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PubMed2003

Non-invasive monitoring of renal transplant recipients: urinary excretion of soluble adhesion molecules and of the complement-split product C4d.

BACKGROUND: The number of inducible adhesion molecules known to be involved in cell-mediated allograft rejection is still increasing. In addition, recent data describe complement activation during acute humoral allograft rejection. The aim of this study was to assess whether specific molecules from either pathway are excreted into urine and whether they can provide useful diagnostic tools for the monitoring of renal transplant recipients. METHODS: Urinary concentrations of soluble adhesion molecules (sICAM-1, sVCAM-1) and of the complement degradation product C4d were determined by standardized ELISA technique in 75 recipients of renal allografts and 29 healthy controls. Patient samples were assigned to four categories according to clinical criteria: GROUP 1: acute steroid-sensitive rejection (ASSR, n = 14), GROUP 2: acute steroid-resistant rejection (ASRR, n = 12), GROUP 3: chronic allograft dysfunction (CAD, n = 20) and GROUP 4: stable graft function (SGF, n = 29). RESULTS: All patients with rejection episodes (groups 1-3) had significantly higher values of urinary sC4d compared with healthy controls and patients with stable graft function (p < 0.05). The urinary levels of sVCAM-1 were significantly higher in group 2 (ASRR) compared with all other groups (p < 0.001). Uniformly low amounts of s-VCAM-1 and complement-split product C4d were excreted by healthy controls (group 0). In contrast, urinary sICAM-1 concentration in healthy controls was almost as high as in group 2 (ASRR) whereas patients with a stable functioning graft (group 4) excreted significantly less sICAM-1 (p < 0.05). CONCLUSION: The evaluation of sVCAM-1 and sC4d excretion in urine can provide a valuable tool with regard to the severity and type of allograft rejection. With respect to long-term allograft survival, serial measurements of these markers should have the potential to detect rejection episodes and prompt immediate treatment.

Adult↗
PubMed1986

I (C3b/C4b inactivator) typing by agarose gel isoelectric focusing and immunoblotting technique.

Genetic polymorphism of I (C3b/C4b inactivator) was studied by the method of agarose gel isoelectric focusing followed by an immunoblotting technique. Serum or plasma samples were pretreated with neuraminidase. The method is rapid, and gives the simple and reliable patterns of I. The allele frequencies calculated from healthy Japanese individuals living in the western part of Japan were: IF* A = 0.126 and IF*B = 0.874.

Blood Proteins↗
PubMed1987

Genetic markers in patients with intracranial aneurysms.

HLA antigens, blood group systems (ABO, Rh, MNSs, P, Kell, Lewis and Duffy) and serum group systems (Hp, Tf, Gc, Pi, Bf, C3 and C4) were studied in a series of patients with intracranial aneurysms. A significantly increased frequency of HLA antigen A28, a significantly decreased frequency of HLA antigen B40, and a significantly decreased frequency of complement factor C4 B2 was found among the patients when compared with controls from the same geographic area.

Complement C4↗
PubMed1989

Glomerular deposition of C4 cleavage fragment (C4d) and C4-binding protein in idiopathic membranous glomerulonephritis.

Renal biopsies from 12 patients with idiopathic membranous glomerulonephritis (IMGN) were investigated by immunofluorescence microscopy for the localization of C4d and C4-binding protein (C4bp). Although Clq and C4 deposits were found in only 2 of 12 cases (16%), C4d and C4bp deposits were identified in 11 cases (92%) in close association with IgG deposits in the glomeruli. The results suggest that complement activation through the classical pathway usually occurs in IMGN. The detection of C4d and C4bp in the glomeruli appears to be a sensitive indicator of the classical pathway activation in IMGN.

Carrier Proteins↗
PubMed1984

Studies on the binding of complement factor C4 in human platelets. Complement activation by means of cold agglutinins.

Normal human platelets were investigated by immunofluorescence techniques for the natural occurrence of and uptake capacity for complement factor C4. Fractions of human platelets were found to carry none or very little C4. Activated C4 was readily taken up by the majority of platelets in vitro. Complement could be activated with pathological cold agglutinins (CA) of mono- or polyclonal types, all with specificity for the I antigen. Complement activation seen in normal human sera was probably due to naturally occurring CA with anti-I specificity. Thrombin potentiated the complement-activating capacity of CA, and complement factor C1 enhanced and stabilized the binding of CA to platelets.

