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PubMed1983

Degradation of human complement component C4b in the presence of the C4b-binding protein-protein S complex.

Vitamin K-dependent protein S and the higher-molecular-weight form of C4b-binding protein (C4bp-high) interact, forming a 1:1 complex with a KD of approx. 1 X 10(-7) M [Dahlbäck (1983) Biochem. J. 209, 847-856]. In the present study the effect of protein S on the degradation of C4b by Factor I (C3b inactivator) and C4bp was investigated both in fluid phase and on cell surfaces, with the use of highly purified components. Fluid-phase degradation of C4b was monitored on sodium dodecyl sulphate/polyacrylamide-slab-gel electrophoresis, and the effect on surface-bound C4b was estimated by haemolytic assay. No effect of protein S could be demonstrated in any of the systems used. Thus, although bound to C4bp, protein S is neither involved in, nor does it affect, the interaction between C4bp and C4b. This indicates that the binding sites on the C4bp molecule for protein S and for C4b are independent and different.

Binding Sites↗
PubMed1984

The effects of iodine and thiol-blocking reagents on complement component C2 and on the assembly of the classical-pathway C3 convertase.

I2 can react with complement component C2 in a two-stage process. In the first stage, a form of C2 with enhanced haemolytic activity is produced. This form of C2 is cleaved to C2a and C2b by C1s at the same rate as native C2. The enhanced C2 haemolytic activity correlates with the ability to form a stable fluid-phase C3 convertase on addition of the C2 to C4b and C1s. It reflects an increased affinity for C4b of C2a formed from I2-treated C2, although the affinity for C4b of I2-treated C2 itself is not markedly increased. The specific activity of C3 convertase formed from I2-treated C2 is the same as that formed from native C2. The second stage of the reaction with I2, which is favoured at high pH or in the presence of excess I2, inactivates C2 on production of a species that cannot be cleaved by C1s. The presence of a single free thiol group in C2, which is the site of modification by I2, was confirmed by titration with p-chloromercuribenzoate, iodoacetamide and 5,5'-dithiobis-(2-nitrobenzoic acid). A single thiol group is also present in Factor B, and the cysteine residue, like that in C2, requires denaturation of the protein before reaction with iodoacetamide and 5,5'-dithiobis-(2-nitrobenzoic acid) but not p-chloro- mercuribenzoate .

Chloromercuribenzoates↗
PubMed1993

Molecular modelling of the domain structure of factor I of human complement by X-ray and neutron solution scattering.

Factor I is a typical multidomain protein of the complement system. It regulates complement activation by proteolytic degradation of C3b or C4b in the presence of factor H, complement receptor type 1, membrane cofactor protein or C4b-binding protein as cofactor. It is constructed from five presumed independently folded domains, namely a factor I module, a CD5-like domain, two low-density-lipoprotein receptor type A domains and a serine-proteinase domain. X-ray and neutron solution scattering was used to study the arrangement of these domains in factor I. Factor I was determined to be monomeric in solution, with an A280(1%,1cm) of 12.3-14.1. Its radius of gyration (RG) was 3.96 nm by X-rays in a high positive solute-solvent contrast, and 3.84 nm by neutrons at infinite solute-solvent contrast. The cross-sectional radius of gyration (RXS) was likewise found to be 1.64 nm by X-rays and 1.55 nm by neutrons. The RG data were not noticeably dependent on the solute-solvent contrast, whereas the RXS data showed a small dependence. The maximum dimension of factor I was determined to be 12.8 nm from the RG and RXS data, and 14-15 nm from the X-ray and neutron distance distribution functions. This length is too short to account for a linear arrangement of the domains in factor I. Small sphere models were developed for factor I in which the largest domain was modelled from the crystal structure for beta-trypsin. The attachment of either an elliptical cylinder or a two-armed V-shaped structure to this domain to represent the remaining four small domains gave good scattering curve-fits for factor I, and were compatible with experimental sedimentation coefficients. The non-extended domain models for factor I imply that the steric accessibility of each domain will be reduced, and this may be important for its functional activity.

Carrier Proteins↗
PubMed1990

Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.

1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

Complement Activation↗
PubMed2001

Complement activation plays a key role in the side-effects of rituximab treatment.

