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PubMed2005

Immune function of C1q and its modulators CD91 and CD93.

C1q is a subcomponent of the first component of complement C1, which is a multimolecular complex comprising one molecule of C1q and two molecules each of the autoreactive proteases, C1r and C1s. This multimolecular complex triggers the classical pathway of complement. Advances in the past several years have provided a partial crystal structure of the C1q subunit. This, together with gene deletion of C1q, has allowed further insight into the multifunctional immune aspects of this molecule. Two C1q-mediated functions that have received intense scrutiny recently are C1q-mediated apoptotic clearance of cell debris and phagocytosis. This has led to a heightened search for specific receptors for the collagen-like region (CLR) as well as the globular heads. Two transmembrane proteins, CD91 and CD93, have been proposed to interact indirectly with the CLR of C1q, promoting apoptotic clearance and phagocytosis, respectively. The aim of this article is to provide an overview of the structural and functional information that implicates CD91 and CD93 in C1q-mediated functional effects.

Animals↗
PubMed1985

Antibody-independent activation of C1, the first component of complement, by cardiolipin.

Lipid vesicles containing phospholipids known to be present in substantial amounts in mitochondrial membranes were tested for their capacity to activate C1. Among them, only cardiolipin (CL) was highly efficient in C1 activation; no such effect was observed with phosphatidylcholine, phosphatidylethanolamine, or phosphatidylinositol. CL was shown to bind specifically C1q, because only unlabeled C1q competed with 125I-C1q for binding to CL. The requirement for C1q was confirmed by the finding that only fully reconstituted macromolecular C1, containing C1q, was activated by CL. The specificity of CL-induced activation of C1 was also demonstrated by introducing adriamycin, an agent known to interact with CL. Whereas adriamycin did not decrease C1 activation induced by immune complexes, it abrogated C1 activation by CL. The latter was shown to be a strong nonimmune activator of C1, because C1-INH did not inhibit CL-induced activation. When the concentration of CL in vesicles was decreased in the presence of phosphatidylcholine, C1 activation was detected only above a critical level of 35 mol% CL, compatible with a minimal density or clustering of CL molecules in the plane of the membrane. Moreover, C1 activation by CL was modulated by the addition of cholesterol. The threshold of CL required for C1 activation was lowered by the incorporation of more than 35 mol% cholesterol into the vesicles. These results show that CL incorporated into liposomes can be a potent nonimmune activator of C1. The negatively charged phosphate groups in CL are likely candidates for Clq-binding.

Cardiolipins↗
PubMed1976

Inhibition of T-lymphocyte rosetting by HL-A alloantisera and complement.

The relationship between HL-A antigens and rosetting of sheep red blood cells (SRBC) with peripheral human lymphocytes has been investigated by incubating them with HL-A antibodies. Although sensitizing the lymphocytes with HL-A alloantisera had no effect on their ability to form rosettes with SRBC, further sensitization with C6 deficient rabbit serum as a source of early complement components inhibited the formation of rosettes with SRBC. The involvement of HL-A alloantibodies in the inhibition of rosette formation was shown first by correlating the HL-A phenotype of the lymphocytes and the HL-A specificity of the alloantisera and, second, by specifically absorbing the HL-A alloantibodies from the alloantisera. Complement was needed to inhibit rosette formation since this effect was lost when rabbit serum was treated to inactivate complement. The participation of complement's classical pathway in rosette inhibition was shown by chelating the Ca2+ ions by EGTA treatment of the C6 deficient rabbit serum. Perhaps, binding of HL-A antibodies and early complement components to the lymphocyte surface disturbs the distribution of the receptors or affects the charge of the cell membrane, thus inhibiting the rosette formation with SRBC.

Antigen-Antibody Reactions↗
PubMed1981

Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase.

