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PubMed1983

Complement activation in shock associated with a surgically provoked bacteriaemia.

The activation of complement (C) factors in a patient exhibiting an anaphylactoid shock 10 min after the initiation of transurethral coagulation of vesical papillomas was studied. Streptococcus faecalis was cultured from he urine before and after the shock and from the blood on two occasions within 2 days after the shock. The shock was associated with a marked but transient complement activation as judged from serial determinations of C3d and C3c by doubledecker rocket immuno electrophoresis and native C3 and C3c by crossed immuno electrophoresis. Conventional total C3 quantitation by rocket immuno electrophoresis did not reveal the activation. A decrease of native C4 to 20% of normal values and the appearance of C4 split products indicated classical pathway activation. Factor B conversion showed the alternative pathway to be involved as well. Total haemolytic complement activity was temporarily reduced, increasing without reaching normal values within 20 hours. The results indicated that the classical pathway was transiently activated, pointing to an acute antigen-antibody reaction, probably caused by the entrance of bacteria and bacterial products into the circulation of an immunized host.

Anaphylaxis↗
PubMed1987

[Complement activation following head and brain trauma].

The prognosis for a patient with a severe head injury is dependent not only upon the location and the degree of this trauma, but also upon additional complications. For example, disseminated intravascular coagulation (DIC) can occur because of the thromboplastic activity of the damaged brain tissue that enters the circulation. The complement (C) system is activated by certain enzymes that cleave the clotting factors. Therefore, after head injuries we searched for C activation because it could result in the adult respiratory distress syndrome (ARDS). Patients and methods. We had two groups of patients: (1) 23 with large destruction and (2) 13 with little destruction of the brain tissue. Eighteen patients in group 1 and 8 in group 2 had isolated brain trauma. Blood samples were taken--upon arrival at the hospital and then 1, 3, 7, 12, 24, and 48 h later; after that we took weekly blood samples up to the completion of their treatment in the intensive care unit. We measured the total hemolytic serum C activity (CH50), activation of alternative pathway hemolysis (APH50), cleavage products C3a and C3d, and total protein. Furthermore, we studied the coagulation parameters of the extrinsic (prothrombin time) and intrinsic (partial thromboplastin time) pathways and fibrinogen content. From the patients records we extracted clinical parameters such as neurological status, intracranial pressure, pathological details on computer tomography hemoglobin and arterial-alveolar oxygen difference. Results. Figure 1 shows the different reactions of the C system in both groups: while patients of group 1 suffered from a decrease in total and alternative hemolytic activity, the other group increases in both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Fluid-phase activation of the alternative pathway of complement by excess factor D in regularly dialyzed patients.

We examined the effect of excess factor D on the alternative pathway of complement (APC). First, we demonstrated that the production of C3a is accelerated in the fluid-phase with the addition of purified factor D. Analysis by sodium dodecylsulfate polyacrylamide gel electrophoresis under reducing conditions showed that the serum iC3b level was elevated when incubated with excess factor D. Secondly, we demonstrated, by measuring the C5a-des-Arg level, that the generation of C5a was promoted in the fluid-phase with the addition of purified factor D. We then studied whether activation of APC is elevated in the blood of patients on maintenance hemodialysis whose sera contained a high concentration of factor D. First, we detected, by fluorescence activated cell sorter analysis, greater amounts of C3d on erythrocytes from the patients (mean fluorescence intensity +/- SD: 7.7 +/- 1.7 arbitrary units) than those from healthy individuals (5.4 +/- 0.5 arbitrary units; p less than 0.001). Secondly, serum C3 level was significantly lower (p less than 0.001) in patients (mean +/- SD: 63.3 +/- 8.2 mg/dl) than in healthy individuals (84.8 +/- 9.5 mg/dl), whereas there was no difference in serum C4 level between patients (32.4 +/- 6.9 mg/dl) and healthy individuals (33.0 +/- 7.4 mg/dl). Serum C5 level was almost the same in patients (10.5 +/- 1.5 mg/dl) and in healthy individuals (11.2 +/- 1.3 mg/dl). These results provide supportive evidence of elevated APC activation in patients with high serum factor D.

Blood Circulation↗
PubMed2000

Blood-brain barrier disruption and complement activation in the brain following rapid correction of chronic hyponatremia.