Treatment with rituximab, a chimaeric anti-CD20 monoclonal antibody, can be associated with moderate to severe first-dose side-effects, notably in patients with high numbers of circulating tumour cells. The aim of this study was to elucidate the mechanism of these side-effects. At multiple early time points during the first infusion of rituximab, complement activation products (C3b/c and C4b/c) and cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-8] were measured in five relapsed low-grade non-Hodgkin's lymphoma (NHL) patients. Infusion of rituximab induced rapid complement activation, preceding the release of TNF-alpha, IL-6 and IL-8. Although the study group was small, the level of complement activation appeared to be correlated both with the number of circulating B cells prior to the infusion (r = 0.85; P = 0.07) and with the severity of the side-effects. We conclude that complement plays a pivotal role in the pathogenesis of side-effects of rituximab treatment. As complement activation can not be prevented by corticosteroids, it might be relevant to study the possible role of complement inhibitors during the first administration of rituximab.

Adult↗
PubMed1996

Prospective cross-over comparisons of three low-density lipoprotein (LDL)-apheresis methods in patients with familial hypercholesterolaemia.

We prospectively compared effectiveness, selectivity and biocompatibility of three LDL-apheresis methods, immunoadsorption (IMAL), dextran sulphate adsorption (DSAL) and heparin-induced extracorporeal LDL precipitation (HELP). Seven patients with familial hypercholesterolaemia were treated twice with each method in random sequence. Reduction in atherogenic lipoproteins was without significant difference: LDL -60% to -75%, VLDL -20% to -30%, triglycerides -20% to -42%. High-density lipoprotein (HDL)-cholesterol was reduced by IMAL only (-27%, P < 0.05); DSAL and HELP did not decrease HDL. Total plasma protein reduction was 13-15% with each method, indicating unselectivity. Albumin was significantly decreased by IMAL (-15%, P < 0.05) but not by the other methods. DSAL and HELP reduced fibrinogen (-40%, -58%, P < 0.0001) and other clotting factors. IMAL had almost no effect on coagulation. The white blood cell count did not change. C3 and C4 complement were decreased (-20% to -46%) by all methods. C5a complement did not increase in systemic blood, but was increased in the extracorporeal circulation of IMAL (+200%) and HELP (+150%). Plasma PMN elastase rose in all methods (+200%) indicating neutrophile degranulation. In conclusion, in this short-term study of a small patient population, effectiveness of the three LDL-apheresis methods was similar, but selectivity and biocompatibility were different. The therapeutic relevance of these differences for long-term treatment remains to be elucidated.

Blood Component Removal↗
PubMed1998

Activation of complement by human IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52.

Activation of the complement cascade by immunoglobulin G (IgG) plays a major role in the host defense against pathogens. Using recombinant human antibodies specific for the leucocyte antigen CD52, different allotypes of human IgG1 subclass were compared for their ability to activate human complement. In addition the roles of the different length hinge regions of IgG1 and IgG3 were investigated. It was found that the naturally occurring allotypes G1m(a,z) and G1m(f), and one artificially created isoallotype, G1m(null), did not significantly differ in their overall ability to cause cell lysis. However, some differences in binding of individual components of the classical activation pathway were detected. More of the complement component C1s seemed to be associated with the allotype G1m(f), although this did not result in an overall improvement in lytic potency. In this system the wild-type IgG3 was found to be less effective in complement lysis than IgG1. By shortening the hinge region of IgG3 to resemble that of an IgG1 antibody, increased complement binding was observed compared with that of wild-type IgG3 and the IgG1 allotypes. The overall lytic potency of the antibody was also improved compared with wild type IgG3 and it was also slightly more effective than the IgG1 allotypes.

Antigens, CD↗
PubMed2001

Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts.

BACKGROUND: The contribution of humoral alloreactivity to the rejection of renal allografts is not well defined because humoral antigraft reactions are not easily detectable in transplant biopsies, and serial measurements of circulating allo-antibodies in the post-transplantation period are not routinely performed. We have developed diagnostic techniques that improve the assessment of humoral alloreactivity in vivo and in vitro. METHODS: Humoral alloreactivity in transplant biopsies derived from 218 single kidney grafts was detected by assessing the deposition of complement fragment C4d in interstitial capillaries. Circulating alloantibodies were determined in corresponding serum samples by flow cytometry using lymphoblastoid cell lines of donor DR-type as target cells and by a conventional microcytotoxicity test. The impact of capillary C4d and other selected variables on renal graft survival was calculated by univariate and multivariate analysis. RESULTS: Capillary C4d, present in 46% of biopsies from first grafts and 72% of regrafts, is related to circulating alloantibodies. Grafts with capillary C4d have a markedly shorter survival than grafts without capillary C4d (50% graft survival, 4 vs. 8 years, P = 0.0001). Among several risk factors, capillary C4d is the strongest predictor of subsequent graft loss in a multivariate analysis (relative risk, 2.1, 95% CI, 1.4 to 3.1). Humoral alloreactivity detectable within six months after transplantation has a much stronger impact on graft survival than alloreactivity detected beyond this period. CONCLUSIONS: Humoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation.