Three mechanisms that regulate the formation and function of the classical pathway C3 convertase (C4b2a) have been elucidated: (a) an intrinsic decay of the enzyme that is temperature dependent; (b) an extrinsic decay mediated by the effect of the serum protein C4b binding protein (C4-bp); and (c) inactivation of C4b by the proteolytic action of C4b/C3b inactivator (C4b/C3bINA), which cleaves that alpha' chain of C4b to yield C4d (alpha 2) and C4c (alpha 3, alpha 4, beta, and gamma chains). A fourth mechanism described here is based on the observation that the IgG fraction of the serum of certain patients with glomerulonephritis contains a protein termed C4 nephritic factor (NFc), which prevents the intrinsic decay of C4b2a. This protein, which prolongs the half-life of surface-bound C4b2a from 7.5 min to greater than 5 h, increases the use of C3 and C5. It also inhibits the decay produced by C4-bp by preventing the dissociation of C2a from the C4b2a complex. Additionally, the C2b/C3bINA alone, or in the presence of C4-bp, fails to cleave the alpha' chain of C4b in the surface-bound stabilized C4b2a complex. This protective property of NFc requires the presence of C2a, because C4b was not protected unless it was bound to C2a. Thus in the presence of NFc, the three natural controls of the function of the classical pathway convertase, intrinsic decay, extrinsic decay, and proteolytic cleavage, are bypassed.

Animals↗
PubMedDate not supplied

C1r serine proteinase of human complement: a case of intramolecular autolytic activation.

This paper presents a short review of our contribution to the knowledge of the structure and function of human C1r, the activation unit of C1, the first component of the classical pathway of complement. On the basis of the domain structure of C1r, a model accounting for its autolytic activation mechanism is proposed. We suggest that this represents the basic mechanism of C1 function.

Complement Activating Enzymes↗
PubMed1996

Complement activation and subclassification of tissue immunoglobulin G in the abdominal aortic aneurysm.

Features of autoimmunity in abdominal aortic aneurysm (AAA) have been described, including increases in IgG content. The present experiments were carried out to determine (1) whether the increases in IgG are subclass specific and (2) whether the IgG complex is associated with an increase in the isoforms of complement C3. Seven AAA, four athero-occlusive (AOD), and two normal (NL) aortic tissue extracts were evaluated for immunoreactive complement (C3) components, both by ELISA and by Western immunoblots (probed with a polyclonal goat anti-human C3). The extracts were also assayed for each of the four subclasses of IgG by ELISA (monoclonal mouse anti-human IgGs). Compared to the amounts of IgG by subclass in normal aorta, AAAs had increases of 193-fold in IgG1, 160-fold in IgG2, 389-fold in IgG3, and 627-fold in IgG4. Increases relative to AOD by subclass were smaller, but each subclass was statistically significantly elevated (P < 0.01) over NL or over AOD. There was a 125-fold increase in immunoreactive C3 by ELISA in AAA vs NL, and Western immunoblotting techniques revealed the presence of multiple C3 degradation products. Increases in IgG1, 2, and 3 may be responsible for activation of complement in AAA by the classical pathway. Since the complement system is one of the major effector pathways of inflammation, the presence of complement-fixing IgG subclasses along with increased C3 in the aneurysm wall may be an important mechanism promoting matrix proteolysis in AAA.

Aorta, Abdominal↗
PubMed1994

Complement-dependent cytotoxic activity of serum mannan-binding protein towards mammalian cells with surface-exposed high-mannose type glycans.

Serum mannan-binding protein (S-MBP), a lectin specific for mannose and N-acetylglucosamine, activates complement through the classical pathway. With the help of complement, S-MBP lyses red blood cells which have been coated with yeast mannan and kills bacteria which have N-acetylglucosamine and/or L-glycero-D-manno-heptose on their core oligosaccharide. In this study, we examined whether mammalian cells, on which S-MBP could bound, are killed by a complement-dependent mechanism. When baby hamster kidney (BHK) cells were treated with an alpha-mannosidase inhibitor, 1-deoxymannojirimycin (dMM), most of the cellular oligosaccharides were transformed from the complex-type to the high mannose-type. S-MBP bound to the dMM-treated BHK cells in the presence of Ca2+, and this binding was eliminated by mannose. When dMM-treated cells, labelled with 51Cr, were incubated with complement, radioactivity was released in a dose-dependent manner by S-MBP and complement. This release was not observed with heat-inactivated complement. These observations suggest that S-MBP is able, with the help of complement, to kill not only exogenous microorganisms but also mammalian cells which have high mannose-type oligosaccharides exposed on their surfaces.