Agglutinins↗
PubMed1989

Assessment of the activation pathways of the complement in psoriatic patients by use of complement fragment C4d and Bb measurements.

We have measured the complement fragment C4d and Bb levels in the plasma of 51 psoriatic patients and 54 normal controls. The C4d and Bb levels were not significantly elevated in the plasma of the psoriatic patients when compared with those of controls, except in patients with more than 60% skin involvement who exhibited an increase in Bb levels. C4d levels, however, did decrease slightly after successful treatment of psoriasis. Although these results suggest that the C4d and Bb levels partly reflect the complement activation in vivo, they do not seem to be suitable parameters to clarify the mechanism of complement activation in psoriasis.

Adolescent↗
PubMed1991

Sarcoidosis and major histocompatibility complex genes with special emphasis on BF F subtypes.

Frequencies for HLA class I and II histoglobulins and C4A, C4B, BF complement proteins were performed for 59 sarcoidosis patients. The DR5 allele was present in 55.9% of patients as compared to 31.5% of controls. We noticed that its increase was more relevant in males and in those with a poor prognosis. BF F allele was significantly over-represented in patients (29.09% vs. 19.15% of control), especially in women. Special emphasis was given to BF F subtyping, to define an association between a particular BF F subtype and patient's sex or disease outcome.

Alleles↗
PubMed1985

Immunoelectrophoretic analysis of C4 split products expressing D but not C epitopes: influence of storage, Ca2+ and Ca2+-chelating agents.

Based on immunoelectrophoretic methods a heterogeneity in the electrophoretic mobility of C4d was observed. C4d was defined immunochemically as C4 molecules expressing D but lacking C epitopes. A beta-mobile form was observed when EDTA or heparin was not added to the sample prior to electrophoretic analysis. This component was generated during electrophoresis. Another C4d component migrating to the post-albumin region probably represented an in vivo generated split product. However, this C4d form was also produced during storage of serum or plasma at room temperature and its formation was enhanced in the presence of EDTA. Based on these findings standard conditions for collection and storage of clinical samples for quantification of C4d by electroimmunoassay are suggested.

Calcium↗
PubMed2004

The Ser460Pro mutation in recombinant protein S Heerlen does not affect its APC-cofactor and APC-independent anticoagulant activities.

Protein S is a vitamin K-dependent plasma protein that functions as an APC-cofactor, but also exhibits anticoagulant activity in the absence of APC. The Heerlen polymorphism of protein S is characterized by a Ser460Pro substitution and lacks glycosylation at Asn458. It is associated with decreased protein S levels due to selective deficiency of free protein S Heerlen. To understand the lack of thrombotic complications associated with the protein S Heerlen mutation, we compared recombinant protein S Heerlen, wild type (wt) protein S and plasma-derived protein S. wt-Protein S and protein S Heerlen each bound 1:1 to C4BP with dissociation constants of 0.27 and 0.33 nM, respectively. Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were equally active as prothrombinase inhibitors in the absence of APC. All three protein S preparations stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and FVIIIa to the same extent. If extrapolated to plasma, it is not likely that the decreased free protein S levels in carriers of the protein S Heerlen mutation are compensated by an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is possible that an unrecognized plasma factor selectively enhances the anticoagulant activity of protein S Heerlen. If not, the reduction of free protein S levels in heterozygous protein S Heerlen-carriers combined with (low) normal total protein S levels apparently minimally affects the total anticoagulant activity of protein S (APC-cofactor and APC-independent activity) and hence is not associated with increased risk of venous thrombosis.

Anticoagulants↗
PubMed1996

Blood protein interactions with titanium surfaces.

Protein adsorption and complement activation were studied on thin evaporated films of titanium (Ti). The surfaces were cleaned in either a radio frequency (RF) plasma unit, or washed sequentially in trichloroethylene, acetone, ethanol, and water. Both methods resulted in hydrophilic surface with low carbon contamination on the outermost oxide (approximately 11-13 at%). In situ ellipsometry suggested that Ti is an intrinsic coagulation activator in vitro, since significant amounts of factor XII (F XII) and high molecular weight kininogen (HMWK) were found on the surfaces after 1 min incubation in heparin plasma. Ellipsometry, performed after serum incubations ranging from 15 s to 30 min showed that the total amount of serum proteins and the deposition of antibodies to complement factor 3c (C3c) increased with serum incubation time. ELISA methods showed increased levels of free iC3b in serum after 10 min incubation of the surfaces, but no detectable amounts of C3 convertase fractions C4d or Bb. Ellipsometric results indicated, however, an increased deposition of antibodies to CIq and IgG on Ti after short serum incubation times. The combined results indicate that Ti-surfaces initially activate complement through the classical pathway. The activation then continues via a positive amplification loop where increased amounts of C3 are deposited on the surfaces via the alternative pathway.

