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PubMedDate not supplied

Role of fibronectin and complement in immunopathogenesis of acute and subacute hepatic failure.

The present study describes the plasma levels of soluble fibronectin (FN), C3d, the breakdown product of C3 complement and Ba, the breakdown product of properdin factor B, in 30 patients of uncomplicated acute viral hepatitis (AVH), 64 patients of fulminant hepatic failure (FHF) and 29 patients of subacute hepatic failure (SAHF) with different hepatitis viral infections. Aetiological analysis of these patients demonstrated hepatitis B, hepatitis C and hepatitis non-A, non-B, non-C (NANB-NC) infections in 6.7, 13.3 and 80% cases, respectively, of the AVH group; 18.8, 42.2. and 39.0% cases, respectively, of the FHF group; and 31.0, 34.5 and 34.5% cases of the SAHF group. None of them had hepatitis A infection. The analysis of data showed that the plasma FN level was significantly reduced in patients with FHF and SAHF as compared to AVH patients and healthy persons. Fibronectin levels in AVH was comparable to that in the healthy group. Further, the FN level was not dependent on the nature of aetiological virus. The level of C3d in plasma was significantly high in all patients of FHF and SAHF, irrespective of their viral aetiology, compared to the AVH group and the healthy group. Like FN, the C3d level was comparable in the AVH and healthy groups. However, the Ba level was comparable to the normal value in all types of infections including the AVH, FHF and SAHF groups. These findings were used to explain the possible roles of fibronectin and complement in the immunopathogenesis of liver injury in patients of acute liver failure of viral aetiology.

Adult↗
PubMed1986

Detection of complement activation in immune complex diseases: six methods compared.

We compared the performance of six complement tests: electrophoresis, immunofixation, immunoelectrophoresis, and nephelometric quantifications of C3, C4, and C3d. We used 123 blood samples from 60 control subjects and 63 patients with immune complex diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rheumatoid arthritis, acquired immunodeficiency syndrome, renal diseases, vasculitis, cryoglobulinemia, Gram-negative bacteremia, Hashimoto's thyroiditis, rheumatic heart disease, malaria, and chronic active hepatitis. Immunofixation and quantification of C3d were better for detecting complement activation, their sensitivity rates (90.5% and 89.3%, respectively) being higher than those of the other tests studied. Immunofixation is a relatively simple and inexpensive test, provides good resolution of protein bands, and yields results that are easily quantified with a densitometer. Nephelometry of C3d provides more rapid and accurate quantitative results than immunofixation, but commercial reagents are not yet available. The causes of false-positive results in complement tests and the mechanisms of complement activation in AIDS are also discussed.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Membrane-bound immunoglobulins and complement components on young and old red cells.

In order to characterize changes in membrane-bound immunoglobulins and complement components, red cells (RBCs) were separated into young and old populations by simple centrifugation. Old RBCs had reduced mean corpuscular hemoglobin volume, increased mean corpuscular hemoglobin concentration, and reduced sialic acid. Using radioactive anti-antiglobulin techniques, old RBCs were shown to have more IgG, IgM, IgA, and C3d on their surfaces than did young RBCs; there was no increase on old RBCs of C3b, factor B, C4b, or C5. Similar results were observed with RBCs strongly coated with C3d in vivo from a patient with cold agglutinin disease. RBCs taken into ethylenediamine tetraacetate, washed thoroughly in saline, and then stored for prolonged periods in Alsever's solution or kept in autologous ethylenediamine tetraacetate plasma, at 4 degrees C, showed no increase in RBC-bound C3d with increased storage time. If, however, blood was taken into citrate-phosphate-dextrose and maintained at 4 degrees C in autologous plasma, a significant increase in RBC-bound C3d was observed in the mixed-cell population with prolonged storage time. Order donor blood units, taken into citrate-phosphate-dextrose and stored at 4 degrees C as packed red cells, showed higher levels of RBC-bound C3d in the mixed-cell population than did units stored for a shorter time. In no case did donor unit RBCs give a positive direct antiglobulin test on serologic testing with anti-C3d. The findings complement data already collected on membrane and cytoplasmic changes in aging RBCs and may contribute to an understanding of RBC senescence.

Anticoagulants↗
PubMed1988

Cell cycle control of a Burkitt lymphoma cell line: responsiveness to growth signals engaging the C3D/EBV receptor.