1-Deoxynojirimycin↗
PubMed2000

An ethnopharmacological study on common privet (Ligustrum vulgare) and phillyrea (Phillyrea latifolia).

Ligustrum vulgare and Phillyrea latifolia leaves were well known in the Mediterranean historical medicine for their oropharyngeal anti-inflammatory effects. At the present time a popular phytotheraputical use of these species remains only in a few isolated southern European areas. Phytochemical and phytopharmacological studies of the methanolic extractives of their leaves were carried out. Flavonoidic fractions as well as different isolates, apigenin and luteolin derivatives showed significant in vitro complement inhibiting effects on the classical pathway of the complement system. A possible phytoceutical utilisation of the aerial parts of these species could represent (especially regarding the genus Phillyrea) an interesting perspective for many semi-arid Mediterranean regions.

Complement Activation↗
PubMed2003

Role for complement in development of Helicobacter-induced gastritis in interleukin-10-deficient mice.

The mechanisms by which the immune response can eradicate gastric Helicobacter infection are unknown. We hypothesized that Helicobacter-induced activation of the complement system could promote both inflammation and eradication of Helicobacter from the stomach. In vitro studies demonstrated that Helicobacter felis activates complement in normal mouse serum but not in serum from Rag2(-/-) mice, indicating that H. felis activates complement through the classical pathway. Next, we infected complement-depleted wild-type control and interleukin-10-deficient (IL-10(-/-)) mice with H. felis. Helicobacter infection of wild-type mice elicited a mild, focal gastritis and did not alter serum complement levels. Infection of IL-10(-/-) mice with H. felis elicited severe gastritis. After the initial colonization, the IL-10(-/-) mice completely cleared Helicobacter from the stomach by day 8. In contrast to wild-type mice, H. felis-infected IL-10(-/-) mice had a marked increase in serum complement levels. Complement depletion of wild-type mice did not affect the intensity of gastric inflammation or the extent of Helicobacter colonization compared to that for the wild-type control mice. In contrast, complement depletion of Helicobacter-infected IL-10(-/-) mice decreased the severity of gastritis, decreased the Helicobacter-induced infiltration of neutrophils into the stomach, and delayed the clearance of bacteria. In vitro studies of stimulated splenocytes and neutrophils from IL-10(-/-) mice produced a twofold increase in complement production compared to that for wild-type mice. Pretreatment with IL-10 inhibited this increase. These studies identify a role for complement in the local immune response to gastric Helicobacter in IL-10(-/-) mice and suggest a role for IL-10 in the regulation of complement production.

Animals↗
PubMed1999

Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood.

R6.5 (BIRR-1, Enlimomab), a murine IgG2a mAb to the human ICAM-1, inhibits leukocyte adhesion to the vascular endothelium, thereby decreasing leukocyte extravasation and inflammatory tissue injury. In initial clinical trials, R6.5 proved to be beneficial in reducing both disease activity in refractory rheumatoid arthritis and the incidence of acute rejection after kidney and liver allograft transplantations. However, adverse effects such as fever, leukopenia, or cutaneous reactions were not infrequent. We studied the effects of R6.5 on neutrophil function in whole blood samples ex vivo. Surprisingly, at the concentrations achieved in clinical trials, R6. 5 activated neutrophilic granulocytes, as indicated by a significant increase in expression of the adhesion molecule beta2-integrin CD11b, a concurrent decrease in L-selectin expression, and an enhancement of the oxidative burst activity. Neutrophil activation was not exerted by an anti-ICAM-1 mAb of the IgG1 isotype, by isotype-matched, irrelevant anti-2-phenyloxazolone mAb, or by F(ab')2 fragments of R6.5. Neutrophil activation was completely inhibited by soluble complement receptor type 1. We conclude that in whole blood, R6.5 activates resting neutrophils in a complement-dependent manner. This finding can explain, at least in part, the side effects associated with R6.5 therapy.