In previous studies we developed a rat model in which demyelination is reproducibly produced following rapid correction of chronic hyponatremia and demonstrated that the development of demyelination in this model is strongly associated with NMR indices of blood-brain barrier (BBB) disruption. Because complement is toxic to oligodendrocytes, we evaluated the hypothesis that BBB disruption precipitated by correction of hypoosmolality is followed by an influx of complement into the brain, which then contributes to the demyelination that occurs under these conditions. We studied four groups of rats with immunocytochemical analysis using primary antibodies to IgG and the C3d split-fragment of activated complement: (1) normal rats; (2) rats in which hyponatremia was maintained for 7 days; (3) chronically hyponatremic rats in which the plasma [Na(+)] was rapidly corrected with hypertonic saline administration 20 h prior to perfusion; and (4) chronically hyponatremic rats in which the plasma [Na(+)] was rapidly corrected with hypertonic saline administration 5 days prior to perfusion. In normonatremic and uncorrected hyponatremic rats only background staining was observed in areas lacking a BBB and in blood vessel walls, whereas marked increases in IgG and C3d staining were seen in the brains of rats both 20 h and 5 days after rapid correction of hyponatremia. The staining intensity was significantly correlated with the degree of neurological impairment. These results provide evidence for functional BBB disruption following rapid correction of hyponatremia and support the hypothesis that complement activation may be involved in the pathogenesis of osmotic demyelination.

Animals↗
PubMed1985

The generation of active fragments of complement receptor type 2 by trypsin digestion.

B lymphocytes and Raji cells express the complement receptor type 2 (CR2) of 145 kDa which recognises the C3d fragment of C3. When intact cells are treated with trypsin, CR2 is degraded. There is a parallel loss in C3d-mediated rosetting and in proteins which bind to C3d-Sepharose. Initially 97 and then 83 kDa fragments of CR2 are produced which retain C3d binding activity. These fragments are associated with the cell surface and mediate rosetting. Purified 125I-labelled CR2, solubilised in detergent, produces fragments of apparently identical size on treatment with trypsin. The 83 kDa fragment produced by trypsin treatment closely resembles the major C3d binding protein spontaneously released into Raji cell culture medium.

B-Lymphocytes↗
PubMed1989

Complement activation in plasma exchange by single filtration and centrifugation and in cascade filtration.

C3d was assayed in samples of blood plasma obtained before and after centrifugation, single filtration or cascade filtration, and also in samples of waste plasma obtained after termination of exchange. In blood plasma, cascade filtration was followed by an increase of the mean C3d concentration from 20 to 50 mU/l (p less than 0.001, n = 15), whereas single filtration and centrifugation were followed by a minor decrease. Waste plasma of cascade and single filtration contained 113 +/- 42 mU/exchange (n = 15, mean +/- SD) and 83 +/- 46 mU/exchange (n = 8), respectively. In centrifugation, the concentration of C3d of waste plasma never exceeded that of blood plasma, and the total amount of C3d of waste plasma was only 4 +/- 6 mU/exchange. In contrast to filtration, the centrifugation technique seemed not to be afflicted with any increase in the break down of complement component C3.

Blood Proteins↗
PubMed1987

Complement activation in patients with amebic liver abscess.

Serum or plasma concentrations of components of the classical (C1q, C4) and alternative (C3, factor B) pathways, regulatory protein factor H, and one of the C3 products of degradation, C3d, were determined in 19 patients with amebic liver abscess (ALA). Patients were divided into two groups. Thirteen patients that recovered under medical treatment who had a significantly shorter clinical course on admission (P less than 0.05) (group 1) exhibited either normal (C1q; C4; factor B; C3d) or increased levels of these components (C3, P less than 0.001; factor B, P less than 0.01). On the other hand, 16 patients that recovered after medical treatment and abscess drainage (group 2) exhibited significantly diminished serum levels of C1q (P less than 0.05), C3 (P less than 0.001), factor B (P less than 0.01) and factor H (P less than 0.05), and normal levels of C4, and C3d as compared to the control group. The relationships among the complement components studied were suggestive of activation of the complement system through the classical pathway in patients within group 1 and through both pathways in group 2. Sera of 3 out of the 5 patients who initially exhibited low plasma levels of C3d showed an increase during convalescence. Plasma levels of C3d were demonstrated to show a direct correlation with serum albumin and SGOT in this group of patients. Possible implications of the complement system in the immunopathogenesis of ALA are discussed.

Complement Activating Enzymes↗
PubMed1980

Immunological studies on human thymus. Occurrence and distribution of immunoglobulins and immunological receptors in myasthenia gravis and control patients.

