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PubMed1996

Altered expression of host-encoded complement regulators on human cytomegalovirus-infected cells.

Human cytomegalovirus (HCMV)-infected cells persist in the presence of anti-HCMV antibody, suggesting that HCMV has evolved mechanisms to evade host immune defenses. Insofar as no virus-encoded complement inhibitors have been identified for HCMV, we hypothesized that HCMV infection may alter the expression of host-encoded cell surface complement inhibitors. Herein, we report that cell surface expression of two complement regulator proteins, CD55 and CD46, which are members of the regulators of complement activation (RCA) gene cluster, increased up to eightfold following infection of fibroblasts or glioblastoma cells with HCMV, but not after infection with HSV-1 or adenovirus. However, the cell surface expression of a third complement regulator, CD59, which is not a member of the RCA gene cluster, was not altered during HCMV infection. Functional studies using purified complement components demonstrated that up-regulation of CD55 suppressed the activity of cell-associated C3 convertases on HCMV-infected cells. Furthermore, increased CD55 expression protected infected cells from complement-mediated lysis, an effect which directly correlated with the length of HCMV infection. Increased expression of host-encoded complement regulator proteins may provide protection of HCMV-infected cells from the host immune response in vivo, through increasing the resistance of infected cells to complement-mediated lysis and decreasing the deposition of C3-derived products on the cell surface.

Antigens, CD↗
PubMed1998

Genetic complementation among three panels of mouse hepatitis virus gene 1 mutants.

Temperature-sensitive (ts) mutant viruses have been useful for the study of replication processes in many viral systems. To determine how our panel of MHV-JHM-derived RNA- ts mutants (Robb et al., 1979) is genetically related to other panels of MHV RNA- ts mutants, we tested our mutants for complementation with representatives from two different sets of MHV-A59 ts mutants (Koolen et al., 1983; Schaad et al., 1990). These three ts mutant panels together comprise eight genetically distinct complementation groups. Considerable genetic similarity was observed among the three mutant panels. Only three complementation classes are unique to their particular mutant panel, and genetically equivalent mutants were not observed within the other two mutant panels. There are two overlapping complementation groups between the mutant sets derived from MHV-A59 and four overlapping complementation classes between the MHV-JHM panel and the MHV-A59 panels. Two complementation groups had representative mutants in all three mutant panels. One of these latter complementation classes demonstrated nonreciprocal complementation patterns consistent with intragenic complementation.

Animals↗
PubMed1979

Analysis of complement receptors on B-lymphocytes in human milk.

Experiments were performed on human B-lymphocytes in paired samples of milk and blood from the same patient to determine the numbers and percentages of lymphocytes with complement receptors, utilizing the erythrocyte-antibody-complement (EAC) rosette assay. Studies on nine paired samples show the numbers, as well as the percentages, of complement-reactive cells (CRCs) in milk are significantly lower than in blood. Milk lymphocytes were cultured in media containing serum for a 24 hour period to determine if the observed lower numbers of CRCs in milk were due to saturation of the lymphocyte receptors with free complement, as well as to determine if the culture of the cells in nutrient media might result in the reformation of shed complement receptors. Similarly, peripheral blood lymphocytes were incubated in milk supernatant to determine if free complement or other factors in milk might interfere with the EAC assay. These studies support previous findings from this laboratory that B-lymphocytes in milk represent a subpopulation of cells different from those in peripheral blood. The paucity of B-lymphocytes bearing complement receptors in milk may be due to the following: (1) B-lymphocytes in milk may be plasmablasts and/or antibody-producing plasma cells--both known to lack complement receptors; (2) selective processes operating at the mammary alveolar epithelium allowing transit of certain subclasses of maternal immunoglobulins may also allow transepithelial passage of B-lymphocytes with surface immunoglobulins, but no complement receptors. These possibilities are currently being studied.

Antibodies↗
PubMed1984

In vivo and in vitro effects of sodium azide on mouse complement.