Acetone↗
PubMed1996

Blood protein interactions with chromium surfaces.

Protein adsorption, contact activation, and complement activation were studied on thin evaporated films of chromium (Cr) in vitro. The surfaces were, prior to the experiments, cleaned in either ethanol and water, or in a basic peroxide solution (RCA standard clean 1, SC-1). Surface spectroscopic studies of the outermost oxides showed a significant reduction of carbon contaminants after washing in SC-1 but also suggested an increase in the oxidation state as compared with the ethanol-washed surfaces. In situ ellipsometry combined with antibody techniques was used to determine protein deposition and antibody binding onto surfaces after incubations in heparin plasma or in normal serum. Incubation times from 1 to 10 min in serum showed increased depositions of serum and antibodies to complement factor 3c (C3c) and was larger on ethanol-washed surfaces than on surfaces washed in SC-1. ELISA methods indicated increased amounts of iC3b in serum for both surfaces, but no presence of C3 convertases (C4d or Bb fractions). A low or transient complement activation via the classical pathway was indicated on ethanol washed Cr, since deposition of secondary antibodies to complement factor Iq (CIq) was observed only after short incubation times in serum. No procoagulant activity of Cr was indicated, since only low amounts of antibodies to factor XII (F XII), prekallikrein (PKK), and high molecular weight kiniogen (HMWK) bound to the surfaces after incubations in heparin plasma. These results were confirmed using a colorimetric assay where the relative amounts of free plasma kallikrein was assessed using a chromogenic substrate, H-D-Pro-Phe-Arg-pNA (S-2302).

Adsorption↗
PubMed1991

Leukocyte adhesion-deficient neutrophils fail to amplify phagocytic function in response to stimulation. Evidence for CD11b/CD18-dependent and -independent mechanisms of phagocytosis.

Stimulation of PMN with inflammatory mediators markedly augments Fc and CR1 receptor-mediated ingestion. However, CD11/CD18-deficient PMN from three patients with complete leukocyte adhesion deficiency (LAD) failed to recruit phagocytic function in response to phorbol esters, cytokine, or Arg-Gly-Asp-containing ligand stimulation. Because stimulated ingestion is protein kinase C (PKC)-dependent, our data indicate that LAD PMN exhibit only PKC-independent phagocytosis. The defect in PKC-dependent ingestion is specific for CD11b/CD18 and not secondary to the chronic or recurrent infections which occur in this disease. The LAD phenotype for phagocytic function can be reproduced in normal PMN by the anti-CD11b MAbs OKM1 and OKM10. In contrast, MAb Mo1 (anti-CD11b) and MAb IB4 (anti-CD18) inhibit both CD11b/CD18-dependent and -independent mechanisms of ingestion by normal PMN. Their ability to inhibit CD11b/CD18-independent ingestion may be mediated by cAMP, as shown by experiments with a protein kinase A inhibitor HA1004 and by direct measurement of cAMP levels in immune complex- and FMLP-stimulated PMN. These data indicate that CD11b/CD18-independent and -dependent mechanisms of phagocytosis exist and that some effects of anti-CD11b/CD18 MAbs may be mediated by alterations in cAMP levels.

Antibodies, Monoclonal↗
PubMed1997

Effect of beta 2glycoprotein I and human monoclonal anticardiolipin antibody on the protein S/C4b-binding protein system.

The effect of beta 2glycoprotein I (beta 2GPI) and human monoclonal anticardiolipin antibody (aCL) on the protein S/C4b-binding protein (C4BP) system was evaluated. The binding of C4BP to protein S was assessed by ELISA in the presence of beta 2GPI with/without human monoclonal aCL. beta 2GPI downregulated the binding between S and C4BP significantly. Human monoclonal aCL abolished the beta 2GPI inhibitory effect in a calcium (Ca++) independent fashion. In separate experiments, the reactivity of aCL towards protein S in the presence or absence of beta 2GPI and cardiolipin was investigated. Monoclonal aCL bound to protein S only in the presence of a combination of beta 2GPI and cardiolipin. This binding was Ca++ dependent. These findings suggest that human monoclonal aCL increases the affinity of C4BP for protein S, and that protein S may represent one of the targets for aCL when combined with beta 2GPI and cardiolipin. Both issues may explain acquired free protein S deficiency and the attendant risk of thrombosis in patients with aCL.