Suspended cells and tissue sections from myasthenia gravis (MG) and control thymuses were characterized for surface expression and histological distribution of immunoglobulin (Ig) and receptors for sheep erythrocytes (SE), the Fc part of IgG (Fc gamma) and of IgM (Fc mu) and complement factors C3b and C3d (CR). In sections the cortical areas from both MG and control thymuses expressed SE as well as Fc gamma receptors, whereas medullary areas only showed weak SE binding. In contrast to control patients, MG thymuses also contained Ig+ cells confined to nodular areas of the thymic medulla. These nodules stained for both IgG and IgM, and were polyclonal with respect to light chains. In several cases IgD was found as well. In addition, the nodular areas were positive for C3b and C3d receptors. In serial sections, these Ig+ CR+ nodules corresponded to morphologically characteristic lymphoid follicles. Such B cell follicles were observed in variable numbers in all MG thymuses, whether hyperplastic or with normal histology. Five thymomas gave heterogeneous results with regard to immunological markers. Comparison of methods showed that receptor and Ig indication on sections was more sensitive than corresponding tests on thymus cells in suspension.

Adult↗
PubMed2000

Role of IgM & IgA rheumatoid factors in complement activation in patients with juvenile rheumatoid arthritis.

We studied the relationship between the degree of complement activation in juvenile rheumatoid arthritis (JRA) with the levels of circulating IgM and IgA rheumatoid factors (RF). Forty children with JRA and 25 matched controls were included in the study. Levels of C3d (a degradation product of complement component C3), circulating immune complexes (CICs), IgM RF and IgA RF were measured by ELISA. Levels of C3d, CICs, IgM RF and IgA RF were elevated in patients with JRA as compared to controls. Levels of C3d had a linear relationship with levels of CICs (P < 0.05) but not with levels of circulating IgM RF and IgA RF. Thus, complement activation occurs in children with JRA and is associated with raised levels of CICs but not with levels of circulating IgM and IgA RF. Circulating IgM and IgA RF have little, if any, role in complement activation observed in patients with JRA.

Adolescent↗
PubMed1998

The complement system and adaptive immunity.

The complement system covalently attaches C3d to microbial antigens which binds to CR2 on B lymphocytes, leading to a markedly enhanced adaptive immune response to that antigen. The enhancement is mediated by the cross-linking of the CR2-CD19 complex to mIg which augments the activation of several intracellular signalling pathways. Two additional receptors of the B lymphocyte, FcgammaRIIB and CD22, have opposing effects when cross-linked to mIg, the former suppressing signalling by recruiting the inositol phosphatase, SHIP, and the latter by activating the phosphotyrosine phosphatase, SHP-1. Two principles emerge from these studies: innate immunity guides the adaptive immune response, and activation of the B lymphocyte is determined by co-receptors which evaluate the biological characteristics of antigen.

Animals↗
PubMed2000

Heparin-coated circuits reduce occult myocardial damage during CPB: a randomized, single blind clinical trial.

OBJECTIVES: Cardiopulmonary bypass is associated with a diffuse systemic inflammatory response that can cause considerable morbidity, including organ dysfunction and bleeding. Heparin-coated circuits have been shown to give a reduced inflammatory response with clinical benefits during open-heart surgery. However, the effects on lipid peroxidation, neutrophil activation and myocardial ischemic damage in the human have remained unknown. METHODS: In a randomized single blind trial, complement activation, neutrophil counts, malondialdehyde, and cardiac enzymes were studied in 39 patients undergoing open-heart surgery. Two groups were perfused with cardiopulmonary bypass circuits with (n=20) or without heparin-coating (n=19). RESULTS: The different complement factors (C3, C4, C3d, C3d/C3 and the C-function), neutrophil levels, MDA and the cardiac enzyme levels were comparable before CPB was started and significantly increased in both groups during bypass. There were significant intergroup differences in the neutrophil levels and MDA after reperfusion (P<0.0001). Furthermore, significant positive correlations between the lipid peroxidation, expressed as MDA levels, and the levels of neutrofils and the cardiac enzyme, CK-MB were seen within the groups. CONCLUSIONS: Heparin coated circuits did lead to a decreased neutrophil response and MDA level. The correlations between CK-MB and neutrophil and MDA levels suggest neutrophil activation leading to lipid peroxidation that may influence myocardial damage. Heparin coating improved biocompatibility and was associated with less occult myocardial ischemic damage in patients undergoing open heart surgery.

Aged↗
PubMed1986

Complement activation in bronchial asthma evaluated by the C3d/C3 index.

