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PubMed1985

Mianserin protein binding in serum and plasma from healthy subjects and patients with depression and rheumatoid arthritis.

Mianserin protein binding was measured in serum from 43 healthy subjects and plasma from 12 elderly depressed patients and 23 patients with rheumatoid arthritis. Free fraction (mean +/- SD) was 5.5 +/- 0.7% in the healthy subjects, 5.0 +/- 0.8% in the elderly subjects and 6.0 +/- 1.0 in the patients with rheumatoid arthritis. In the group of elderly patients treated with mianserin, a high correlation (r = 0.83, P less than 0.001) between total and free concentrations of mianserin was found. In both groups a high linear correlation (r = +0.90, P less than 0.001) between the free fraction of mianserin and that of imipramine was found, the latter being about twice as high as for mianserin. In both healthy subjects and arthritis patients the degree of protein binding was positively correlated to the concentration of alpha 1-acid-glycoprotein and complement C3c, and somewhat more weakly to haptoglobin. In the healthy subjects protein binding was also highly positively correlated to the concentration of apolipoprotein B, whereas no such correlation was found in the rheumatoid arthritis patients. In the rheumatoid arthritis patients protein binding was highly correlated to the concentration of hemopexin and somewhat more weakly to ceruloplasmin and fibrinogen; a weak negative correlation to the concentration of albumin was also found. Since significant intercorrelations between the concentrations of these proteins were found, the correlation to the degree of binding of mianserin may not necessarily represent binding of the drug to the protein.

Adult↗
PubMed1985

Plasma protein binding of imipramine in patients with rheumatoid arthritis.

In 23 patients with rheumatoid arthritis the plasma protein binding of 3H-imipramine and the plasma levels of 13 proteins were measured in order to examine the significance of the proteins for the binding of imipramine. The degree of 3H-imipramine binding did not differ significantly from that in healthy controls. It was positively correlated with the concentrations of fibrinogen, alpha 1-acid-glycoprotein, ceruloplasmin, complement C3c, haptoglobin and hemopexin. Erythrocyte sedimentation rate was also highly positively correlated with binding. The concentration of several of the proteins showed a significant covariation. The 3H-imipramine binding was negatively correlated with the concentration of albumin and the latter was negatively correlated with some of the proteins mentioned-above. No correlation with the levels of apolipoproteins A and B was found. There appears to be more a qualitative than a quantitative change in 3H-imipramine binding in patients with rheumatoid arthritis.

Aging↗
PubMed1986

Effect of lithium therapy on inflammatory response.

Chemiluminescence produced by normal cells was reduced in response to zymosan which was opsonized with serum from patients on prophylactic lithium therapy, compared to control serum from normal subjects (68 +/- 3.1 vs. 93 +/- 3.4 mV/5 X 10(5) cells). Preincubation of normal cells with serum from patients also resulted in reduced chemiluminescence activity when the cells were stimulated with autologous serum-coated zymosan (47 +/- 4.5 vs. 64 +/- 6.3 mV/5 X 10(5) cells). Spontaneous complement conversion was increased in the serum of patients on lithium therapy (46.3 +/- 3.8 vs. 25.3 +/- 2.5% conversion). These studies demonstrated that lithium, at safe therapeutic levels (0.4-0.9 mmol/liter), significantly altered complement conversion and had a marked affect on chemiluminescence activity by normal cells.

Adult↗
PubMed1987

IgG binding to cytoskeletal intermediate filaments activates the complement cascade.