Animals↗
PubMed2005

Evaluation of a new condensed extra-corporeal circuit for cardiac surgery: a prospective randomized clinical pilot study.

This prospective randomized clinical pilot study was conducted to evaluate a recently introduced reduced volume CPB system that is coated with the biopassive Xcoating. Twenty-two patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB), either with a fully heparin-coated CPB circuit (control, n=11) or with an Xcoating coated condensed extra-corporeal circuit (CondECC, n=11), were included. We examined activation of the complement system (C3bc and C4bc), activation of neutrophils (BPI), the acute phase response (interleukin (IL)-6, and acute phase proteins (LBP, AGP, and CRP)), myocardial tissue injury (troponin T), hemolysis (free hemoglobin (FHb)), and clinical outcome parameters. Preoperative risk profiles were identical for both patient groups. All patients went through the procedure without major complications and were discharged from the hospital. FHb and BPI levels at the end of pump support (p < 0.01) and at 15 min after the administration of protamine (p < 0.05) were significantly higher in the control group. In addition, FHb levels were still significantly elevated upon arrival on the cardiothoracic intensive care unit (CICU) in the control group (p < 0.05). C3bc and C4bc, acute phase proteins, IL-6, and troponin T concentrations, and clinical outcome variables were identical in both patient groups. In conclusion, the evaluated condensed extracorporeal circuit is a flexible and multifunctional CPB sytem that offers safe procedures. Furthermore, the results indicate improved biocompatibility of this option for extracorporeal circulation.

Acute-Phase Proteins↗
PubMed1986

Different patterns of C3 and C4 activation in the varied types of juvenile arthritis.

Quantitative assays for C3 and C4 activation were carried out simultaneously on blood from children with varied types of juvenile arthritis. Factor VIII-related antigen was also measured as an indicator of vascular damage. In active systemic juvenile arthritis, the C4d/C4 ratio was frequently elevated and was usually associated with elevated C3d/C3 ratios and elevated concentrations of factor VIII-related antigen. Children with chronic polyarticular arthritis, no matter which forms of onset they had had, also had increased levels of the C4d/C4 ratio, C3d/C3 ratio, and factor VIII-related antigen, but these were less consistent and were not associated with each other. In contrast, in pauciarticular arthritis there was a uniquely isolated increase in the C3d/C3 ratio. This work implies that there are different mechanisms responsible for complement activation in the different types and at different stages of juvenile arthritis.

Adolescent↗
PubMed1990

A case of first trimester prenatal diagnosis of 21-hydroxylase deficiency with human complement C4 cDNA probe.

Early prenatal diagnosis of 21-hydroxylase (21-OHase) deficiency would enable treatment to be done to protect the fetus from masculinization and/or life-threatening adrenal crisis at birth. We report here the prenatal diagnosis of 21-OHase deficiency with human complement component C4 cDNA to probe DNA from chorionic villi at 10 weeks of gestation. Southern analysis with human C4 cDNA identified TaqI restriction fragment length polymorphisms (RFLPs) in the family. Family analysis with these RELPs showed that the fetus was not affected at greater than 99% probability, because the frequency of recombination between the 21-OHase B gene and the C4 gene would be extremely low.

Adrenal Hyperplasia, Congenital↗
PubMed1990

HLA class I-, complement C4- and 21-hydroxylase probes in the genetic analysis of 21-hydroxylase deficiency.

In order to develop an optimal strategy for the prenatal diagnosis of steroid 21-hydroxylase (EC 1.14.99.10) deficiency, we investigated 16 affected families with salt wasting syndrome. Genomic DNA derived from peripheral white blood cells was digested with 6 different restriction enzymes. Hybridisation was carried out with DNA-probes of the HLA class I region, the 21-hydroxylase- and the complement C4 genes. All the families were informative in at least three different loci. Twelve out of the 16 families were informative by neutral polymorphisms or disease related variants of the 21-hydroxylase gene or the adjoining C4 locus. The reliability of prediction in these cases exceeded 99%. The remaining 4 families were informative only in the HLA class I region, tantamount to a reliability of prediction of about 98%. In none of the cases did we have to fall back on semiquantitative gene dose assessments. We further describe new polymorphisms in the 21-hydroxylase region for the enzyme Pvu II and EcoR V.

Adolescent↗