CR2, the receptor for the C3d fragment of the third complement component and for Epstein-Barr virus (EBV) has been shown, on mouse B cells, to be involved in the control of B-cell proliferation by acting as a receptor for macrophage-derived growth factors. We examined whether the growth of a Burkitt lymphoma cell line, RAJI, could be influenced by ligands of human CR2. In serum-free culture, purified human C3d, as well as three monoclonal antibodies to distinct epitopes on human CR2, were capable of enhancing the growth rate of RAJI cells two to five-fold. This effect could not be observed if even trace amounts of serum were present in the culture medium. Simultaneous addition of pairs of antibodies did not enhance the growth rate, suggesting that a particular engagement of CR2 may be critical in order to induce a stimulatory effect. These results indicate that in a homologous serum-free human B-cell system human C3d as well as monoclonal antibodies to human CR2 can induce B-cell proliferation and that CR2-mediated triggering of B cells can be induced via epitopes other than the C3d-binding site. In addition we conclude that--unlike normal human B cells--at least some human B-lymphoma cells respond to CR2-mediated stimuli in the absence of any T-cell derived factors. Therefore the control mechanisms exerted through CR2 must still be intact on these autonomously growing cells.

Antibodies, Monoclonal↗
PubMed1989

A knowledge-based system for automatic interpretation of an analytical profile of complement factors.

A comprehensive assay to evaluate the complement system includes functional tests of both classical and alternative pathways and immunochemical measurements of C3, C4, B, C1-INA, and C3d. The purpose of this analytical profile is to screen for rare hereditary deficiencies and acquired abnormalities of complement and to define the activation pathway in cases of complement consumptive processes. Based on several years' experience, a routine was established in our laboratory to report the data to the clinician, together with a computer-generated interpretive statement. This routine was formulated into a knowledge base by specifying a series of decision rules for each of the complement disorders. After the rules were tested and updated against some 400 complement profile analyses, reasonable analytical comments were produced by the system. This knowledge-based system for reporting and interpreting complement results offers several advantages: the interpretative work is facilitated and made more reliable; a consistent interpretative comment is generated that is recognized and therefore more meaningful for the clinician; the communication of analytical procedures and policy is enhanced.

Artificial Intelligence↗
PubMed1999

Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes.

BACKGROUND: Prolonged warm or cold ischemia is associated with poor survival of cardiac transplants, and ischemic changes in early posttransplantation endomyocardial biopsies correlate with the later development of chronic rejection. In animal models, tissue ischemia has been shown to activate complement. METHODS: To determine whether ischemic changes in endomyocardial biopsies were associated with complement deposition, biopsies obtained 1-3 weeks after transplantation from 33 patients were evaluated immunohistologically for C4d and C3d deposition as well as for IgM, IgG, and IgA. The histological changes associated with ischemic injury were scored independently, using previously reported criteria without knowledge of the immunohistochemical results. RESULTS: Diffuse capillary and pericapillary deposition of C4d or C3d were detected in endomyocardial biopsies of 14 of the 33 patients. The majority of biopsies (79%) with C4d or C3d deposits had histological evidence of ischemic injury, including eight of the nine biopsies containing both C4d and C3d deposition. In contrast, only 8 of 18 (45%) of the biopsies without C4d or C3d deposition had ischemic injury. Only trace amounts of IgM and no IgG or IgA were demonstrable in the biopsies. Only 2 of the 14 biopsies with C4d or C3d deposition had evidence of moderate acute rejection, whereas 5 of the 18 biopsies without C4d or C3d deposition had moderate acute rejection. However, C4d and C3d deposition did correlate with repeated acute rejection episodes on subsequent biopsies. CONCLUSIONS: Thus, ischemic changes are associated with the activation of complement. Complement activation may in turn promote tissue injury and provide a potential target for future treatment.

Adult↗
PubMed1992

The influence of tourniquet ischaemia on post-operative degranulation of polymorphonuclear granulocytes.

Degranulation of polymorphonuclear granulocytes following minor surgery and the contributory role of temporary tissue ischaemia in a limb were examined in 22 otherwise healthy patients undergoing elective arthroscopy under general anaesthesia with and without tourniquet. Apart from an increase in lactate levels following tourniquet release there was no difference in complement split product C3d, cortisol, leukocyte or creatinine kinase levels between the two groups. There was a post-operative increase in the plasma E alpha 1-proteinase inhibitor concentration, whereas lactoferrin values decreased 4 h following tourniquet deflation. Anaesthesia and minor surgery are followed by post-operative release of polymorphonuclear neutrophil elastase. This release is not related to complement activation and is apparently unaffected by 50 min of lower limb ischaemia. Anaesthesia and minor surgery do not cause lactoferrin release.