Adult↗
PubMed2003

Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection.

BACKGROUND: Peritubular capillary (PTC) deposition of complement split factor C4d in renal allografts has been shown to be closely associated with circulating antidonor antibodies and a marker for relatively poor graft survival. Monocyte/macrophage (MO) infiltration of renal allografts has been shown to adversely affect graft survival. The purpose of this study was to assess whether the two phenomena are related. METHODS: Twenty-three biopsies (from 15 patients) demonstrated diffuse strong staining of PTC for C4d (C4d+ group) and acute tubular injury with or without significant cellular rejection, while 28 biopsies (with acute rejection) but negative for PTC C4d served as controls (C4d- group). RESULTS: The C4d+ group demonstrated significantly greater glomerular and interstitial MO infiltration than did the C4d- group [3.4 +/- 2.0 vs. 0.2 +/- 0.3 MO/glomerulus, P < 0.0001; 12.9 +/- 9.2 vs. 6.5 +/- 5.0 MO/high power field (hpf), P = 0.0030]. Neutrophilic (PMN) infiltration of glomeruli and PTC was also significantly greater in the C4d+ group than in the C4d- one (0.8 +/- 0.6 vs. 0.3 +/- 0.3 PMN/glomerulus, P = 0.0003; 0.9 +/- 0.8 vs. 0.4 +/- 0.3 PTC PMN/hpf, P = 0.0035). CONCLUSION: The results indicate a close association between PTC C4d deposition and MO infiltration, particularly glomerular, and confirm previous observations regarding the correlation of PTC C4d staining and PMN infiltration.

Acute Disease↗
PubMed2003

Plasmapheresis in C4d-positive acute humoral rejection following kidney transplantation: a review of 4 cases.

Acute and chronic rejection after kidney transplantation has long been exclusively attributed to cellular and vascular mechanisms. Modern immunosuppressive therapy, therefore, addresses the cellular immune system. Rising experiences in kidney transplantation in the last few decades have revealed that some types of rejection are refractory to the conventional immunosuppressive treatment. Humoral rejection. which has previously been reported as a crucial factor in hyperacute rejection, is now suspected to play also an important role in acute and chronic rejection. Acute humoral rejection (AHR) is characterized by immunohistochemical detection of C4d deposits in peritubular capillaries. As shown for other antibody-mediated diseases, such as some autoimmune diseases, plasmapheresis has been suggested to be an efficient therapeutic approach in AHR. We present four patients with C4d-positive AHR in the early phase after kidney transplantation. In three of the four patients, humoral graft rejection was successfully treated by plasmapheresis. Graft function was significantly improved with a stable long-term outcome. One patient lost the graft. Although the number of patients with C4d-positive AHR treated by plasmapheresis is limited, plasma exchange appears to be an efficient and powerful therapeutic approach to control humoral rejection.

Acute Disease↗
PubMed2000

Complement activation in acquired and hereditary amyloid neuropathy.

The pathogenesis of the axonal degeneration in acquired or hereditary amyloidosis is unknown. In this immunohistochemistry study, we examined 20 sural nerve biopsies from individuals with amyloid neuropathy (14 acquired and 6 hereditary) for evidence of complement activation. Complement activation products were detected on and around amyloid deposits within peripheral nerves. We found no difference in the extent, location or pattern of complement activation products between the 2 forms of amyloidosis. The presence of early classical pathway activation markers in the absence of antibody in hereditary cases suggests an antibody-independent activation of the classical pathway through binding of C1q. The lack of Factor Bb-suggested alternative pathway activation was not significant in these cases. The detection of C5b-9 neoantigen on amyloid deposits demonstrated that the full complement cascade was activated. Complement activation on amyloid deposits and the generation of C5b-9 in vivo may contribute to bystander injury of axons in the vicinity of amyloid deposits.

Aged↗
PubMedDate not supplied

Cryopreservation of complement-coated erythrocytes.

Cells coated with complement components (C3b-C4b and C4b cells) were prepared by various methods and stored in liquid nitrogen using a low-glycerol, rapid freeze technique. Freshly coated cells, and cells coated and then frozen were tested versus various antiglobulin and anticomplement reagents to evaluate the reactivity of such frozen, stored, complement-coated human red blood cells. Liquid nitrogen preservation of such coated cells proved to be feasible when such cells were compared with freshly coated control cells.

