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PubMed1996

cDNA cloning, sequencing and chromosomal assignment of the gene for mouse complement factor I (C3b/C4b inactivator): identification of a species specific divergent segment in factor I.

Factor I is an essential regulatory serine proteinase of the complement cascade. It cleaves and inactivates the C3b and C4b constituents of the C3 and C5 convertases and thereby regulates many complement-mediated activities. The human protein is a heterodimer composed of a 50 kDa non-catalytic subunit (which contains several domains, i.e. FIM, CD5, LDLr type A) disulfide linked to a 38 kDa catalytic subunit. Recent characterization of Xenopus factor I cDNA revealed a 29 residue negatively charged region in its heavy chain which is absent in the human protein (Kunnath-Muglia et al., Molec. Immun. 30, 1249-1256, 1993). We report the complete cDNA sequence of mouse factor I as well as a partial chicken factor I cDNA sequence. Alignment of these two sequences with the published sequences for human and Xenopus proteins (a) demonstrates an overall conservation of primary structure and domain organization of mouse factor I, and (b) defines a divergent segment (D segment) in each species. In Xenopus protein, the D segment includes the 29 residue negatively charged region. In each of the four species examined, the D segment differed in length, sequence, organization, and number of repeated subregions. These differences reflect a considerable evolution of D segment. The significance of the diversity of the D segment is at present unclear. We also report the chromosomal localization of the mouse factor I gene (Cfi) to distal chromosome 3 near Egf.

Amino Acid Sequence↗
PubMed1978

Complement C3 convertase: cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells.

The alternative or properdin pathway of complement is primarily controlled by the endopeptidase C3b inactivator (C3bINA) and the nonproteolytic glycoprotein beta1H. The molecular mechanisms of control were investigated by performing binding studies of radiolabeled complement proteins to C3b bearing sheep erythrocytes (E(S)C3b). C3b was found to have distinct binding sites for beta1H, C3bINA, Factor B, and properdin. beta1H binding increased C3bINA binding 30-fold, while Factor B binding prevented C3bINA action on C3b and was competitive with beta1H binding. Properdin binding, which facilitates Factor B interaction with C3b, had no effect on the beta1H and C3bINA sites. Activators such as rabbit erythrocytes (E(R)) have previously been shown to interfere with the effectiveness of the control by C3bINA and beta1H, thereby allowing unrestricted formation of C3 convertase. Such restriction of control does not occur on the surface of E(S), a nonactivator of the alternative pathway. On the basis of comparative binding studies, restriction of control is explained entirely by reduced binding of beta1H to E(R)C3b relative to E(S)C3b. Access of properdin, Factor B, C3bINA, and the Fab fragment of anti-C3 to the two cell types was unrestricted. Restriction of beta1H control could be generated on the surface of E(S) by removal of cell-surface sialic acid with neuraminidase (acylneuraminyl hydrolase; EC 3.2.1.18). This enzymatic treatment converted E(S) from a nonactivator to an activator of the alternative pathway.

Binding Sites↗
PubMed1993

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2.

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with the VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely proved these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.

Blood Coagulation↗
PubMed2001

Complement-regulator factor H and related proteins in otitis media with effusion.

Otitis media with effusion (OME) is a common disease in childhood. It is characterized by chronic inflammation in which the proinflammatory activity of the complement (C) system is one of the underlying factors. The C system becomes strongly activated in the middle ear effusion (MEE) fluid, but the reasons for this are not known. Here we demonstrate by using complement Bb fragment ELISA that MEE specimens strongly activate the alternative C pathway (AP) in normal human serum (NHS). Some of the MEEs were also found to promote lysis of rabbit erythrocytes by NHS. These findings indicated a disturbance in the fluid-phase regulation of the AP in MEE. The main regulator of the AP, factor H (FH), and proteins structurally related to it (FHL-1, FHR-1, -2, -3, and -4) were present in the MEE fluids of OME patients. Relative to serum, the FHR proteins were more abundant in the MEEs. In addition, we detected the recently discovered 65-kDa FH-related protein FHR-5 in the MEE. The FHR proteins share binding sites with FH in the C3d region of C3b. Thus they may compete with FH in binding to C3b and interfere with the regulatory activity of FH. Consequently, a disturbance in AP control in the MEE may lead to an ongoing excessive C activation and inflammation in OME.

Apolipoproteins↗
PubMedDate not supplied

Modulation of C4b-binding protein isoforms during the acute phase response caused by orthopedic surgery.

Orthopedic surgery is described as an event with a high risk of thromboembolic diseases. This is probably a consequence of a synergistic combination of different risk factors in the patients subjected to this type of surgery, including age, immobilization, anesthesia and different hypercoagulable states. After surgery patients develop an acute-phase response that leads to changes in several plasma proteins. One of these proteins is the complement regulator C4b-binding protein (C4BP). We have recently shown that in some acute-phase patients C4BP is incorrectly controlled (with elevation of the C4BP beta-containing isoforms), leading to a potential hypercoagulable state by decreasing the plasma levels of free (active) protein S. Here we have studied whether patients subjected to orthopedic surgery have an appropriate modulation of the C4BP isoforms during their postoperative acute-phase responses. We have analyzed the evolution of the C4BP isoforms in serial samples from 11 patients who have undergone knee (or hip) prosthesis surgery (mean age 70 years), or scoliosis surgery (mean age 18 years). Our data suggest a similar evolution of C4BP isoforms in all these patients, with an almost exclusive increase of C4BP isoforms lacking C4BP beta polypeptides and steady levels of free protein S.