The cellular plasma membrane becomes permeable to macromolecules during the cell injury process. This results in exposure of the interior of the cell to plasma proteins and to high-affinity binding of the Fc part of IgG to intermediate filaments (Hansson, G K, Starkebaum, G A, Benditt, E P & Schwartz, S M, Proc natl acad sci USA 81 (1984) 3103). Such IgG binding could be an early step in a process that serves to eliminate the injured cell. We have now identified its effect on the complement system. Intermediate filaments were reconstituted in vitro from purified vimentin, and incubated with plasma proteins. Cross-linker experiments showed binding of the heavy chain of IgG to vimentin, indicating that the vimentin protein carries an Fc-binding site. In contrast, no direct binding of complement factor Clq to vimentin could be detected. Binding of both IgG and Clq could, however, be detected by immunofluorescence when cytoskeletons of cultured endothelial cells were incubated with fresh serum. Therefore, IgG binding to filaments in the presence of serum is accompanied by Clq binding to IgG. This was in turn followed by fixation of C4 and C3 to intermediate filaments in a process that was dependent on both Ca2+, Mg2+ and Clq, indicating that it was part of a complement activation via the classical pathway. Exposure of fresh serum to intermediate filaments also resulted in production of the anaphylatoxic complement cleavage fragment. C3a, with a dose-response relationship between the amount of filaments present and the amount of C3a generated. Chemotactic activity towards granulocytes and monocytes was also generated by exposure of serum to intermediate filaments, and this activity was dependent on the presence of complement factor C5 and on the classical complement activation cascade, implying that it was due to the C5a peptide. Exposure of the interior of the cell to plasma proteins thus results in binding of IgG to intermediate filaments and activation of the complement cascade via the classical pathway. This, in turn generates bioactive mediators which may recruit leukocytes to the injured cell (C5a) and have profound effects on vascular permeability (C3a, C5a). We propose that this is part of a scavenger mechanism for the elimination of damaged cells.

Binding Sites↗
PubMed1986

Measurement of C3 conversion by ELISA estimation of neo-determinants on the C3d moiety.

An ELISA assay estimating neo-determinants on the C3d moiety is described. The C3d neo-determinants were detected by incubating the sample on F(ab')2 anti-C3d-coated plates followed by development with biotin-labelled anti-C3d and enzyme-labelled avidin. The assay was compared with rocket immunoelectrophoresis (IE) and crossed IE. Serum from a factor I deficient patient showed no detectable C3d when analysed by rocket IE, but activation was evident when analysing by crossed IE or ELISA. The results suggest that the neo-determinants detected by ELISA become exposed when C3 is split into C3a and C3b and this interpretation was supported by kinetic analysis of C3 activation by the three methods.

Complement Activation↗
PubMed1990

Effects of plasmapheresis and autotransfusion on complement recovery in dogs.

To study selectively the dilutional aspects of severe blood loss on the serum complement system, we developed an animal model consisting of isovolumic phlebotomy and reinfusion of washed autologous erythrocytes. This model avoided hypoperfusion, ischemia, and transfusion of foreign antigen. We measured total serum protein, C3 antigen, total complement hemolytic activity, and alternative pathway hemolytic activity. Each of the first three parameters dropped to 55% of initial value (P less than 0.005) by the end of the phlebotomy/reinfusion procedure and returned to normal levels by Day 1 or 2. C3 antigen and total complement hemolytic activity then rose to 150% of normal by Day 4 and gradually returned to normal within 2 weeks. Alternative pathway activity, by contrast, fell by more than 80% (P less than 0.005) within the first 6 hr, recovered by Day 4, and gradually rose to about 140% of normal by Day 21. Trauma patients treated for heavy blood loss who suffer depletion of hemolytic complement during the first few hours may be at greater risk of infection due to immune deficiencies. The implication of the results presented here is that the alternative pathway may be particularly weakened during blood loss and transfusion by simple dilution in addition to the effects of processes omitted in this model. Knowledge of the kinetics of complement recovery, independent of other effects usually accompanying trauma, may be helpful in determining whether these patients might benefit from exogenous manipulation of the complement system.

Animals↗
PubMed1991

Expression of the major rheumatoid factor cross-reactive idiotype in pediatric patients with systemic lupus erythematosus.

Rheumatoid factor cross-reactive idiotype (RF-CRI) is expressed in high concentrations in the sera of some patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). To determine if RF-CRI is specifically expressed in rheumatic disease or if it is secondary to polyclonal B-cell activation, we examined sera of 23 children with SLE, 16 adolescents with infectious mononucleosis (IM), and age-matched pediatric controls for RF-CRI expression. Concentrations of RF-CRI in serum, determined by an inhibition ELISA, were 24 +/- 17 micrograms/ml (mean +/- SD) in 25 normal children, 31 +/- 17 in 16 young adults with IM, and were significantly increased, 70 +/- 80 micrograms/ml, in the 23 children with SLE (p less than 0.036). Eleven of 23 SLE patients had serum RF-CRI greater than the mean +/- 2 SD for normal children. Ten of 23 SLE sera contained IgM rheumatoid factor (RF) activity. One patient with IM had a borderline elevated RF-CRI level, and 5 IM patients had RF in their sera. The serum IgM concentrations in sera were: SLE (192 +/- 93 mg/dl) and IM (234 +/- 77 mg/dl) sera. These levels were significantly elevated compared to controls (132 +/- 44 mg/dl), p less than 0.031 for SLE and p less than 0.001 for IM, suggesting that polyclonal activation of B cells was present in SLE and IM patient groups. Increased expression of RF-CRI in the SLE patients correlated directly with high titer anti-DNA antibody values (r = 0.3965, p less than 0.05) and RF activity when human IgG (r = 0.5026, p less than 0.05) was used as the RF binding substrate and inversely with serum C3 levels (r = 0.3925, p less than 0.05). RF-CRI expression did not correlate with RF that bound rabbit (r = 0.3123, p greater than 0.05). Increased serum RF-CRI expression is not a result of polyclonal B-cell activation. RF-CRI may be selectively up-regulated in patients with SLE.