A microtiter hemolytic assay was utilized to determine sodium azide (NaN3) modulation of B6C3F1 and C3H mouse serum complement levels in vivo and in vitro. Functional complement was expressed in CH50 units per milliliter. Experiments were performed to determine the in vitro effect of NaN3 on complement mediated lysis of IgM sensitized rabbit erythrocytes. Concentrations of 5, 10, 20, 30, 40, 60, and 80 mM NaN3 were added to microtiter wells containing Tris buffer, IgM sensitized rabbit erythrocytes, and serum complement from naive female C3H mice. Although NaCl and KCl controls had an inhibitory effect, NaN3 demonstrated a significant dose-dependent inhibition of complement-mediated lysis. In the three in vivo experiments, female B6C3F1 mice were exposed to NaN3 and physiological saline (vehicle control). Complement hemolytic ability was evaluated after a 1-day, single iv injection of 0.2, 2.0, and 20.0 mg/kg NaN3; at Days 1, 2, 3, 4, and 6 of a 6-day time course study after ip administration of 20 mg/kg NaN3; and at the end of an 11-day study involving daily injections of 10, 15, and 20 mg/kg NaN3 given ip. No significant changes in complement-mediated hemolysis were observed in the in vivo experiments. These studies indicate that NaN3 does not affect mouse complement levels in vivo. However, NaN3 suppresses in vitro complement hemolytic ability.

Animals↗
PubMedDate not supplied

The role of complement and activated microglia in the pathogenesis of Alzheimer's disease.

A variety of inflammatory mediators including complement activation products, protease inhibitors, and cytokines are colocalized with beta-amyloid (A beta) deposits in the Alzeimer's disease (AD) brain. Activation products of the early complement components C1, C4, and C3 are always found in neuritic plaques and to a lesser extent in varying numbers of diffuse plaques. In contrast to these findings, no immunohistochemical evidence was obtained for the presence of the late complement components C7 and C9 and the complement membrane attack complex in the neuropathological lesions in AD brains. The mRNA encoding the late complement components C7 and C9 appears to be hardly or not detectable. These findings indicate that in AD the complement system does not act as an inflammatory mediator through membrane attack complex formation, but through the actions of the early complement products. In this review we focus on the role of complement in the pathological amyloid cascade in AD. In our opinion, the early complement activation products play a crucial role as mediators between the A beta deposits and the inflammatory responses leading to neurotoxicity.

Alzheimer Disease↗
PubMed2006

Complement expression in common carp (Cyprinus carpio L.) during infection with Ichthyophthirius multifiliis.

A real-time PCR assay for determination of the complement response to infection with the ectoparasite Ichthyophthirius multifiliis in carp is presented. Specific primers were designed for selected genes representing the three pathways of the carp complement system. The investigated complement molecules were C1r/s, C3, C4, C5, factor I, factor B/C2-A (Bf/C2-A), mannose-binding lectin (MBL) and MBL-associated serine protease (MASP). The expression of the selected genes was analyzed on RNA extracts from skin, liver, and whole blood from carp at 3, 12, 24, 36, and 48 h post-infection (pi) with I. multifiliis. A pronounced up-regulation of Bf/C2-A, in skin, blood, and liver (250-, 60-, and 4-fold respectively), was observed at later sampling points pi (24-48 h). In addition, an intermediate (from 5 to 13-fold) down-regulation of MASP was observed in skin and liver samples at 36 and 48 h pi with respect to control fish. MBL was expressed only in liver and no variation in the transcription level of this lectin was observed. Complement factor C3 was significantly up-regulated in liver (4-fold up-regulation, 24 h pi). The presented results indicate that infection with the parasite I. multifiliis in carp to a large extent stimulates the expression of complement molecules. Moreover, the dramatic and early up-regulation of Bf/C2-A in skin indicates a role of this molecule as an acute-phase reactant. Furthermore, our study confirms the role of fish skin as an important extra-hepatic site of expression of complement molecules as well as an active regulator of complement expression. Expression of some of the components of the complement system in blood suggests that leukocytes in carp act as an important extra-hepatic source of complement molecules.

Animals↗
PubMed2006

Complement depletion enhances pulmonary inflammatory response after liver injury.