Adolescent↗
PubMed1988

A discontinuous factor H binding site in the third component of complement as delineated by synthetic peptides.

Factor H, a very important regulator of alternative pathway activation, exerts its effects by binding to the third component complement, C3. In this study we present evidence that factor H reacts with at least two sites in the third component of complement (C3), and we have mapped one of these sites within the C3d fragment of C3. By using direct binding assays of an anti-human H anti-idiotypic antibody (alpha alpha H) and of H to C3 fragments, it was shown that both bound to the C3b and C3d (but not to C3c) fragments of C3. Cleavage of C3d by CNBr generated two major fragments with Mr values of 12,500 (residues 997-1107) and 8,600 (residues 1178-1252). Binding studies with these two fragments showed that only the Mr 8,600 fragment bound to both H and alpha alpha H. Several synthetic peptides (A58, 1192-1249; P28, 1187-1214; P16, 1194-1209; P14, 1201-1214; B17, 1206-1222; J28, 1222-1249; and J16, 1234-1249) were synthesized according to the primary sequence of the Mr 8,600 fragment. Based on the differential binding of these synthetic peptides to H, their inhibitory effect on H binding to C3b or C3d, and their effect on H cofactor activity, we mapped the H binding site in C3 to a discontinuous site spanning residues 1187-1249 of the C3 sequence. By studying the inhibition of H binding to C3b or C3d by the different synthetic peptides, we also present evidence that a second binding site in C3b for H exists.

Amino Acid Sequence↗
PubMed1990

Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I.

The factor I-mediated cleavage of C3b, using factor H as a cofactor was completely inhibited by diisopropylfluorophosphate (DFP) when factor I and C3b were incubated with DFP before the addition of factor H. Inhibition, although to a lesser degree, was observed when factor H was present during DFP-exposure. No inhibition in factor I activity was seen when factor I and H were incubated with DFP either alone or together. It was also demonstrated that the 38-kDa subunit of factor I bound radiolabeled DFP when factor I and C3b together were exposed to DFP. These observations suggest that factor I interacts with C3b in a manner that exposes its catalytic site to DFP, an interaction that is independent of factor H. The inhibitory effect by DFP on factor I led us to further investigate the factor I cleavage products of iC3b, inasmuch as previous reports were ambiguous as to whether digestion occurs in the presence of DFP. Digestion of C3b bound to activated thiol Sepharose (ATS-C3b) in the presence of factor H at low pH and ionic strength and in serum by complement activation produced C3d,g-like fragments with apparent molecular mass of 41 and 43 kDa. These fragments were shown to have three different N-terminal and two different C-terminal ends. The major fragments had N-terminal sequences starting with Glu933, as shown by sequence determination. Traces of fragments extending beyond this point were also found, shown by Western blot analysis using a panel of mAb previously shown to bind to epitopes exposed within a region of C3 spanning residues 929 to 943, as well as a shorter fragment starting with Glu938. When digestion of C3b is carried out in the presence of DFP, the factor I level necessary for digestion is elevated and may explain how the first two cleavages producing iC3b but not the following giving C3d,g, can occur. The finding of several factor I cleavage sites in the C3d,g region of C3 demonstrates that factor I has a broad specificity, mainly for arginyl bonds. It has also been shown to digest a lysyl bond exposed in ATS-bound C3b.

Amino Acid Sequence↗
PubMed1987

Screening for complement deficiencies in unselected patients with meningitis.

Two hundred and nine patients consecutively admitted to hospital with a tentative diagnosis of meningitis were screened for complement deficiency by measuring classical and alternative pathway serum haemolytic complement activity and the plasma concentration of C3d. Abnormal test results were followed up by quantitative immunochemical measurements of individual complement components. No patients with homozygous complement deficiency were found in our material. One patient with pneumococcal meningitis with probable heterozygous C2-deficiency was identified. Patients with purulent meningitis of various etiologies or meningococcal disease had significantly increased plasma C3d concentration at admission compared to patients with serous meningitis or without meningitis. Furthermore, increased plasma level of C3d at admission in patients with purulent meningitis or meningococcal disease was associated with an increased lethality. Our findings do not support the hypothesis that complement deficiency is commonly associated with sporadically occurring meningococcal disease or purulent meningitis.

