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PubMed2005

Kinetic studies on the interactions of heparin and complement proteins using surface plasmon resonance.

Heparin is a naturally occurring polysaccharide known to interact with complement proteins and regulate multiple steps in the complement cascade. Quantitative information, in the form of affinity constants for heparin-complement interactions, is not generally available and there are no reports of a comprehensive analysis using the same interaction method. Such information should improve our understanding of how exogenously administered pharmaceutical heparin and the related endogenous polysaccharide, heparan sulfate, regulate complement activation. The current study provides the first comprehensively analysis of the binding of various complement proteins to heparin using surface plasmon resonance (SPR). Complement proteins C1, C2, C3, C4, C5, C6, C7, C8, C9, C1INH, factor I, factor H, factor B and factor P all bind heparin but exhibit different binding kinetics and dissociation constants (Kd) ranging from 2 to 320 nM. By taking into account these Kd values and the serum concentrations of these complement proteins, the percentage of each binding to exogenously administered heparin was calculated and found to range from 2% to 41%. This study provides essential information required for the rational design of new therapeutic agents capable of regulating the complement activation.

Complement Activation↗
PubMed1985

Role of terminal complement pathway in the heterologous phase of antiglomerular basement membrane nephritis.

Terminal complement components, including the membrane attack complex, have been demonstrated in glomeruli of patients with immune complex and anti-GBM nephritis. We recently demonstrated the functional significance of C6 in the mediation of experimental membranous nephropathy in rabbits. In the present study, the role of C6 was examined in the heterologous phase of rabbit anti-GBM nephritis by studying normal and C6-deficient (C6D) rabbits. In C6D rabbits, C6 hemolytic activity was less than 0.01% of control. All control rabbits became heavily proteinuric in the first 24 hr following injection of a standard dose of sheep anti-rabbit GBM antibody (mean, 42.0 +/- 26.3; range, 18.4 to 83.5 mg protein/mg creatinine, N = 5). In contrast, C6D rabbits excreted a mean of only 5.1 +/- 5.5 mg/mg creatinine (range, 0.06 to 14.4, N = 6, P = 0.002). Protein excretion in normal rabbits was less than 0.06 mg/mg creatinine. Both control and C6D rabbits had similar deposits of sheep anti-rabbit GBM IgG in glomeruli when measured by radiolabeling techniques (control 15.8 +/- 2.71, N = 5; C6D 18.7 +/- 1.99 micrograms of sheep IgG/10(4) glomeruli, N = 6, P greater than 0.05). Control rabbits had a greater rise in serum creatinine in the first 24 hr (1.74 +/- 1.15 vs. 0.53 +/- 0.44 mg/dl, P less than 0.05). Both groups had similar deposits of sheep IgG and rabbit C3 by IF. By light microscopy at 4 and 24 hr, both groups had qualitatively similar proliferative changes and similar numbers of neutrophils infiltrating glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Preoperative depletion of C3 improves the survival of guinea pig-to-rat cardiac xenograft recipients.

Rat strains with congenitally reduced total hemolytic complement activity do not reject cardiac xenografts hyperacutely. Prolongation of graft survival in the guinea pig-to-C6-deficient PVG rat donor/recipient combination has been observed. However, experience with this model has been complicated by a high postoperative mortality from respiratory distress. The authors hypothesized that placement of the xenograft resulted in local activation of complement, which contributed to remote pulmonary injury leading to respiratory dysfunction. To test this hypothesis, an attempt was made to reduce early complement component activation with the use of an antibody to rat C3 in C6-deficient PVG recipients. Six of eight untreated C6-deficient PVG recipients died in the immediate postoperative period with vigorously beating heart grafts, whereas only 2 of 14 C6-deficient recipients pretreated with anti-rat C3 antibody died within 24 h postoperatively. Although pretreatment with anti-C3 antibody improved survival of recipients, the duration of cardiac xenograft survival was similar whether the recipients were pretreated or not. The use of anti-C3 antibody in C6-deficient rats is a valid approach to studying xenotransplantation in the absence of hyperacute rejection and has an additional advantage in that it does not require the use of expensive reagents such as cobra venom factor.

Animals↗
PubMed2006

Antibody and complement mediated injury in transplants following sensitization by allogeneic blood transfusion.