Hepatic cryoablation can produce acute lung injury, with activation of nuclear factor (NF)-kappaB in the remnant liver and lungs, production of C-X-C chemokines, and neutrophil infiltration of the lungs. Activated complement stimulates NF-kappaB and cytokine secretion from Kupffer cells. The role of complement in the development of acute lung injury after cryoablation was examined using HLL transgenic mice (5'HIV-LTR-Luciferase gene; 5' HIV-LTR is an NF-kappaB-dependent promoter). Total complement depletion was achieved with preoperative administration of cobra venom factor (CVF). After hepatic cryoablation, bioluminescent NF-kappaB activity increased in the nonablated liver remnant by 4 hours in both control (119,093 +/- 22,808 net RLU/mg protein) and CVF-treated mice (117,722 +/- 14,932) from cumulative baseline (657 +/- 90, P < 0.0001). In the lung, complement-depletion induced significantly greater increases in NF-kappaB activation at both early and later times. Likewise, chemokines were higher in complement-depleted mice relative to controls (KC: 493 +/- 43 versus 269 +/- 29 pg/mg protein, P < 0.001; MIP-2: 171 +/- 29 versus 64 +/- 13 pg/mg protein, P < 0.0001). Pulmonary myeloperoxidase activity was equivalent at 24 hours, but complement-depletion caused a significantly more rapid influx of neutrophils. Complement depletion results in increased pulmonary inflammation following liver cryo injury via relative upregulation of NF-kappaB activity. Activated complement is not the initiator of the systemic inflammatory response; in fact, downstream components of the complement cascade may diminish subsequent inflammation.

Analysis of Variance↗
PubMed1999

Identification of a novel complement-dependent serum-elicited inward current in the Xenopus oocyte provoking Ca2+ influx and subsequent activation of Cl- channels.

The membrane spanning complement channel is assumed to be a nonselective ion 'pore', although little evidence is available to support this hypothesis. In this paper we provide evidence that Ca2+ entry and Cl- exit occur rapidly after complement activation and precede the development of a long-lasting complement-dependent inward current. Addition of rabbit serum (a source of heterologous complement) and mouse anti-human insulin receptor antibody to a single Xenopus oocyte expressing human insulin receptor was shown to stimulate an initial hyperpolarising current followed by a sustained depolarising current. On voltage clamping the oocyte, a novel long-lasting inward current generated by serum addition was detected. Complement classical pathway-stimulated calcium influx into the oocyte was directly demonstrated using 45Ca influx measurements. In addition, we found that Ca2+ influx was required for the stimulation of the complement alternative pathway-dependent inward current. The novel conductance elicited by the classical pathway was outwardly rectifying, had a reversal potential of -35 +/- 8 mV (or -52 +/- 7 mV in the presence of chloride channel inhibitors), was inhibited by nifedipine, and was observed in the presence but not in the absence of the pore-forming complement component C9. As overactivation of complement does play a role in many inflammatory or autoimmune diseases, inhibition of early complement-mediated ion flux might restrict tissue damage and aid recovery from such diseases.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1998

Amniotic fluid complement C3 as a marker of intra-amniotic infection.

OBJECTIVE: To determine the value of amniotic fluid (AF) complement C3 as a marker of intra-amniotic infection and to compare complement C3 with other rapid markers of intra-amniotic infection. METHODS: One hundred four women with singleton gestations, in preterm labor with intact membranes, at 23-35 weeks' gestation underwent transabdominal amniocentesis. Amniotic fluid was analyzed for white blood cell (WBC) count, lactate dehydrogenase (LDH), glucose, Gram stain, and complement C3. Cultures for aerobes, anaerobes, and mycoplasma species also were performed. The median values of complement C3, WBC, LDH, and glucose were compared between the culture-positive and -negative groups. Complement C3 was compared with WBC count, LDH, glucose, and Gram stain for sensitivity, specificity, positive and negative predictive values, and accuracy in the prediction of a positive AF culture. Descriptive statistics, receiver operating characteristic curve, Fisher exact test, and Wilcoxon rank-sum test were used for analysis. RESULTS: The prevalence of positive cultures was 11.5% (12 of 104). The culture-positive group had a significantly higher median C3 (7.0 mg/dL) than the median C3 (3.0 mg/dL) of the culture-negative group (P < .001). Also, the median values of WBC (1120.5 cells/mm3) and LDH (2697 U/L) were significantly higher and the median glucose (6.5 mg/dL) was significantly lower among women with positive AF cultures than among women with negative AF cultures (WBC=1 cell/mm3; LDH=165 U/L; glucose=45 mg/dL; P < .001). Eleven of the 12 culture-positive cases had a C3 of 5 mg/dL or more, whereas four of the 92 culture-negative cases had a C3 of 5 mg/dL (P < .001). Nine of the 12 culture-positive cases but none of the 92 culture-negative cases had a C3 of 6 mg/dL or more (P < .001). The relative risks of a positive AF culture were 65.27 (95% confidence interval [CI] 9.08, 469.27) and 31.67 (95% CI 10.40, 96.43) times greater among women with AF complement C3 levels of 5 and 6 mg/dL or more, respectively. Depending on the cutoff point used, complement C3 had similar or higher sensitivity, specificity, positive predictive value, and negative predictive value for intra-amniotic infection when compared with WBC count, LDH, glucose and Gram stain. CONCLUSION: Amniotic fluid complement C3 has value in the diagnosis of intra-amniotic infection in preterm labor with intact membranes. Complement C3 is available readily and compares favorably with other rapid markers of AF infection. This study supports the general concept of fetal inflammatory response to microbial invasion of AF.