In order to demonstrate a suspected complement activation in bronchial asthma, we measured the C3d (split product of C3) and the C3d/C3 ratio in 73 adults. Both are considered to be a sensitive index of complement activation. Compared with the value obtained in 47 normal subjects, the C3d level and the C3d/C3 ratio level were found significantly higher in asthmatic subjects. Fourteen asthmatics presented an increased C3d/C3 above the calculated limit of normality. These 14 subjects differed from the other asthmatics by a significantly lower C4 plasmatic level, suggesting an activation of the classical pathway of the complement system. Nevertheless, the clinical significance of these observations remains difficult to interpret in view of the absence of significant differences of clinical, allergologic and respiratory functional parameters between asthmatics with low or high C3d/C3 index.

Adolescent↗
PubMed1987

Pulmonary dysfunction is common during a cytomegalovirus infection after renal transplantation even in asymptomatic patients. Possible relationship with complement activation.

In 24 patients with a cadaveric renal allograft, serial measurements after transplantation were made of the diffusing capacity for carbon monoxide (DLCO) together with serial measurements of C3d, the stable conversion product of the complement factor C3, and determinations of the anaphylatoxin C3a. Twelve patients were studied during an active cytomegalovirus (CMV) infection, and 12 patients were studied during allograft rejection or during a stable phase after renal transplantation (control subjects). No patients had pulmonary symptoms nor abnormal chest radiographs or arterial blood gas determinations. During an active CMV infection, DLCO was significantly reduced compared with the measurements made during allograft rejection or during a stable phase after renal transplantation. This was true both with (p less than 0.01) and without (p less than 0.01) correction for the hemoglobin concentration. Serum C3d levels were increased in 8 of the 12 patients with a CMV infection, but not in any of the patients in the control group. In 8 patients with a CMV infection, measurements were made of the anaphylatoxin C3a, and were found to be significantly higher than the levels in the control population (p less than 0.01). We conclude that our data are consistent with pulmonary dysfunction in every patient with an active CMV infection. The concomitant findings of complement activation and formation of anaphylatoxins suggest a causal relationship of the complement activation and a decreased DLCO, although further studies are warranted to determine the exact role of complement in the pulmonary events during an active CMV infection after renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Isolation of avirulent clones of Candida albicans with reduced ability to recognize the CR2 ligand C3d.

Four clones of the yeast Candida albicans, isolated on the basis of their tolerance to clotrimazole, were compared with their parental strains in terms of growth, morphology, virulence, and cell surface complement receptor activity. In a newly described synthetic medium, these clones, designated C1, C2, N, and P, produced germ tubes or pseudohyphae, but no true hyphae, in a pattern which was specific for each strain. The growth of each clone at 37 degrees C, under conditions which favor the filamentous growth form of the organism, was equal to that of the parental strain (H12). The pathogenicity of each clone was tested in an intravenous mouse model. None of the mice infected with the tolerant clones but all of the mice infected with H12 developed severe renal candidiasis after infection with 1.4 x 10(6) to 2.0 x 10(6) CFU/ml. The number of CFU of each clone from the mouse kidney was reduced about 3 or 4 orders of magnitude in comparison with the wild type. As a correlate, we measured the complement receptor activity (CR2 and CR3) of each clone. The C3 ligands, iC3b and C3d, were conjugated to sheep erythrocytes (E) sensitized with antibody (A) to the erythrocytes (EA). We found that all tolerant clones showed reduced recognition of C3d-bearing sheep erythrocytes (EAC3d) in rosetting assays. Clone P showed more than an 80% reduction in rosetting of EAC3d in comparison with H12 cells. In contrast, recognition of iC3b (EAiC3b) by each of the clones was similar to that by H12 cells. When dithiothreitol extracts of clone P and H12 were compared by immunoblot, both quantitative and qualitative differences in reactivities were observed with antibodies specific for the Candida C3d receptor and with antiserum from a patient with chronic mucocutaneous candidiasis.

Animals↗
PubMedDate not supplied

Immunologic and immunogenetic studies in rheumatic fever and rheumatic heart disease.