BACKGROUND: Many patients on the waiting list for transplants are sensitized from previous blood transfusions, pregnancy, or transplants. We investigated the role of complement in acute and chronic pathology in hearts transplanted to sensitized rats. METHODS: Blood was transfused from allogeneic PVG.R8 rats or control isogeneic PVG.1U rats to C6-sufficient and -deficient PVG.1U rats. Three weeks later hearts were transplanted from PVG.R8 donors and low-dose cyclosporin A was initiated. RESULTS: Allogeneic but not isogeneic blood transfusion elicited strong immunoglobulin (Ig) M, IgG1 and IgG2b alloantibody responses. Sensitization caused accelerated acute rejection of cardiac allografts by C6-sufficient recipients (4 days). In contrast, allografts functioned over 40 days in all C6-deficient recipients, but sensitization caused increased interstitial fibrosis and chronic vasculopathy. Circulating alloantibodies were associated with deposits of C4d on the vascular endothelium together with pericapillary accumulation of neutrophils and macrophages in the grafts. In contrast, T cells accumulated in periarterial lymphatics that did not have C4d deposits. CONCLUSIONS: Presensitization by allogeneic blood transfusion causes accelerated acute graft rejection in the presence of the complete complement cascade. In the absence of C6, macrophages colocalized with deposits of C4d and T cells accumulated in the periarterial lymphatics.

Animals↗
PubMed1984

Tissue culture demyelination by normal human serum.

Serum from all of 20 normal individuals induced some degree of demyelination when applied to well-myelinated mouse cerebellum cultures. An intact complement sequence through C5 is required. Demyelinating activity was heat labile at 56 degrees C for 30 minutes but was not destroyed at 50 degrees C for 30 minutes (which inhibits properdin factor B and alternate complement pathway activation, but not the classic complement pathway). Sera from patients with agammaglobulinemia, C4 deficiency, or C6 deficiency all induced demyelination. Our results suggest that tissue culture demyelination results from nonimmunoglobulin activation of the alternate complement pathway and is not limited to sera from patients with neurological disease.

Animals↗
PubMed1974

Glomerular complement components in human glomerulonephritis.

154 of 255 individual human renal biopsies studied by immunofluorescence contained varying combinations of immunoglobulins (Ig), complement (C) components C1q, C3, C4, C5, C6, C8, C3 proactivator (C3PA), and/or properdin. 10 patients had linear deposits of Ig in glomeruli characteristic of antiglomerular basement membrane (GBM) antibodies; nine patients had C3 deposits (minimal in three) with generally lesser amounts of C1q, C4, C5, C6, and/or C8. 118 of the patients had granular deposits of Ig, suggesting immune complex glomerulonephritis; 114 of these had deposits of C3, usually accompanied by C1q, C4, C5, and/or C6. These observations indicate that the entire C sequence is deposited in glomeruli in most Ig-mediated glomerulonephritides. However, certain cases of anti-GBM glomerulonephritis with few or no C deposits may utilize pathways of injury independent of C.21 patients had granular C3 deposits without detectable Ig. C5, C6, and C8 were present in the majority of these patients while C1q was absent and scant C4 was observed in only two patients. The presence of only late-acting C components in the absence of Ig, C1q, and C4 suggests selective, possible nonimmune activation of the alternate C pathway. Finally, five patients had granular deposits of C3, C5, C6, and/or C8 diffusely in all or most glomeruli with a lesser number of glomeruli having additional focal granular deposits of Ig, C1q, and C4. This observation suggests that at least two patterns of C activation can occur simulatenously, possibly triggered by antecedent immune complex deposition and then perpetuated by an as yet undetermined mechanism.

Adult↗
PubMed2000

Genetics of the complement system.

After a brief history of complement genetics, general considerations and applications to our understanding of immune function, evolution, population structure and migration and forensic medicine, selected topics in complement genetics are presented. For individual complement proteins, genetic polymorphisms and deficiency states are described, as are the molecular bases of some of them. The clinical abnormalities exhibited by some patients with complement deficiency states are discussed, as are possible pathophysiologic mechanisms for them. The chromosomal location and the close linkage and a sharing of structural features by groups of complement proteins, such as the complotypes of the major histocompatibility complex, the regulators of complement activation, Clr and Cls, and the terminal components C6, C7 and C9, are presented in some detail. From these facts, the broad outlines are drawn of the evolution of the classical and alternative complement pathways from the lectin pathway and the terminal pathway from a common progenitor. From markers within the complotype region, rough conclusions are delineated regarding the evolution of C2, factor B, C4A and C4B alleles.