Adolescent↗
PubMed1985

Generation of the bioactive kallikrein-derived fragment, C3d-k, by HANE-plasma.

Recent studies have concluded that after complement activation the final physiologic degradation products of C3 are C3c and the fragment of relative molecular mass (Mr) 42,000 which contains the C3d and C3g domains and was therefore named C3d,g. Using fluorescent labelled C3b as a substrate, we have determined the putative C3d,g ('C3d,g') producing activity of both normal and hereditary angioneurotic oedema (HANE) plasmas. In normal plasmas, the rate of production of C3d,g was 1.0 +/- 0.2 X 10(-10) mol/ml/h and this activity was blocked by antibodies to I. In contrast, HANE, plasmas (deficient in C1INH) showed more than twice as much 'C3d,g' production as normal plasmas and both antibodies to I and kallikrein were required to inhibit this activity. Because of this result, a more sensitive gel system was employed to detect the Mr 42,000 peptide and two 'C3d,g' fragments of approximately equal intensity with Mr of 42,000 and 43,000 were defined. Incubation of purified kallikrein with labelled iC3b produced a C3d,g-like fragment, C3d-k, that aligned with the band of 43,000 Mr generated in HANE plasma. These results indicate that HANE plasma, in contrast to normal plasma, generates the bioactive C3d-k fragment. C1INH blocks the activities of kallikrein and C1s, and C3d-k generation in HANE plasma is probably secondary to the proteolytic activity of kallikrein.

Angioedema↗
PubMed1984

Plasma C3d/C3 quotient as a parameter for in vivo complement activation.

Plasma levels of C3 and C3d in 30 healthy donors and 58 patients with systemic lupus erythematosus were determined by rocket immunoelectrophoresis and Con-A affinoimmunoelectrophoresis. Significantly decreased levels of C3 were found in approximately 50% of the SLE sera. Slight increases of free C3d were found in 55%, and marked increases in 9% of the SLE sera; the remaining SLE sera did not show increased C3d levels. When results were expressed as quotients of plasma C3d/C3, a significant pattern emerged and 70% of the SLE sera clearly fell outside the normal range. 10% of the SLE sera had normal C3d/C3 indices but had markedly depressed C3 levels. We conclude that in cases where total serum C3 is not markedly reduced (less than 60% of normal), the C3d/C3 quotient may be a more sensitive parameter for assessing in vivo complement activation than C3 or C3d determinations alone.

Complement C3↗
PubMed1991

The complement system in HIV disease.

Different aspects of the relationship between the HIV infection and the complement system were studied. 1. No significant differences were found between seronegative controls, asymptomatic, and symptomatic (ARC, AIDS) HIV-seropositive patients in the plasma levels of complement components C4, Bf, and C3. 2. Using sensitive ELISA assays, a significant increase was observed in the levels of protein-protein complexes which are formed at the activation of the classical (C1r-C1s-C1-INH) and alternative (C3b-Bb-P) pathways, indicating that both complement pathways are activated in the HIV disease. No significant differences were found, however, in the levels of these complexes between the groups of asymptomatic and symptomatic HIV-infected patients. 3. Artificial immune complexes of synthetic peptides representing some immunodominant epitopes of HIV envelope (gp120, and gp41) proteins, and human polyclonal anti-HIV IgG were found to weakly activate both the classical and alternative complement pathways. 4. An elevated percentage of the lymphocytes carrying a complement activation fragment, C3d, was detected in the blood of HIV seropositive patients as compared to the seronegative controls. No significant positive correlation was found between the percentage of these cells and that of any T cell subsets tested.

Complement Activation↗
PubMed1982

An immunoperoxidase study of immunological factors in skin lesions across the spectrum of leprosy.