In order to evaluate all the important limbs of the immune system in the same patient population with rheumatic fever (RF) and rheumatic heart disease (RHD) cellular and humoral immune parameters as well as the immunogenetic profile in 265 North Indian patients with RHD were evaluated. They were studied for class in HLA antigens and 165 of them were also evaluated for the class II (DR locus) antigen profile. Data obtained was compared with 400 and 134 healthy controls respectively of the same ethnicity. Humoral immune parameters (Serum immunoglobulins IgG, IgA; Serum complement fractions C3, C4, C3d; circulating immune complexes and B lymphocyte numbers) and cellular immune parameters (total leucocyte and lymphocyte counts; T lymphocyte sub-populations--CD4, CD8 counts; lymphocyte migration inhibition to an extracellular streptococcal antigen, streptolysin 'O') were studied in 23 patients with RF, 21 patients with "inactive" RHD and 20 normal controls. Patients of RHD were noted to have an increased frequency of DR3 (P less than 0.001; Relative risk = 2.3) and a decreased frequency of DR2 (P less than 0.001; Relative risk = 0.3) as compared to the controls. Patients of RF had evidence of an altered regulatory T cell function (increased CD4/CD8 ratio) and decreased cell mediated immunity to streptolysin 'O'. An increased humoral immune response (increased B cell counts, elevated serum IgG, circulating immune complexes and C3d) was noted in patients of RF as well as "inactive" RHD. An integrated pathogenetic model with immune response associated antigens of the DR locus influencing selection of cardiac cross-reactive antigens by the antigen processing macrophages, an altered regulatory T cell function with decreased suppressor T cell activity leading to an abnormal immune response is proposed to explain the pathogenesis of RF.

HLA Antigens↗
PubMed1997

Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer's disease patients.

The pathogenesis of white matter lesions, which are frequently found in ischemic cerebrovascular disease and Alzheimer's disease, remains unclear. Using light and electron microscopic immunohistochemistry for glial fibrillary acidic protein (GFAP) as a marker, the present study focused on the role of astroglia which show characteristic morphological alterations. Of 29 brains of patients with cerebrovascular disease and Alzheimer's disease, 4 brains showed extensive swelling and vacuolation of white matter astroglia with their processes disintegrated and beaded (termed clasmatodendrosis). No such cells were observed in 6 control patients. Clasmatodendritic astroglia were not intensely eosinophilic using hematoxylin and eosin staining and included large lipophilic granules in their perikarya. These astroglia were immunoreactive for serum proteins such as immunoglobulins, fibrinogen and complement C3, C1q and C3d, as well as for proteins which are known to increase in reactive astroglia, such as vimentin, alpha-B crystallin, apolipoprotein-E and laminin. Double labeling for GFAP and microglial cell markers indicated that these cells were of astroglial lineage. Immunoelectron microscopy for GFAP revealed that clasmatodendritic astroglia had condensed chromatin, lysosomes and large membrane-bound osmiophilic cytoplasmic inclusions, which corresponded to the lipophilic granules observed with light microscopy. These cytochemical features collectively suggest that clasmatodendritic astroglia incorporate edema fluid and phagocytose cellular debris, and eventually degenerate as a result of cerebral edema.

Aged↗
PubMed1988

Immunohistopathologic findings in proliferative diabetic retinopathy.

We performed immunopathologic studies on pars plana specimens obtained by biopsy in patients with diabetes mellitus type I or II and by autopsy in diabetic patients and normal subjects. Frozen sections were treated with several antisera, including anti-IgG, complement components, and major histocompatibility complex antigens, as well as anti-factor VIII to detect vascular structures. The results showed IgG in a linear pattern at the basal pole of pigment epithelial cells and complement deposits of C3c, C3d, and C4 at the same location and in the stroma. HLA-DR expression was found at the level of the pigmented cells. These data suggest that some autoimmune processes may be involved in proliferative diabetic retinopathy at the level of the pigment epithelium, but it is unknown whether they are an epiphenomenon of neovascularization or if they play a role in its initiation.

Adult↗
PubMed2004

Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches.

Compstatin is a 13-residue cyclic peptide that has the ability to inhibit the cleavage of C3 to C3a and C3b. The effects of targeting C3 cleavage are threefold, and result in hindrance of: (i) the generation of the pro-inflammatory peptide C3a, (ii) the generation of opsonin C3b (or its fragment C3d), and (iii) further complement activation of the common pathway (beyond C3) with the end result of the generation of the membrane attack complex. We will report on our progress on: (i) rational design of more active compstatin analogues based on the three-dimensional structure of compstatin, (ii) experimental combinatorial design based on the generation of a phage-displayed peptide library partially randomized with the implementation of structure-induced restraints, and (iii) theoretical combinatorial design based on a novel computational optimization method, structure-induced restraints and flexible structural templates. All three approaches have resulted in analogues with improved activities. Currently, the lead analogue has the sequence acetyl-I[CVYQDWGAHRC]T-NH(2) (where the brackets denote cyclization), and is 16-fold more active than the parent peptide. We will also report on our progress towards understanding the dynamic character of compstatin using molecular dynamics simulations. The identification of an ensemble of interconverting conformers of compstatin with variable populations is a first step towards the incorporation of dynamic elements in the design of new analogues using dynamics-activity relationships in addition to structure-activity relationships.

Animals↗