Animals↗
PubMed1981

Large scale isolation of functionally active components of the human complement system.

In the present work a scheme is presented for the isolation of multiple components of human complement in a functionally and biochemically pure state and with full hemolytic activity. These preparative procedures allow high recovery of milligram and gram quantities of particular complement components from a large pool (2-11 liters) of fresh EDTA plasma in no more than four chromatographic steps. Many components (C3bINA, C5, C3, C1EI, C4, and C9) are recovered functionally pure or highly purified following the first chromatographic step employing DEAE-Sephacel and may be utilized as reagents with no further purification. Prior to anion exchange, individual units of plasma are treated with inhibitors of complement activation and serum proteases, the pooled plasma is fractionated with polyethylene glycol, depleted of plasminogen on Sepharose-lysine, and rapidly ultrafiltered to low ionic strength and high protein concentration. The high degree of resolution of the components on DEAE-Sephacel subsequently obtained is demonstrated by the functional recovery and purification in a representative experiment as indicated (in their order of elution) for the following proteins: C3bINA (24%, 18-fold), C2 (74%, 12-fold), C7 (87%, 14-fold), factor B (55%, 8.7-fold),, C8 (50%, 16-fold), C6 (82%, 25-fold), beta 1H (39%, 12-fold), C5 (62%, 111-fold), C3 (99%, 64-fold), C1EI (42%, 135-fold), C9 (80%, 297-fold), and c4 (78%, 164-fold). Other components separated by these procedures include C1q and C4 binding protein. Additional steps described, which demonstrate the utility and effectiveness of this preparative scheme, have allowed isolation of C3, C5, and C7 as pure components with full hemolytic activity as judged by functional, immunochemical, and physicochemical criteria. C8, also isolated as a homogeneous protein, was recovered with partial hemolytic activity. All these components were recovered in high yield and in the purification as indicated: C3 (61%, 103-fold), C5 (24% 1350-fold), C7 (19%, 2260-fold), and C8 (32%, 547-fold). Complement components C6, beta 1H, factor B, and C2 in addition to C3bINA, C1EI, C4, and C9 are recovered partially purified with good activity and are amenable to further purification.

Complement C3↗
PubMed1992

Activation of the fifth component of human complement by oxygen-derived free radicals, and by methionine oxidizing agents: a comparison.

The fifth component of human complement, C5, was activated by non-enzymical, chemical treatment in either of two ways: 1) by oxidation with a hydroxyl radical (OH.) generating system consisting of H2O2, FeEDTA, and ascorbate, activation product called C5(H2O2); 2) by oxidation with chloramine T, activation product called C5(Cl-T). Evaluating earlier findings, completed by new results, both products were compared. Both products are C5-like in that they are capable of binding C6 and form the nucleus for the cytotoxic complex C5-9. Both differ from C5b, the natural activation product of C5, as they comprise the whole, uncleaved C5 protein, and do not immediately decay when not bound to C6. In both cases the treatment involves oxidation of methionine residues in the C5 protein. However, while chloramine T specifically attacks only methionine, oxidation by the OH. generating system involves other amino acid residues, in addition. This probably explains the lower yield of C5b-like activity after treatment with H2O2, and other quantitative differences between C5(H2O2) and C5(Cl-T). Whereas the generation of C5(H2O2) may be physiologically relevant, C5(Cl-T) may prove to be a suitable object for the study of changes in the C5 molecule essential for its activation.

Chloramines↗
PubMed2003

Expression of complement messenger RNAs and proteins by human oligodendroglial cells.

