intravenous saline solution only. RESULTS: Complement sufficient PVG (C+) rats rejected cardiac xenografts hyperacutely despite mode of treatment: PVG (C+) rats which received saline solution (n = 5) rejected their xenografts at 10.8 +/- 2.6 minutes, and those receiving NPC 15669 (n = 5) rejected at 13.9 +/- 5.3 minutes. Histologic examination showed edema, platelet aggregation, and hemorrhage but no cellular inflammatory infiltrate. As expected, complement-deficient PVG (C-) rats had markedly longer xenograft survival in the saline solution-treated group (n = 5) with graft function being sustained 14.7 +/- 6.1 hours. NPC 15669 treatment (n = 4) further prolonged graft function to 61.0 +/- 4.7 hours. In addition to edema, platelet aggregation, and hemorrhage, histologic analysis of these grafts at the time of rejection was characterized by an infiltration of neutrophils. CONCLUSIONS: We conclude that neutrophils play a critical role in cardiac xenograft rejection when complement activation is restricted. Combined inhibition of complement and neutrophil adhesion prolongs xenograft survival longer than inhibition of either component alone.

Animals↗
PubMed2002

Attenuation of experimental allergic encephalomyelitis in complement component 6-deficient rats is associated with reduced complement C9 deposition, P-selectin expression, and cellular infiltrate in spinal cords.

The role of Ab deposition and complement activation, especially the membrane attack complex (MAC), in the mediation of injury in experimental allergic encephalomyelitis (EAE) is not resolved. The course of active EAE in normal PVG rats was compared with that in PVG rats deficient in the C6 component of complement (PVG/C6(-)) that are unable to form MAC. Following immunization with myelin basic protein, PVG/C6(-) rats developed significantly milder EAE than PVG/C rats. The anti-myelin basic protein response was similar in both strains, as was deposition of C3 in spinal cord. C9 was detected in PVG/C rats but not in PVG/C6(-), consistent with their lack of C6 and inability to form MAC. In PVG/C6(-) rats, the T cell and macrophage infiltrate in the spinal cord was also significantly less than in normal PVG/C rats. There was also reduced expression of P-selectin on endothelial cells, which may have contributed to the reduced cellular infiltrate by limiting migration from the circulation. Assay of cytokine mRNA by RT-PCR in the spinal cords showed no differences in the profile of Th1 or Th2 cytokines between PVG/C and PVG/C6(-) rats. PVG/C rats also had a greater increase in peripheral blood white blood cell, neutrophil, and basophil counts than was observed in the PVG/C6(-). These findings suggest that the MAC may have a role in the pathogenesis of EAE, not only by Ig-activated MAC injury but also via induction of P-selectin on vascular endothelium to promote infiltration of T cells and macrophages into the spinal cord.

Animals↗
PubMed1979

Development and genetic differences of complement activity in rabbits.

The ontogeny of haemolytic complement in rabbit serum and the genetic differences of the activity in five strains of adult rabbits were investigated by single radial haemolysis in gel and a microtiter method with purified complement components and the appropriate haemolytic intermediate cells. The haemolytic complement activity was found as early as the 15th day of foetal life, and increased with age reaching approximately adult level by the 120th day of life. Marked strain differences in both total haemolytic activity and C3 levels of adult rabbit sera were observed. The repeatability of haemolytic activity for an individual serum taken at different times was higher than that for C3 level was observed. An inherited complement deficiency, due to the lack of C6, was found in a strain of Angora rabbits. The genetic studies confirmed that this complement defect was transmitted as an autosomal recessive trait.

Aging↗
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↗
PubMed1988

Complement fixation by pemphigus antibody. V. Assembly of the membrane attack complex on cultured human keratinocytes.

Previous studies have shown that pemphigus vulgaris (PV) IgG will fix early complement components (C1q, C4, and C3) to cultured murine epidermal cell surfaces and that PV IgG and complement alter epidermal cell membrane integrity. The present study was undertaken to determine if assembly of terminal complement components (C5, C6, C7, C8, and C9) and expression of C5b-9 neoantigens occur when PV IgG interacts with human keratinocyte (HuK) cell surface antigens in the presence of a source of complement. Monoclonal antibodies specific for C5, C6, C7, C8, C9, and C5b-9 neoantigens were screened for reactivity to the individual complement components in an assembled complex of human C5b-9 on rabbit red blood cell ghosts. Monoclonal antibodies (tissue culture supernatants) that bound to antigenic determinants accessible in the C5b-9 complex were selected for this study using immunofluorescence methods. HuK treated with PV IgG fixed C5, C6, C7, C8, C9, and C5b-9 neoantigens in a characteristic speckled pattern, while normal IgG did not. Heat inactivation or EDTA treatment of the complement source, or substitution of C2-depleted serum abolished C5, C6, C7, C8, C9, and C5b-9 neoantigen staining. PV IgG and complement also resulted in significant cytotoxicity to cell membranes as assessed using an ethidium bromide-fluorescein diacetate assay. These results suggest that PV IgG will activate the membrane attack complex of the complement system on HuK cell surfaces, resulting in cytotoxicity to cell membranes, further implicating complement in the pathogenesis of pemphigus.