Adult↗
PubMedDate not supplied

Phylogenetic aspects of the complement system.

During evolution two general systems of immunity have emerged: innate or, natural immunity and adaptive (acquired), or specific immunity. The innate system is phylogenetically older and is found in some form in all multicellular organisms, whereas the adaptive system appeared about 450 million years ago and is found in all vertebrates except jawless fish. The complement system in higher vertebrates plays an important role as an effector of both the innate and the acquired immune response, and also participates in various immunoregulatory processes. In lower vertebrates complement is activated by the alternative and lectin pathways and is primarily involved in the opsonization of foreign material. The Agnatha (the most primitive vertebrate species) possess the alternative and lectin pathways while cartilaginous fish are the first species in which the classical pathway appears following the emergence of immunoglobulins. The rest of the poikilothermic species, ranging from teleosts to reptilians, appear to contain a well-developed complement system resembling that of the homeothermic vertebrates. It seems that most of the complement components have appeared after the duplication of primordial genes encoding C3/C4/C5, fB/C2, C1s/C1r/MASP-1/MASP-2, and C6/C7/C8/C9 molecules, in a process that led to the formation of distinct activation pathways. However, unlike homeotherms, several species of poikilotherms (e.g. trout) have recently been shown to possess multiple forms of complement components (C3, factor B) that are structurally and functionally more diverse than those of higher vertebrates. We hypothesize that this remarkable diversity has allowed these animals to expand their innate capacity for immune recognition and response. Recent studies have also indicated the possible presence of complement receptors in protochordates and lower vertebrates. In conclusion, there is considerable evidence suggesting that the complement system is present in the entire lineage of deuterostomes, and regulatory complement components have been identified in all species beyond the protochordates, indicating that the mechanisms of complement activation and regulation have developed in parallel.

Animals↗
PubMedDate not supplied

Anti-thymocyte globulin treatment of a patient for paroxysmal nocturnal haemoglobinuria-aplastic anaemia syndrome: complement activation and transient decrease of the PNH clone.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal stem cell disorder resulting in insufficient and defective haematopoesis associated frequently with aplastic anaemia (AA). A deficiency of the glycosyl phosphatidylinositol (GPI)-anchored complement activation regulatory proteins CD55 and CD59 is responsible for an increased sensitivity of erythrocytes to complement attack leading to chronic intravascular haemolysis with haemoglobinuria. In this study we investigated the effects of complement activation caused by anti-thymocyte globulin (ATG) treatment on the PNH clone in a patient affected with the PNH/AA-syndrome. Fluid phase complement components C3, C4, C6 and terminal complement complex (TCC) were assayed by ELISA. CD55, CD59 and cell-associated TCC were monitored by flow cytometry. ATG treatment resulted in profound systemic complement activation which led to a decrease in the levels of native C3 and C4 to 65% and 40%, respectively, of the original levels on day 5 and of C6 and TCC to 61% and 23%, respectively, on day 10. A return to pre-treatment levels was observed for C3 by day 15, for C6 by day 30 and for C4 by day 90. Flow cytometry revealed that the deficiency in the GPI-anchored protein was restricted to granulocytes, while lymphocytes remained unaffected. Cell-bound TCC increased by 1.67-fold and 2.37-fold on day 5 and day 10, respectively, decreasing to 1.40-fold and 1.30-fold on day 15 and day 30, respectively. The percentage of PNH granulocytes as identified by the absence of the CD55- and CD59-antigens exhibited a temporary decrease from 72% on day 0 to 65% on day 5 and 59% on day 10 and returned thereafter to the original percentage of 70% by day 15 and exceeding this level to 76% on day 30 and 79% on day 90. We report profound activation of the classical pathway of the complement cascade and the terminal complement complex by the globulin leading to a transient decrease of the PNH clone, presumably due to subsequent lysis of the PNH cells devoid of complement regulatory proteins.