Acute-Phase Reaction↗
PubMed1990

Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma.

C1 inhibitor (C1INH), the major plasma inhibitor of activated C1, kallikrein, and activated Hageman factor, may be an important factor in limiting inflammatory injury mediated by the complement and contact systems. C1INH is thought to be synthesized primarily in the liver; however, the regulators of hepatic C1 inhibitor synthesis are completely unknown. In this report, we analyze the regulation of C1INH synthesis by hepatocyte stimulating factors in human hepatoma cell lines and primary hepatocytes. Interleukin-6 and interferon gamma increase C1INH production in both hepatoma cells and hepatocytes. These cytokines stimulate de novo synthesis of functional C1INH, acting at a pretranslational level as assessed by Northern blotting. The stimulatory effects of interleukin-6 and interferon gamma on C1INH synthesis are separate and are differentially modulated by interleukin-1. These results establish that hepatic C1INH synthesis is regulated by hepatocyte stimulating factors and reveal novel interactions between these factors.

Acute-Phase Proteins↗
PubMed1989

Characterization of a synthetic peptide that inhibits the interaction between protein S and C4b-binding protein.

Protein S is unique among the vitamin K-dependent proteins found in blood plasma because it is a cofactor rather than a zymogen of a serine protease. Instead of a trypsin-like domain, protein S contains a domain that has sequence homology with steroid binding proteins. In order to understand the function of this structural domain, peptides have been synthesized with amino acid sequences that are homologous between human protein S and rat androgen binding protein. Two peptides, corresponding to amino acids 400-407 (PINPRLDG) and 605-614 (GVQLDLDEAI) of the protein S sequence have been tested for their effects on protein S function. Neither peptide altered the clotting of bovine or human plasma. The peptide GVQLDLDEAI enhanced the anticoagulant activity of human-activated protein C in human plasma while the peptide PINPRLDG had no effect. The peptide GVQLDLDEAI was observed to inhibit the binding of protein S to C4b-binding protein in plasma, resulting in increased concentrations of free protein S. GVQLDLDEAI was also observed to enhance the disassociation of the protein S.C4b-binding protein complex when purified complex was used. Finally, C4b-binding protein was observed to bind to GVQLDLDEAI. These results suggest that the carboxyl-terminal region of protein S, which contains the sequence GVQLDLDEAI, is involved in the interaction between protein S and C4b-binding protein.

Amino Acid Sequence↗
PubMed1985

Application of molecular cloning to studies on the complement system.

The isolation of cDNA and, in certain cases, genomic clones has been reported for the following complement proteins: C1q, C2, C3, C4, C5, C9, and factor B, C4b-binding protein and C1-inhibitor. The availability of cloned DNA has allowed rapid advances to be made in the understanding of the structure (from the derived amino acid sequences), function, biosynthesis and genetics of these proteins. This is most strongly illustrated from recent studies on the C2, factor B and C4 genes, which code for the class III molecules of the major histocompatibility complex, especially as certain allelic forms of these genes may be associated with disease susceptibility.

Animals↗
PubMed2005

Complement regulatory proteins are incorporated into lentiviral vectors and protect particles against complement inactivation.

Lentiviral vectors pseudotyped with G glycoprotein from vesicular stomatitis virus (VSV-G) and baculovirus gp64 are inactivated by human complement. The extent of vector inactivation in serum from individual donors was examined and results showed wide donor-dependent variation in complement sensitivity for VSV-G-pseudotyped lentivectors. Amphotropic envelope (Ampho)-pseudotyped vectors were generally resistant to serum from all donors, while gp64-pseudotyped vectors were inactivated but showed less donor-to-donor variation than VSV-G. In animal sera, the vectors were mostly resistant to inactivation by rodent complement, whereas canine complement caused a moderate reduction in titer. In a novel advance for the lentiviral vector system, human complement-resistant-pseudotyped lentivector particles were produced through incorporation of complement regulatory proteins (CRPs). Decay accelerating factor (DAF)/CD55 provided the most effective protection using this method, while membrane cofactor protein (MCP)/CD46 showed donor-dependent protection and CD59 provided little or no protection against complement inactivation. Unlike previous approaches using CRPs to produce complement-resistant viral vectors, CRP-containing lentivectors particles were generated for this study without engineering the CRP molecules. Thus, through overexpression of native DAF/CD55 in the viral producer cell, an easy method was developed for generation of lentiviral vectors that are almost completely resistant to inactivation by human complement. Production of complement-resistant lentiviral particles is a critical step toward use of these vectors for in vivo gene therapy applications.

Animals↗
PubMed1979

Evidence for glomerular modulation of complement activation.