Autoantigens↗
PubMed2004

Inhibition of C5 or absence of C6 protects from sepsis mortality.

Inhibiting complement anaphlytoxin C5a during sepsis may prevent sepsis mortality. Although human anti-C5 antibodies exist, their therapeutic use in microbial sepsis has been avoided because of the hypothesis that inhibiting C5b will prevent formation of the bactericidal membrane attack complex (MAC) and worsen clinical outcome. We wished to test the hypothesis that inhibition of C5 would improve outcomes in sepsis. Sepsis was induced in rats by laparotomy and cecal ligation and puncture (CLP) by an IACUC-approved protocol. Sham animals underwent laparotomy without CLP. Following CLP rats were randomized to receive a single IV dose of purified IgG ant-C5 antibody (Ab) or control IgG Ab. Anti-C5 Ab treated rats (n = 20) had significantly lower mortality vs. controls (n = 21), 20% vs. 52% (P = 0.019, log-rank). Analysis of bacterial load by culture of spleen and liver homogenates showed a reduction in colony forming units in anti-C5 Ab treated rats vs. control IgG (P = 0.003 and 0.009, respectively). Anti-C5 treatment reduced lung injury as measured by total MPO content of lung tissue (P = 0.024). Finally, rats genetically deficient in C6 production, unable to form MAC but capable of producing C5a and C5b, were protected from CLP-induced sepsis mortality. Our results show that in anti-C5 antibody therapy prevents CLP sepsis-induced mortality and improves lung injury. Inhibition of the complement MAC does not increase bacterial load or mortality, therefore, the use of anti-C5 therapy may be beneficial rather than detrimental in sepsis.

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↗
PubMed1978

Inherited deficiency of the sixth component of complement: a silent or null gene.

Four families have been studied, some members of which have inherited deficiency of the sixth component of complement. The genetically determined electrophoretic variants of C6 were evaluated in all family members. Seven individuals were found who did not have the variant found in the serum of the parent from whom they inherited the deficiency. It is inferred that the isolated low levels of C6 in these individuals results from the heterozygous state of a normal C6 variant gene and a silent or null C6 gene; the genes determining electrophoretic variants and the low serum levels of C6 are allelic.

Alleles↗
PubMed1980

Hemolytic complement activity in normal human donor corneas.

Normal human donor corneas were minced into small fragments and eluted for 16 to 23 hours at 4 degrees C. The corneal eluates were then studied for hemolytic complement activity of C1, C4, C2, C3, C5, C6, and C7 with 50% hemolysis (CH50) of sensitized sheep RBCs. Sera from ten normal volunteers were also assayed for hemolytic complement activity in CH50 units per milliliter. For each complement component, the mean hemolytic activity in corneas was compared with the mean hemolytic activity in sera. These comparisons suggest that molecular weight may be a factor in determining the concentration of complement components in the cornea. The present study provides normal values of hemolytic complement activity for further studies of complement consumption in corneal diseases.

Adult↗
PubMed1975

Immunochemical analyses of membrane-bound complement. Detection of the terminal complement complex and its similarity to "intrinsic" erythrocyte membrane proteins.

(1) Membranes of sheep erythrocytes lysed with antibody and human or rabbit complement were solubilized in non-ionic detergents (Triton X-100 or Berol EMU-043) and analysed immunochemically using antisera directed against individual complement components. The precipitation behaviour of membrane-bound C3, C5, C6 and C9 components of complement was examined by immuno-double diffusion, rocket- and crossed immunoelectrophoresis performed in agarose gels containing 1% non-ionic detergent. (2) Membrane-bound C5, C6 and C9 are antigenically altered compared with the native (serum) components. (3) Immuno-double diffusion in the presence of non-ionic detergents reveals formation of C5-C6-C9 complexes on the membranes; these complexes are stable in non-ionic detergent. No complex formation was detected in serum between native C5, C6 and C9 components. There was also no evidence for complexing between membrane-bound C3, C4 or membrane proteins and the "late-reacting" complement components. (4) The extractability of complement components by various manipulations has been studied by use of quantitative rocket immunoelectrophoresis. Up to 65% of membrane-bound C3 is readily extracted by dialysis of membranes against 1mM EDTA, pH 8.0, 100 mM EDTA, pH 8.0, 1.2 NaCl plus or minus EDTA, by extraction in isotonic buffers at 37 degrees C, by heating at 45 degrees C over several hours, or by treating membranes with 1 mM p-chloromercuribenzoate sulfonate. In contrast, less than 6% of the terminal complement complex can be eluted by any of the described methods or combination of methods. (5) Our data suggest that the terminal complement complex associates with membrane "core" components through apolar interactions.