Neurons, astrocytes, microglia, and endothelial cells are capable of synthesizing most, if not all, of the complement proteins. Little is known, however, about the capacity of oligodendroglial cells to generate complement components. This study evaluated expression of complement mRNAs and their protein products by human oligodendrocytes. Cells were isolated and cultured from white matter of seven adult cases that had undergone surgical temporal lobe resection for epilepsy. Oligodendroglial cultures were characterized by the expression of such cell type-specific mRNAs as myelin proteolipid protein (PLP), oligodendrocyte-specific protein (OSP), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and were further characterized by immunostaining for such differentiation markers as myelin basic protein (MBP), PLP, CNPase, and O4. RT-PCR analysis showed that the oligodendroglial cells expressed detectable levels of complement mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 gamma subunit, and C9. Immunostaining was positive for C1q, C1s, C2, C3, C4, C5, C6, C7, C8, and C9. Double immunostaining for the oligodendrocyte marker O4 and the complement protein C3 demonstrated that all O4-positive cells were also positive for C3, indicating constitutive C3 expression. These results indicate that oligodendroglial cells may be a source of complement proteins in human brain and thus could contribute to the pathogenesis of several neurodegenerative and inflammatory diseases of the CNS, such as Alzheimer's disease, multiple sclerosis, and progressive supranuclear palsy, where complement-activated oligodendrocytes are abundant.

Adult↗
PubMed2001

Phenazine-1-carboxamide production in the biocontrol strain Pseudomonas chlororaphis PCL1391 is regulated by multiple factors secreted into the growth medium.

Pseudomonas chlororaphis PCL1391 controls tomato foot and root rot caused by Fusarium oxysporum f. sp. radicis-lycopersici. The production of phenazine-1-carboxamide (PCN) is crucial for this biocontrol activity. In vitro production of PCN is observed only at high-population densities, suggesting that production is under the regulation of quorum sensing. The main autoinducer molecule produced by PCL1391 was identified structurally as N-hexanoyl-L-homoserine lactone (C6-HSL). The two other autoinducers that were produced comigrate with N-butanoyl-L-homoserine lactone (C4-HSL) and N-octanoyl-L-homoserine lactone (C8-HSL). Two PCL1391 mutants lacking production of PCN were defective in the genes phzI and phzR, respectively, the nucleotide sequences of which were determined completely. Production of PCN by the phzI mutant could be complemented by the addition of exogenous synthetic C6-HSL, but not by C4-HSL, C8-HSL, or any other HSL tested. Expression analyses of Tn5luxAB reporter strains of phzI, phzR, and the phz biosynthetic operon clearly showed that phzI expression and PCN production is regulated by C6-HSL in a population density-dependent manner. The introduction of multiple copies of the regulatory genes phzI and phzR on various plasmids resulted in an increase of the production of HSLs, expression of the PCN biosynthetic operon, and consequently, PCN production, up to a sixfold increase in a copy-dependent manner. Surprisingly, our expression studies show that an additional, yet unidentified factor(s), which are neither PCN nor C4-HSL or C8-HSL, secreted into the growth medium of the overnight cultures, is involved in the positive regulation of phzI, and is able to induce PCN biosynthesis at low cell densities in a growing culture, resulting in an increase of PCN production.

Antifungal Agents↗
PubMed1986

Human alveolar macrophages synthesize the functional alternative pathway of complement and active C5 and C9 in vitro.

Attachment of protein to agarose beads cultured with macrophages in protein-free medium containing 3H-leucine, shows that de novo synthesis of protein with affinity to the beads takes place. We also found that monoclonal antibodies against human C3c, C3g, and a C9-neoantigen as well as polyclonal antibodies against human C5 and C9, bound to agarose beads that had been kept with the macrophage cultures. Demonstration of C3 derivatives on the agarose beads shows that the essential complement factors of the alternative pathway are synthesized and have been activated by the beads. Deposition of C5 and the detection of a neoantigen of C9 on the beads, indicates that the whole terminal complement pathway has been formed and activated. We conclude that human alveolar macrophages form in vitro the functional alternative pathway of complement, C5 and C9, and we have indirect evidence for synthesis of C6, C7, and C8.

Antibodies, Monoclonal↗
PubMedDate not supplied

Polymorphism of the complement components in human pathology.

The complement system is an important part of non clonal or innate immunity that collaborates with acquired immunity to kill pathogens and to facilitate the clearance of immune complexes. The complement is made up of 20 distinct plasma proteins and 9 different membrane proteins. Three components, factor B, C2 and C4 (with 2 isotypes), are coded by polymorphic HLA-linked genes and are sometimes referred to as class III antigens, inherited as compact units called complotypes. The C4 genes are the most polymorphic, including a common null allele (Q0) at both the C4A and C4B loci. Other polymorphic complement factors (not linked to HLA) are C3 (2 common alleles), C6 and C7 (closely linked, with 3 and 2 alleles, respectively). A certain degree of polymorphism has also been described for complement receptors and membrane control proteins. No differences in functional activity are usually detected among different alleles. Immune-mediated diseases are associated with C4Q0, in particular: systemic lupus erythematosus and discoid-systemic lupus erythematosus, insulin-dependent diabetes mellitus, liver cirrhosis, celiac disease and IgA/IgG4 deficiency. Even if optimal HLA markers do become available, genetic counselling is usually not the ultimate goal for dealing with most of the HLA-associated common diseases, although their study could help to better delineate disease pathogenesis.