Anemia, Aplastic↗
PubMed2002

Experimental non-transmissible marker vaccines for classical swine fever (CSF) by trans-complementation of E(rns) or E2 of CSFV.

Three mutants with deletions in the E2 gene of the infectious DNA copy of the classical swine fever virus (CSFV) strain-C were constructed: one missing the B/C domain of CSFV-E2 between amino acids (aa) 693 and 746, one missing the A domain between aa 800 and 864, and one missing the complete E2 between aa 689 and 1062. All three CSFV-E2 deletion mutants were unable to generate viable virus, indicating that each of the antigenic domains of E2 is essential for viability of CSFV. To rescue the CSFV-E2 deletion mutants SK6 cell lines constitutively expressing glycoprotein E2 of CSFV were generated. The rescued viruses infected and replicated in SK6 cells as demonstrated by expression of viral proteins, but this primary infection did not result in reproduction of infectious virus. Thus, these E2 complemented viruses are considered non-transmissible. In previous experiments, we showed that simultaneous injection of E(rns) complemented virus (Flc23) via intradermal (ID), intramuscular (IM) or intranasal (IN) routes conferred protection to pigs against a lethal challenge with CSFV [J. Virol. 74 (2000) 2973]. Here, we evaluate different routes of application (ID, IM or IN) with E(rns) complemented virus Flc23 in order to find the best route for complemented CSFVs. Intradermal injection with Flc23 protected pigs against a lethal CSFV challenge, whereas intramuscular injection induced partial protection, and intranasal injection did not mediate a protective immune response in pigs at all. We used the intradermal route of vaccination to test the E2 complemented viruses. Vaccination of pigs via the intradermal route with the E2 complemented CSFVs also resulted in the induction of antibodies and in (partial) protection against CSFV challenge. Pigs vaccinated with E2 complemented virus Flc4 (deletion B/C domain) survived a lethal CSFV challenge, whereas partial protection was induced in pigs vaccinated with Flc47 (deletion E2) or Flc48 (deletion A domain) E2 complemented viruses. Serological data demonstrate that these E2 complemented mutant viruses are, in combination with well known diagnostic tests based on E2, potential marker vaccines for CSF.

Animals↗
PubMed1998

Intragenic complementation at the argininosuccinate lyase locus: reconstruction of the active site.

Intragenic complementation has been observed at the argininosuccinate lyase (ASL) locus and the ASL alleles in the ASL-deficient cell strains of two complementation phenotypes have been identified. The frequent complementers, strains that participate in the majority of the complementation events, were found to be either homozygous or heterozygous for the Q286R allele, while the high-activity complementers, those strains in which complementation is associated with a high restoration of activity, were found to be either homozygous or heterozygous for the D87G allele. Direct proof of the intragenic complementation observed at the ASL locus has been obtained with the co-expression of the D87G and Q286R alleles in COS cells. A significant increase in the ASL activity was observed when the two alleles were co-expressed relative to the expression of each mutant allele alone. The increase in activity was comparable to that observed previously in the fibroblast complementation studies. The structure determinations of ASL and the homologous eye lens protein, duck delta II crystallin, have revealed that the active site of ASL is made up of residues from three different monomers. The structural mapping of the Q286 and D87 residues shows that both are located near the active site but that, in any one active site, each is contributed by a different monomer. The molecular symmetry of the ASL protein is such that when mutant monomers combine randomly, one active site will contain both mutations and at least one active site will contain no mutations at all. It is these 'native' active sites in the hybrid Q286R/D87G proteins that give rise to the partial recovery of enzymatic activity observed during intragenic complementation.

Animals↗
PubMed2003

Characteristics of CD59 up-regulation induced in porcine endothelial cells by alphaGal ligation and its association with protection from complement.