Adolescent↗
PubMed1989

Effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery.

The influence of high doses of methylprednisolone on complement activation and endotoxin concentration was investigated in two groups of eight patients undergoing coronary artery bypass grafting. Group 1 received methylprednisolone, 30 mg/kg, at the induction of anesthesia; group 2 served as the control group. The endotoxin concentrations increased significantly in both groups at the start of cardiopulmonary bypass. During cardiopulmonary bypass, the endotoxin concentrations were significantly higher in the steroid group compared with the control group (p less than 0.01). After completion of surgery, the endotoxin concentrations declined to almost zero within seven days in both groups. Complement activation was significantly reduced in the steroid-treated group during cardiopulmonary bypass compared with the control group (P less than 0.01). The clinical outcome after the first postoperative week was the same in the two groups. It appears that high-dose steroids can reduce complement activation during cardiopulmonary bypass, although the clearance of endotoxins may also be reduced.

Aged↗
PubMed1990

Identification of specific serum proteins synthesized de novo by monolayer cultures of glandular cells of gestational endometrium.

Monolayer cell cultures (n = 3) of glandular epithelium of gestational endometrium obtained from three apparently healthy women undergoing elective termination of pregnancy (7-9 weeks gestation) were established. De novo synthesis of eight serum proteins (albumin, alpha 1-antitrypsin, ceruloplasmin, beta-lipoprotein, alpha 2-macroglobulin, fibronectin and complement factors C3 and C4) was demonstrated by the incorporation of radiolabelled substrate ([35S]methionine) employing autoradiography (AR) in combination with crossed immunoelectrophoresis (XIE), referred to as ARXIE, and line immunoelectrophoresis (LIE), referred to as ARLIE. By contrast, there was no evidence for de novo synthesis of IgA, haptoglobin and orosomucoid. Our findings suggest that the gestational endometrium may contribute to the production of several proteins considered to be synthesized and secreted mainly by the liver and reticulo-endothelial system. The simple techniques used here to identify the de novo synthesis of human serum proteins could be applied to investigate protein synthesis by a wide range of tissues and cells.

Blood Proteins↗
PubMed1990

The level of mannan-binding protein regulates the binding of complement-derived opsonins to mannan and zymosan at low serum concentrations.

When sera diluted to 5% in a buffer containing calcium and magnesium were incubated with mannan-coated ELISA plates, C4 fragments, properdin and factor B were bound to the plates as well as the expected opsonic C3 fragments, C3b and C3bi. The calcium-dependent lectin mannan-binding protein, which is structurally similar to C1q, was also shown to bind in this assay and analysis of sera from 179 healthy blood donors revealed that the binding levels of all these proteins were highly significantly correlated. Results obtained with a previously described C3b opsonic assay using zymosan also correlated with the mannan-binding levels. When the sera were diluted to 5% in the presence of Mg-EGTA there was no detectable binding of complement proteins to the mannan surface, confirming that no alternative pathway activation occurred at this serum concentration. When sera were diluted to 5% in a buffer containing EDTA in order to study immunoglobulin binding in the absence of complement activation, the levels of bound IgG1, IgG2, IgG3, IgA and IgM antibodies were found to be completely unrelated to the C3bi binding levels previously observed. The results suggest that in this experimental system using low concentrations of serum, mannan-binding protein initiates an antibody-independent mechanism of cleavage of the classical pathway component C4, which subsequently regulates the degree of cleavage of C3 and recruitment of alternative pathway proteins.