Adrenal Hyperplasia, Congenital↗
PubMed2003

Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation.

BACKGROUND: Complement has been implicated in the pathophysiology of renal ischemia-reperfusion (I/R) injury. However, the mechanism underlying complement-mediated renal I/R injury is thus far unknown. To investigate the involvement of complement in I/R injury, we studied the activation and deposition of complement in a murine model of renal I/R injury. Furthermore, we examined the effect of inhibition of complement-factor C5 on renal I/R injury. METHODS: Mice were subjected to 45 min of unilateral ischemia and subsequent contralateral nephrectomy and reperfusion for 2, 12, or 24 hr. Mice were control treated or treated with BB5.1, a monoclonal antibody that prevents cleavage of complement factor C5, thereby preventing C5a generation and formation of the membrane attack complex (MAC). RESULTS: Renal I/R induced extensive deposition of C3 early after reperfusion, whereas C6 and C9 deposition (MAC formation) occurred relatively late. I/R-induced complement deposition was mainly localized to tubular epithelium. Treatment with BB5.1 totally prevented MAC formation but also reduced C3 deposition. Inhibition of C5 strongly inhibited late inflammation, as measured by neutrophil influx and induction of the murine CXC chemokines macrophage inflammatory protein-2, KC, and lipopolysaccharide-induced CXC chemokine. Anti-C5 treatment furthermore abrogated late I/R-induced apoptosis, whereas early apoptosis was not affected. Moreover, BB5.1 treatment significantly protected against I/R-induced renal dysfunction. CONCLUSIONS: Renal I/R is followed by activation of the complement system and intrarenal deposition of C3 and MAC. Complement activation plays a crucial role in the regulation of inflammation and late apoptosis. Complement inhibition, by preventing C5 activation, abrogates late apoptosis and inflammation, being strongly protective against renal function loss.

Animals↗
PubMed1997

Role of T cells in the mediation of Heymann nephritis. ii. Identification of Th1 and cytotoxic cells in glomeruli.

The role of immunoglobulin (Ig) and complement as mediators of Heymann nephritis (HN) has been questioned by recent studies showing that HN can be induced in a C6-deficient rat that cannot assemble the membrane attack complex of complement. Also, the severity of HN can be reduced by therapy directed at CD8+ T cells, which has no effect on antibody (Ab) production or immune deposits. To identify whether T cells may contribute to the glomerular injury of active HN in Lewis rats, the mononuclear infiltrate and cytokine mRNA in glomeruli and kidney interstitium were examined. Groups of Lewis rats immunized with Fx1A in CFA developed HN, and were compared to controls that received CFA only. Proteinuria, the marker of glomerular filtration barrier dysfunction, was absent at four weeks but present at eight weeks in HN. Serum anti-Fx1A Ab and glomerular Ig were present in HN at both time points. Immunoperoxidase staining with monoclonal Abs identified, at eight weeks, a glomerular infiltrate of CD4+ and CD8+ T cells, and macrophages, but not NK cells. Semiquantitative RT-PCR of isolated glomeruli at eight weeks demonstrated expression of cytokine mRNA for Th1 CD4+ cells (IFN-gamma and TNF-beta/LT, but not IL-2), cytotoxic CD8+ T cells (granzyme A and perforin), and macrophages (TNF-alpha and IL-10), but not Th2 CD4+ cells (no increase in IL-4, IL-5 and IL-6). At eight weeks, the cellular infiltrate and pattern of cellular activation in glomeruli was different to that in renal cortex. In the cortical infiltrate CD8+ cells were a lesser component, and NK cells were increased, as were CD4+ cells and macrophages. RT-PCR identified increased cytokine mRNA for macrophages, Th1 and Th2 cells, but not cytotoxic effector T cells. At four weeks, T cells including CD4+ and CD8+ cells were identified in the isolated glomeruli of rats with HN, but there was no increase in cytokine mRNA expression. There was no infiltrate or increase in cytokine mRNA detected in renal cortex at four weeks. Anti-Fx1A Ab's and glomerular deposition of Ig develop many weeks before the onset of proteinuria, when there is only a small cellular infiltrate present. The progressive development of infiltrates of activated T cells, principally Th1 and cytotoxic effector cells, and macrophages, within glomeruli is coincident with the development of proteinuria. These findings raise the possibility that these cells contribute to the mediation of the glomerular injury and proteinuria of HN.