The immunoperoxidase technique was used to assess the quantity and situation of various immunological factors in 24 skin biopsies which represented the leprosy spectrum from TT to LL. The factors were immunoglobulins (IgG and IgM), complement components (C3, C3d and Clq), plasminogen, muramidase (lysozyme), C-reactive protein and alpha-1-antitrypsin. The results were compared with previous reports on the assessment of these factors in serum. The quantities of these factors in the lesions produced peaks at TT and LL, with a dip in the BT-BB region (C-reactive protein and alpha-1-antitrypsin excepted). The immunoglobulins, present mainly in plasma cells and lymphocytes, correlated in general with reports of serum levels. The complement components were present in appreciable amounts, though the serum levels are depressed; they were seen in young mononuclear cells with a low bacterial load. All factors produced an ascending gradient in active lesions from BT to BL or LL, which correlated with the bacterial load and its viability. In regression (studied only in LL) there was a decrease in all factors. In TT there was an increase in most factors which did not correlate with the antigen load, and which probably resulted in an excess of antibody over antigen. In active LL there is probably an antigen excess. The results suggest the possibility that there is a common defect from BT to LL, in which the generation of immunological factors within the lesion of immunological factors within the lesion is a secondary response to the antigenic load. In TT alone (a rare group) is there an enhanced immunological response unrelated to the antigen load. In support of this was the finding of Ia antigen only in TT lesions.

Complement System Proteins↗
PubMed2001

Immunopathology of secondary-progressive multiple sclerosis.

Twenty-three plaques obtained at early autopsy from 2 patients with secondary-progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low-grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary-progressive multiple sclerosis.

Adult↗
PubMed1990

The complement system in ischemic heart disease.

The mechanisms by which tissue injury after acute myocardial infarction (AMI) occurs has not been fully elucidated. Recent evidence in experimental models has suggested involvement of the complement system in microvascular and macrovascular injury subsequent to AMI. With respect to angina pectoris, whether or not the complement system is activated is not clear. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation, including C3d, C4d, Bb, and SC5b-9 complexes, in 31 patients with AMI, 17 patients with unstable angina pectoris, 19 patients with stable angina pectoris, and 20 normal volunteers. The plasma C3d levels increased in patients with AMI and in those with unstable angina pectoris (p less than 0.01). The plasma levels of C4d, Bb, and SC5b-9 increased only in patients with AMI (p less than 0.01). The plasma SC5b-9 level was related to peak creatine phosphokinase (r = 0.71) and inversely related to the ejection fraction (r = -0.71). The plasma SC5b-9 level of patients with congestive heart failure was higher than that of patients without congestive heart failure in AMI. These results show that activation of complement system occurs after AMI and show an association of myocardial damage with complement activation. With respect to angina pectoris, the complement system is mildly activated in patients with unstable angina pectoris; however, the cardiac function of patients with unstable angina pectoris is not damaged. The complement system of patients with stable angina pectoris is not activated.

Angina Pectoris↗
PubMed2002

Effect of modified ultrafiltration on the inflammatory response in paediatric open-heart surgery: a prospective, randomized study.

Modified ultrafiltration (MUF) is often used in conjunction with paediatric cardiac surgery with cardiopulmonary bypass (CPB) and is thought to improve clinical outcome. It is unclear whether these improvements (if any) are due to the removal of inflammatory mediators. In this prospective study, 18 children aged 12-24 months undergoing uncomplicated cardiac surgery with methylprednisolone added in the pump prime were randomized to receive CPB with (n = 10) and without (n = 8) MUF. Cytokines (TNFalpha, IL-6, IL-1beta, IL-10, IL-1ra), complement split products (C3d, C4d) and coagulation system activation (F1 + 2, ATIII) were measured pre-, peri- and up to 48 h postoperatively. For clinical outcome, the alveolar-arterial oxygen (A-a) gradient, transfusion requirement, drain loss, mean blood pressure and requirement for inotropic support were registered up to 24 h postoperatively. Our results show an improvement in postoperative oxygenation as well as a tendency towards decreased drain loss and improved haemodynamics in the MUF group. There were no intergroup differences detectable for TNFalpha, IL-1beta, IL-1ra, complement and coagulation markers. We conclude that MUF in itself does not significantly influence TNFalpha, IL-1beta, IL-1ra and the complement and coagulation profiles in children undergoing cardiac surgery with CPB. Despite this, there was some evidence for improved clinical outcome. Our results do not support that MUF improves postoperative organ function by modulation of the measured markers of inflammation.

Biomarkers↗
PubMed1991

Reactions of the immune system in chronic degenerative neurological diseases.

Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fc gamma R1), for complement 3 and 4, and for vitronectin. In AD, the complement proteins C1q, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.

Alzheimer Disease↗