BACKGROUND: Activation of endothelial cells may result in proinflammatory and procoagulant changes, or in changes that protect the endothelial cells (EC) from injurious insults. Stimulation of porcine EC with human anti-porcine antibodies, or lectins from Bandeiraea simplicifolia that bind terminal Galalpha(1-3)Gal (abbreviated alphaGal), can induce EC protection from cytotoxicity by human complement. These EC also exhibit up-regulation of CD59 protein and mRNA expression. Porcine CD59 has been reported to protect porcine cells from human complement. Therefore we investigated the specificity requirements and other characteristics of the induced CD59 up-regulation, as well as the role of up-regulated CD59 in lectin-induced protection of EC from human complement. METHODS: Aortic EC were incubated in vitro with alphaGal-binding lectins B. simplicifolia lectin I isolectin B4 (IB4) and B. simplicifolia lectin I (BS-I) and CD59 expression was assessed by flow cytometry and enzyme linked immunosorbent assay (ELISA). Binding requirement was studied using disaccharides containing either alphagalactosyl or betagalactosyl moieties to inhibit CD59 up-regulation. Protection from complement killing was assessed after incubation of EC with human serum as a source of anti-porcine antibodies and complement. The role of CD59 in lectin-induced protection was studied in the presence of an anti-pig CD59 antibody and after removal of CD59 using phosphatidylinositol (PI)-specific phospholipase C (PI-PLC). RESULTS: We found that induction of CD59 up-regulation required specific binding of the lectin to terminal alphaGal and was not induced either by soluble factors that may be released from EC by stimulation with the lectin or by TNF-alpha, IFN-gamma, or IL-1alpha. Unstimulated or BS-I-treated EC showed little or no expression of decay accelerator factor (DAF). Removal of membrane-associated CD59 (and other proteins that are associated with the membrane through PI linkage) with PI-PLC from EC that had been exposed to lectin restored their complement sensitivity to various degrees, depending on the extent of lectin-induced protection. Cytotoxicity was completely restored in cells that exhibited partial protection induced with lectin at low doses or for a short period of time. However, EC that were fully resistant to complement did not regain sensitivity to complement after removal of CD59. Changes in CD59 expression did not modify the degree of C9 binding. CONCLUSIONS: Induction of CD59 expression required specific binding of the lectin to terminal alphaGal and was not induced by soluble factors that may be released from EC by lectin stimulation. Increased CD59 expression may contribute to this form of protection from complement; however, mechanisms other than CD59 up-regulation appear to be essential for the development of full protection.

Animals↗
PubMed1966

Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. 3. The membrane defects caused by complement lysis.

1. The defects produced on the membrane of the human red blood cell by the action of complement and antibody have been studied by the use of the electron microscope. These are round to slightly ovoid holes and are surrounded by an irregular ring, about 20 A thick. The mean diameter of the holes is about 103 A if human complement is used (regardless of the antibody used for sensitization) and about 88 A if guinea pig complement is used. 2. The holes in normal and PNH red cells appear to be identical, under the same conditions. The membrane defects produced by lysis of PNH cells with acidified normal serum (the Ham's test) are identical to those produced by complement lysis with specific antibody, indicating that complement is undoubtedly the cause of such lysis. 3. Evidence is presented that when human complement acts on human red cells sensitized with anti-I antibody, each complete activation of complement leads to the production of a cluster of holes. This contrasts to the action of guinea pig complement, on sheep cells, each activation of which leads to a single hole. 4. The maximum number of anti-I antibody molecules which can attach to a human red cell (i.e. the minimum number of antigen sites) is about 500,000 for both normal and PNH cells. 5. The number of holes produced during lysis of the PNH cell is the same as that of the normal cell. When all cells are lysed by am excess of C', a mean of about 90,000 holes are present on each membrane. When complement is limited, a larger proportion of PNH cells are lysed due to their peculiar sensitivity to C' but the number of holes on each lysed cell is the same as for normal cells lysed by the same concentration of C'.

Antibodies↗
PubMed1999

Assessment of complement deficiency in patients with meningococcal disease in The Netherlands.