Animals↗
PubMed1975

Interaction of complement components with a serum-resistant strain of Salmonella typhimurium.

Salmonella typhimurium C5 is under normal conditions (physiological saline containing 0.002 M Mg2+) resistant to the action of antibody and complement (C). It becomes sensitive, however, when suspended in tris(hydroxymethyl)-aminomethane buffer (Reynolds and Pruul, 1971; Reynolds and Rowley, 1969). The interaction of complement components with this strain sensitized with specific antibody has been studied to identify the intermediate step at which inhibition occurs. The components C1 yields C2 react normally, as has been shown by lysis of complement-treated cells incubated with complement in ethylenediaminetetraacetic acid. Also, the reaction of C3 can be demonstrated by positive immune adherence and agglutination with anti-C3. The complement-treated cells do not, however, react with rabbit C6 to 9 or rabbit serum lacking C6 in tris(hydroxymethyl)aminomethan buffer. We conclude from these date that C5 can not react effectively under normal conditions. In contrast, if bacteria-antibody complexes are pretreated with rabbit serum lacking C6 in tris(hydroxymethyl)aminomethane buffer, they are readily lysed by incubation with C6 to 9. Thus, C5 can react with the bacterial surface in tris(hydroxymethyl)-aminomethane buffer.

Animals↗
PubMed1972

Molecular analysis of the membrane attack mechanism of complement.

The molecular arrangement of the membrane attack mechanism of complement was explored. The molar ratios of the components within the C5-9 assembly on the target cell surface were determined using human complement proteins in highly purified and radiolabeled form. With the aid of monospecific complement antisera it was possible to probe the spatial relationships between the components of the assembly. C5 and C6, in the presence of C7, were bound to EAC1-3 in equimolar quantities irrespective of the amounts and the relative proportions of C5, C6, and C7 offered. The amount of C8 bound to EAC1-7 increased with input and at saturation of all C8 binding sites the molar ratio of bound C8/bound C5 approached 1.0. Uptake of C9 by EAC1-8 increased with input and at saturation of all C9 binding sites the molar ratio of bound C9/bound C8 became 6.0. However, calculations suggest that the binding of three C9 molecules to one C8 molecule is sufficient to achieve a full hemolytic effect. Evidence was obtained indicating that binding and hemolytic function of C9 depends upon cooperative interaction of multiple C9 molecules. Binding of C8 to EAC1-7 and the generation of hemolytic C8 sites were inhibited by antibody to either C5, C6, or C7. Uptake of C9 by EAC1-8 and the generation of hemolytic C9 sites were strongly inhibited by anti-C8 and to a lesser degree by anti-C5. Binding of C9 (but not hemolysis) was also reduced by antibody to C6 or C7. The data are consistent with the concept that the fully assembled membrane attack mechanism of complement consists of a decamolecular complex: a trimolecular arrangement composed of C5, C6, and C7 forms the binding site for one C8 molecule which in turn furnishes binding sites for six C9 molecules, saturation of three sites apparently being sufficient for expression of full cytolytic activity of the complex. This work made it possible to design a simple molecular model.

Animals↗
PubMed1982

Production of first component of complement by corneal fibroblasts in tissue culture.

Corneal fibroblasts were studied to determine if they have the ability to synthesize and secrete complement components in tissue culture. Culture media were assayed for functional complement activity of C1, C4, C2, C3, C5, C6, and C7 with the use of 50% hemolysis of sensitized sheep RBCs. Only C1 showed a progressive increase in hemolytic activity at days 3, 5, 7, 9, and 11 of tissue culture. This increase in hemolytic C1 could be reversibly inhibited by cycloheximide, an inhibitor of protein synthesis. Corneal fibroblasts may be a potential source of C1 in the cornea.

Aged↗