Animals↗
PubMed1993

Complement activation in stored platelet concentrates.

Activation of platelets during preparation and/or storage of platelet concentrates in plastic containers at room temperature has recently been recognized. Many different biologic causes of this activation have been postulated. Activated complement, as a multi-enzyme system, is one of the possible sources of molecules leading to platelet activation. To detect complement activation, functional complement activity and the generation of complement-derived ligands were investigated in platelet concentrate supernatant plasma during 5 days of storage at room temperature. Hemolytic tests for functional classical and alternative pathway activity were used, as was the kinetic test for complement-mediated inhibition of immune complex precipitation. The presence of C3 activation products (C3, C3c, C3dg) was investigated in plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting procedures and on platelets by immunofluorescence. Activation of complement was evident during storage, and C3c and C3d fragments were clearly demonstrated in plasma. The amount of C3d fragments on platelets gradually rose during the first 3 days of storage. At the end of 5 days of storage, the platelets became C3d negative. There are two possible mechanisms of C3d disappearance--shedding and/or further degradation of C3d fragments. Those results indicated that complement activation and the generation of complement-dependent ligand-receptor interaction may be mechanisms for platelet activation in concentrates stored at room temperature.

Binding Sites, Antibody↗
PubMed1997

Complement activation in vitro by the red cell substitute, liposome-encapsulated hemoglobin: mechanism of activation and inhibition by soluble complement receptor type 1.

BACKGROUND: Liposome-encapsulated hemoglobin (LEH) has been developed as an emergency blood substitute, yet its effect on human complement has never been explored. Considering that complement activation is a major pathogenic factor in the respiratory distress syndrome that often develops in trauma and shock, LEH-induced complement activation may be a critical safety issue. STUDY DESIGN AND METHODS: Various LEH and corresponding empty liposomes were incubated with normal human sera, and various markers of complement activation (serum levels of C4d, Bb, SC5b-9, and CH50; C5a-induced granulocyte aggregation; membrane deposition of C3b) were measured. Incubations were also performed in the presence of (ethylene-bis[oxyethylenenitrilo]tetraacetic acid) (EGTA) and Mg++ (EGTA/Mg++) and soluble complement receptor type 1. RESULTS: LEH and liposomes activated human complement, as indicated by significant changes in one or more markers. The effect was primarily due to the presence of the phospholipid vehicle; small, unilamellar, highly homodispersed vesicles induced the greatest degree of complement activation. Complement activation was partially inhibited by EGTA/Mg++. The latter finding, together with the parallel increases in serum C4d and Bb, suggests activation of both the classical and alternative pathways. Soluble complement receptor type 1 (0.05-20 micrograms/mL) efficiently inhibited all vesicle-induced complement activation. CONCLUSION: Because of complement activation, the use of LEH for transfusion may require careful evaluation of safety. Soluble complement receptor type 1 may be useful as a prophylactic agent for complement activation-related complications of liposome infusions.

Blood Substitutes↗
PubMed1997

Complement activation during storage of whole blood, red cells, plasma, and buffy coat.

BACKGROUND: The process of separating whole blood into components and the storage of blood components may cause the release of toxic metabolites from the complement cascade. The aim of this study was to determine whether the storage of blood components leads to the activation of the complement cascade and the release of anaphylatoxins. STUDY DESIGN AND METHODS: Blood from 12 healthy volunteers was collected and stored either as whole blood or as components: red cells in saline-adenine-glucose-mannitol solution, plasma, and buffy coat. The concentrations of anaphylatoxins and other complement proteins in the various blood components were intermittently analyzed during a 5-week storage period. RESULTS: Increasing levels of anaphylatoxins were demonstrated during the storage of whole blood and plasma. Elevated concentrations of the anaphylatoxins C3a and C5a were observed during the storage of whole blood. Increased C5a levels were observed after 7 days of storage. High concentrations of C3a were found in plasma after 14 days of storage. Low or non-detectable levels of C3a; C5a, and other complement components were found in red cells stores in saline-adenine-glucose-mannitol solution. CONCLUSION: The study demonstrated activation of complement during the storage of whole blood and plasma but not in red cells in storage solution. The transfusion of larger volumes of stored whole blood or plasma may contribute to the risk of development of organ dysfunction. Therefore, it is advisable to use red cells in storage solution.

Anaphylatoxins↗