The frequency of complement deficiency in 176 of 7,732 patients with meningococcal disease in the Netherlands from 1959 through 1992 was assessed. Complement deficiency was found in six patients (3%): 3 (7%) of the patients with Neisseria meningitidis serogroup C disease, 1 (2%) of the patients with N. meningitidis serogroup A disease, and 2 (33%) of the patients with infections due to uncommon serogroups and nongroupable strains of N. meningitidis. Of 91 additional patients with meningococcal infections due to uncommon serogroups, 33% also had complement deficiency. Thirty-four of the 36 complement-deficient patients with meningococcal disease who were from 33 families were 5 years of age or older. Twenty-six additional complement-deficient relatives were found. Screening individuals with meningococcal disease due to uncommon serogroups who were 5 years of age or older identified 30 of the 33 complement-deficient families. Only 27% of the complement-deficient relatives had had meningococcal disease. This risk was lower for relatives with properdin deficiency (18%) than for those deficient in the late component of complement (38%). Therefore, pedigree studies are warranted for identifying those complement-deficient persons who require vaccination for meningococcal disease.

Adolescent↗
PubMed1977

Role of antiserum and complement in the acute antibody-mediated rejection of mouse skin allografts in strain combinations with increasing histoincompatibility.

Acute antibody-mediated rejection (AAR) of mouse skin allografts was studied in nine donor-recipient combinations with increasing histoincompatibility ranging from an H-Y to a complete H-2 plus on-H-2 disparity. AAR was induced by the injection of specific alloantiserum along with a heterologous complement on day 7 after grafting. Sera from rabbits, guinea pigs, and from a human volunteer were used as complement sources. The recipients were treated with antilymphocyte serum on days 0, 2, and 4 to postpone cell-mediated rejection. With increasing histoincompatibility the mean survival time of untreated grafts decreased, the in vitro cytotoxic activity of the alloantiserum rose, and AAR could be induced with lower amounts of antiserum. The higher efficiency of rabbit complement compared with guinea pig complement and human complement, that is known to exist in in vitro cytotoxicity, was also found in vivo. Rabbit complement could induce AAR in combination with relatively weak histoincompatibility (H-2K, H-2D, or non H-2 differences), where guinea pig complement and human complement were ineffective. All three complement species elicited AAR if there was a disparity for H-2D plus non-H2 H-2K plus non H-2, H-2, or H-2 plus non-H2. The rules for immunogenicity of the different histocompatibility loci as they have been described for cell-mediated graft destruction also apply to this humorally mediated rejection process.

Animals↗
PubMed1997

Complement activation as a cause for primary graft failure in an isogeneic rat model of hypothermic lung preservation and transplantation.

Although agents that inhibit complement activation may be beneficial in discordant xenotransplantation, it is not known whether local complement activation occurs and is deleterious after isogeneic lung transplantation. Lungs were harvested from Lewis rats subjected to 4 degrees C 6-hr preservation followed by transplantation into strain-, gender-, and weight-matched recipients. Transplanted lungs demonstrated increased immunostaining for C5b-9 compared with nontransplanted controls, confirming local complement activation in this isograft model. To investigate the physiologic relevance of complement activation in the transplanted lung, the native pulmonary artery was ligated after transplantation, and pulmonary vascular resistance (mmHg/ml/min), arterial oxygenation (mmHg), graft neutrophil infiltration (myeloperoxidase activity, deltaAbs 460 nm/min), and recipient survival were measured at 30 min. Animals received either saline (control; n=22) or soluble complement receptor type-1 (sCR1, 15 mg/kg; n=19) 2 min before reperfusion. Animals treated with sCR1 showed a marked reduction in serum complement hemolytic activity (CH50; 90% lower than that of control animals, P<0.001). Compared with controls, sCR1-treated animals showed reduced pulmonary vascular resistance (2.9+/-1.1 vs. 8.5+/-1.5 mmHg/ml/min, P<0.05), improved arterial oxygenation (194+/-34 vs. 91+/-17 mmHg, P<0.05), decreased neutrophil infiltration (35% decrease, P<0.005), and improved recipient survival (74% vs. 23%, P<0.005). In parallel with the reduction in complement hemolytic activity in sCR1-treated animals, immunohistology of the transplanted lung revealed decreased C5b-9 deposition compared with controls. Taken together, these data indicate that complement activation occurs after lung preservation and transplantation in an isograft model, and that inhibiting complement activation improves outcome after transplantation.

Animals↗