Using indirect immunofluorescence, three regulatory proteins of the complement system, C1-inhibitor (C1-INH), C3b inactivator (C3bINA) and beta 1H globulin have been detected in the glomeruli of patients with glomerulonephritis associated with complement activation. C1-INH and beta 1H were found frequently but C3bINA was rarely detected (only 14 biopsies). beta 1H globulin and C3b inactivator which modulate C3b activity were never found in the absence of C3, but C1-INH was sometimes found in the absence of C1s. The patterns for staining for C1s and C1-INH, C3 and beta 1H were almost identical suggesting that the regulatory proteins are binding to the proteins they regulate, as has been demonstrated in vitro. Thus, in tissues undergoing complement-mediated tissue damage, the extent of complement activation is controlled by the normal regulatory mechanisms.

Complement Activation↗
PubMed1988

Synthesis and regulation of complement protein factor H in human skin fibroblasts.

The alternative pathway of C activation is Ag-independent and forms a first line of defense against infection before immune response. The C3 convertase, C3bBb, formed during activation of the alternative pathway is tightly regulated, with destabilization produced by factor H. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrated that human skin fibroblasts synthesized and secreted factor H protein. Two forms of the protein were identified, the approximately 160-kDa form seen more prominently in serum and a 45-kDa form that has also been identified in serum. The cells contained two forms of factor H mRNA, 4.4 and 1.8 kb. IFN-gamma increased factor H protein synthesis and mRNA content. No effect was observed with LPS. Neither HepG2 cells or human peripheral blood monocytes synthesized factor H protein or contained factor H mRNA.

Cell Line↗
PubMed1988

The surfaces of the parasitic nematodes Trichinella spiralis and Toxocara canis differ in the binding of post-C3 components of human complement by the alternative pathway.

The binding of human complement components C3, C5 and C9 to the surface of the infective larvae of the nematode parasites Toxocara canis and Trichinella spiralis, by the alternative pathway, was examined by direct and indirect immunofluorescence on the intact parasites. This showed that although C3 bound to both nematodes, they differed markedly in the binding of C5 and C9; C5 bound only minimally to T. spiralis, and C9 binding to this parasite was barely detectable. In contrast, both early and late components bound to T. canis to a high density, comparable to, or in excess of, the binding of these components to the infective larvae of the trematode Schistosoma mansoni. The lack of binding of the post-C3 components to T. spiralis did not correlate with enhanced binding of the control protein, Factor H.

Animals↗
PubMed1992

The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S.

PURPOSE: To determine if abnormalities in the protein C/protein S anticoagulant system exist in patients with phospholipid antibodies who had the primary clinical complaint of fetal wastage. PATIENTS AND METHODS: Eleven patients with fetal wastage and phospholipid antibodies were selected for study. Some patients also gave a history of previous thrombotic events related to oral contraceptives and/or pregnancy, but patients were not selected because of a history of clinical thrombosis. The levels of protein C (chromogenic assay), protein S (both free and bound) (Laurell rocket), and C4b-binding protein (Laurell rocket) were measured, and assays for the presence of antibodies against protein S or protein C were performed. RESULTS: Seven of the 11 patients were found to have low levels of free protein S. Total protein S and protein C levels were within the normal range in all patients. Antibodies to protein C and protein S were not found in any patient. These findings suggest that free protein S levels may be abnormally low in some patients with phospholipid antibodies. CONCLUSION: Free protein S levels are abnormally low in some patients with phospholipid antibodies, and this abnormality may be a factor contributing to the thrombotic diathesis associated with phospholipid antibodies.

Abortion, Habitual↗
PubMed1991

Granulocyte-dependent extracellular cytotoxicity is enhanced by complement C3bi and independent of phagocytosis.

We have evaluated phagocytosis, C3-binding and cytotoxicity of human leukocytes simultaneously, using IgM-sensitized C3-fragment-bearing sheep erythrocytes (EAC3b, EAC3bi) as targets. In this method, 51Cr-labelled EAC3b or EAC3bi were added to human peripheral granulocytes anchored by fibronectin onto microtitre plate wells. The degrees of haemolysis, binding and ingestion of the target cells were estimated from the radioactivity released. We found that the granulocytes predominantly lysed EAC3bi but not EAC3b or EAC4b. EAC3bi lysis elicited from granulocytes was as effective as that from lymphocytes under the same assay conditions. However, one difference in the cytolysis of the two effector cells was that EAC3bi bound efficiently to all of the granulocytes similarly to EAC3b, whereas it bound to only 4% of the lymphocytes. The bound cells did not appear to be efficiently phagocytosed by the granulocytes. Blocking studies using antibodies suggested that C3bi receptors, CR3 and CR4, but not other C3-binding proteins, C3b/C4b receptor (CR1), membrane cofactor protein (MCP) or decay-accelerating factor (DAF), are involved in granulocyte-mediated haemolysis. We speculate that simultaneous stimulation of the C3bi receptors and the fibronectin receptor results in elicitation of cytotoxicity by granulocytes.

Carrier Proteins↗