Animals↗
PubMed1984

Immunological studies of human placentae: complement components in pre-eclamptic chorionic villi.

Forty human placentae were studied by immunofluorescence for the presence of complement (C) components C1q, C4, C3d, C6 and C9 with the use of characterized antisera. The tissues were grouped as control placentae from 20 normal pregnancies and 20 from cases of pre-eclampsia (PE): the PE samples were sub-grouped as being obtained from patients with mild or severe PE. All of the C components studied were found in the same distribution for test and control samples, but statistical analysis of each pattern of distribution revealed that the deposition of C1q, C3d and C9 were increased in PE as compared to normal tissues. This impression was strengthened by the finding that the deposition of these C components was further increased when chorionic villus immunopathology was compared between mild and severe PE. These data indicate that immunological mechanisms are operating in PE chorionic villi, and they suggest that, among other mechanisms, immune processes may be operative in the pathophysiology of this clinical disease, and that more studies along these lines are in order to rule either in or out this possibility.

Adolescent↗
PubMed1985

Quantification of the terminal complement complex in human plasma by an enzyme-linked immunosorbent assay based on monoclonal antibodies against a neoantigen of the complex.

The fluid-phase terminal complement complex (TCC), consisting of the components C5b, C6, C7, C8, C9, and the S-protein, has recently been detected in normal human plasma by using antibodies against native terminal complement components. Increased amounts of TCC were then found in several patients with in vivo activation of complement. We now describe a sensitive, specific, and reliable enzyme-linked immunosorbent assay for quantification of the TCC, based on monoclonal antibodies against a neoantigen of the complex. The results indicate that the TCC is present in normal human plasma and in increased amounts in patients with complement activation in vivo, thus confirming previously obtained results. The assay is easy to perform and can be used for examination of large numbers of plasma samples.

Antibodies, Monoclonal↗
PubMed2006

Binding of the lipocalin C8gamma to human complement protein C8alpha is mediated by loops located at the entrance to the C8gamma ligand binding site.

Human C8 is one of five complement components (C5b, C6, C7, C8 and C9) that interact to form the membrane attack complex (MAC). C8 is composed of a disulfide-linked C8alpha-gamma heterodimer and a noncovalently associated C8beta chain. C8alpha and C8beta are homologous to C6, C7 and C9, whereas C8gamma is the only lipocalin in the complement system. Lipocalins have a core beta-barrel structure forming a calyx with a binding site for a small molecule. In C8gamma, the calyx opening is surrounded by four loops that connect beta-strands. Loop 1 is the largest and contains Cys40 that links to Cys164 in C8alpha. To determine if these loops mediate binding of C8alpha prior to interchain disulfide bond formation in C8alpha-gamma, the loops were substituted separately and in combination for the corresponding loops in siderocalin (NGAL, Lcn2), a lipocalin that is structurally similar to C8gamma. The siderocalin-C8gamma chimeric constructs were expressed in E. coli, purified, and assayed for their ability to bind C8alpha. Results indicate at least three of the four loops surrounding the entrance to the C8gamma calyx are involved in binding C8alpha. Binding near the calyx entrance suggests C8alpha may restrict and possibly regulate access to the C8gamma ligand binding site.

Amino Acid Sequence↗
PubMed1983

Multiple sclerosis: immunogenetic analyses of sib-pair double case families. II. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6, and GLO polymorphisms.

The complement component polymorphisms of C2, C4, BF, C3, C6, and the enzyme polymorphism GLO were studied in 13 sib-pair double case families with multiple sclerosis. A significant association was seen between MS patients and the C4 haplotype A4,B2 as compared with their healthy siblings. This finding seems to parallel reports on C2 hypocomplementemia in MS patients since C4 A4,B2 in normal individuals was also seen to be in linkage disequilibrium with the C2 deficiency allele (C2QO) by other investigators.

Complement C2↗