Animals↗
PubMed2003

Complement activation in plasma before and after infliximab treatment in Crohn disease.

BACKGROUND: Crohn disease is characterized by up-regulated intestinal inflammation mainly caused by increased tumour necrosis factor alpha (TNF-alpha) levels. However, the complement system (C) may also have a role in maintaining inflammation. METHODS: Plasma from 26 patients with Crohn disease complicated by fistulizing ano-rectal disease was collected before and after three Infliximab infusions (5 mg kg(-1)). RESULTS: Before treatment, the C3-activation capacities (C3-AC) in plasma from patients with Crohn disease were comparable with values obtained from healthy controls. The classical C pathway-mediated C3-AC, mannan-binding lectin C4-AC, leucocyte count, C-reactive protein concentration and Crohn Disease Activity Index decreased significantly 8 weeks after the first infusion of Infliximab (P < 0.04, Wilcoxon test). CONCLUSIONS: Before treatment, all three C pathways were within the normal range in plasma from patients with Crohn disease; the decrease observed in the classical pathway-mediated C3-AC after treatment with Infliximab reflects a general down-regulation in immune activation.

Adolescent↗
PubMed1993

The role of O-antigen in susceptibility of Serratia marcescens to non-immune serum.

Selection of phage-resistant strains to three different phages, kappa, FSB3 and FSB55, whose primary receptor was lipopolysaccharide, enabled several spontaneous O-defective mutants to be isolated and characterized. Strains ATCC 274 (0:14), 2170 (0:14) and NIMA (0:6) showed serum resistance, whereas their O-side chain defective mutants exhibited high serum susceptibility. Both alternate and classical activation pathways were involved in serum killing activity in Serratia marcescens.

Animals↗
PubMed2004

ACR classification criteria for systemic lupus erythematosus: complement components.

Complement is involved in the pathogenesis of systemic lupus erythematosus (SLE) and has also a seemingly paradoxical protective role in the development of the disease. Low levels of components within the classical pathway of complement especially C1q, C4 and C3 have a high specificity for SLE diagnosis and should be considered as promising for inclusion in classification criteria of SLE.

Biomarkers↗
PubMed1991

Antithrombin III regulates complement activity in vitro.

Heparin, a polyion, exerts its main activity to inhibit coagulation through a serine protease inhibitor, antithrombin III. Previous studies have clearly shown that heparin in the absence of antithrombin III also has the capacity to regulate C activity. The present studies examined the ability of purified human antithrombin III to regulate classical and alternative pathways of C, alone and in the presence of heparin. Antithrombin III alone inhibited generation of both pathways in a dose-related manner; antithrombin III at 8 micrograms/10(7) cellular intermediates inhibited generation of the classical and alternative pathway convertases by 60 and 42%, respectively. Antithrombin III and heparin augmented each other's capacity to inhibit generation of both convertases in a dose-related manner. Antithrombin III did not appear to inhibit on the basis of charge because it is only slightly anionic (isoelectric pH value, 5.0); instead, antithrombin III may have acted as a serine protease inhibitor of the proteolytic enzymes of the C cascades. Antithrombin III acted only to inhibit formation of the alternative pathway convertase but had no activity on terminal lysis by this pathway; similarly, antithrombin III inhibited preformed EAC1,4b,2a,3b but had no activity on classical pathway cellular intermediates containing additional components. Finally, antithrombin III inhibited consumption of factor B hemolytic activity in a reaction mixture that also contained factor D and C3b, suggesting that factor D activity was also inhibited. These studies demonstrate the capacity of antithrombin III to regulate C and suggest that, in concert with heparin, antithrombin III may play an important role in the regulation of C in vivo.

Antithrombin III↗
PubMed1997

Post-traumatic pleural effusion: demonstration of local complement consumption.

The present case report describes a 27-year-old patient who presented with post-traumatic pleural effusion. Analysis of the pleural fluid showed hypereosinophilia (990 mm-3), a decreased level of total complement, and decreased levels of C3 and C4 fractions (less than 50% of normal serum levels), indicating a local consumption mechanism for complement. Complement serum levels (CH50, C3, C4) were normal. All other aetiologic possibilities were eliminated. This case suggests that the immunopathological mechanism of post-traumatic pleural effusion may involve activation of the classical pathway of complement and a recruitment of inflammatory cells such as eosinophils.

Adult↗
PubMed2001

The human gene for mannan-binding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p36.2-3.

The proteases of the lectin pathway of complement activation, MASP-1 and MASP-2, are encoded by two separate genes. The MASP1 gene is located on chromosome 3q27, the MASP2 gene on chromosome 1p36.23-31. The genes for the classical complement activation pathway proteases, C1r and C1s, are linked on chromosome 12p13. We have shown that the MASP2 gene encodes two gene products, the 76 kDa MASP-2 serine protease and a plasma protein of 19 kDa, termed MAp19 or sMAP. Both gene products are components of the lectin pathway activation complex. We present the complete primary structure of the human MASP2 gene and the tight cluster that this locus forms with non-complement genes. A comparison of the MASP2 gene with the previously characterised C1s gene revealed identical positions of introns separating orthologous coding sequences, underlining the hypothesis that the C1s and MASP2 genes arose by exon shuffling from one ancestral gene.

Base Sequence↗
PubMed1981

Serum bactericidal effect on Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The bactericidal activity against Pseudomonas aeruginosa strains isolated from cystic fibrosis patients was determined in a 10% concentration of normal serum or autologous cystic fibrosis serum. Of the 167 strains tested, 77 (46%) were sensitive (greater than 95% killed) in normal serum. Mucoid strains were more frequently sensitive than nonmucoid strains. Twenty-three sensitive strains tested in ethyleneglycoltetraacetic acid-chelated serum were resistant (less than 10% killed), suggesting only classical pathway activation. Absorption of cystic fibrosis serum with the autologous P. aeruginosa strain resulted in decreased killing by that serum. All sera, including the chelated and absorbed sera, had comparable total hemolytic complement levels. Patients in poor clinical condition (5 out of 12), in contrast to patients in good or moderate condition(1 out of 30), were more likely to have P. aeruginosa strains that were serum resistant in autologous serum but sensitive in normal serum. Sera from these five patients in poor clinical condition were capable of killing heterologous P. aeruginosa strains. These results suggest the presence of a protective or "blocking" activity in serum from some patients in poor clinical conditions. This association of a blocking activity with clinical condition may signal a transition point in the progression of cystic fibrosis lung disease and thus may be another contributory factor in the failure of the cystic fibrosis host to control infection.

Antibodies, Bacterial↗
PubMed1984

Generation of the classical pathway C3 convertase (EAC4b2a) by proteolytic enzymes.

The formation of EAC 4b2a is a two step reaction: first, the temperature- and time-independent binding of C2 to EAC4b2a resulting in EAC4b2 , secondly, the enzymatically triggered conversion of EAC4b2 to EAC4b2a . In the classical cascade of complement activation, the generation of C3 convertase activity is triggered by the C1 esterase, C1-s, which is part of C-1. Evidence is presented that the enzymes trypsin, chymotrypsin, plasmin, and pronase are also able to activate EAC4b2 to EAC4b2a . Kinetic studies showed that the formation of C3 convertase by these enzymes was dependent on concentration, temperature, and time. The optimal conditions were found as follows: trypsin, 2 micrograms/ml (final conc.) for 8 min at 23 degrees C; chymotrypsin 165 micrograms/ml for 18 min at 23 degrees C; plasmin 0.8 units/ml for 15 min at 23 degrees C; pronase 1.25 microgram/ml for 15 min at 23 degrees C. Even under optimal (tmax) conditions the number of generated EAC4b2a differed from enzyme to enzyme: trypsin (= 100%), pronase (58.3%), chymotrypsin (47.9%), and plasmin (12.9%). The enzymes were also able to generate C3 convertase activity from C2 which was adsorbed to EAC1i4b , a C1 inactivator treated and therefore hemolytically inactive intermediate ( EAC1i4b2 ). These findings underline the biological importance of C1 esterase replacing enzymes.

Animals↗