Carrier Proteins↗
PubMed1991

A functionally active complement system is present in uterine secretion of the mouse prior to implantation.

Sephadex beads were placed carefully in the uterus on days 2 and 3 and left for 6 to 8 h to absorb uterine secretion. The beads were then removed with volatile silicon oil and mounted on small pieces of nitrocellulose paper. Immuno-staining of these bead blots showed they contained the complement components C1q, C3, C4, and C5. We demonstrated that complement component C3 in the uterine secretion could be activated and deposited on model immune complexes, and also that antibody-coated erythrocytes were lysed in utero, that is, a membrane attack complex was produced. Thus, the mouse uterine secretion at the preimplantation stage contains a functionally active complement system.

Animals↗
PubMed1985

Subnormal sensitivity of neutrophils to complement split product C5a in rheumatoid arthritis: relation to complement catabolism and disease extent.

The capacity of circulating neutrophils for activation by complement was studied in outpatients with classical or definite rheumatoid arthritis during treatment with dextropropoxyphene only. Analysis of dose-response in the Boyden chamber assay of chemotaxis showed that sensitivity to the potent, complement derived anaphylatoxin, C5a, was markedly decreased, especially in those patients with few joints involved. In contrast, peak response to C5a was within the normal range. Increased complement 3c split products in plasma of the patients suggested involvement of complement cascade reactions. Subnormal sensitivity of neutrophils to phlogistic mediators released by complement may tend to limit their recruitment and potentially tissue destroying secretion locally in rheumatoid arthritis.

Adult↗
PubMed1992

A long-term immunological study of childhood onset systemic lupus erythematosus.

Immunological dysregulation is an important cause of the development of systemic lupus erythematosus (SLE). Serological evaluation has been useful in the clinical management of patients and as a prognostic indicator. Sixteen patients who developed SLE as children were followed up for more than three years and immunological data collected. The results showed that (a) complement C3 concentration was lower in the active stage of SLE, especially during a major clinical exacerbation, but rarely preceded a major flare up. The concentration was often normal during the mildly to moderately active stage. In contrast, a low complement C4 concentration often preceded a major clinical exacerbation and could be of longer duration, sometimes persisting regardless of disease activity. (b) A T cell subset distribution study showed persistently low CD4 positive T cells in the peripheral blood of patients with SLE during the long term follow up, strongly suggesting that the intrinsic defect is mainly localised in T helper/inducer cells. These abnormal cellular defects did not tend to return to normal even in long term remission. (c) The persistently higher serum interleukin 2 and interleukin 2 receptor concentrations in SLE strongly suggested that the T cells were preactivated in vivo and that these phenomena might persist even in remission. (d) The best single parameter for predicting active SLE was anti-dsDNA. It was highly correlated with disease activity in most patients, and the asymptomatic increase of anti-dsDNA (greater than or equal to 60 U/ml, radioimmunoassay) was often followed by a major clinical exacerbation, especially in patients with a simultaneously low complement C4 concentration, suggesting that it might be an important warning sign of a major flare up. High dose steroids are indicated in this group of patients.

Adolescent↗
PubMed1991

Analysis of proteins eluted from hemodialysis membranes.

To further investigate the types of interactions occurring between blood and hemodialysis membranes, proteins were sequentially eluted from used dialysers. Four different membranes (cuprophan, hemophan, cellulose acetate and polyacrylonitrile) were successively treated with a hydrogen bond cleaving agent (10 M urea), an ionic detergent destabilizing the hydrophobic interactions between apolar groups (SDS solution), and a hydroxylamine solution at alkaline pH to release postulated covalently bound C3 fragments. The eluted proteins were analyzed by SDS-PAGE and immunological techniques. Total protein determinations demonstrate different behaviour of the membranes as regards the 'protein cake'. Electrophoretic analysis suggests that qualitative and quantitative differences in the binding of the blood proteins are related to the membrane material. Complement fragment studies indicate that the complement activating potential of the dialysis membrane may not be determined by the availability of potential binding sites for activated C3b. An attempt is made to correlate these results with the biocompatibility concept.

Acrylic Resins↗
PubMed1988

Spontaneous glomerular immunoglobulin deposition in young Sprague-Dawley rats.

The frequency, age-onset and distribution of spontaneously deposited immunoglobulins (Igs) in glomeruli of Sprague-Dawley rats has been investigated. Groups of rats (n = 10) were examined at 4-7 day intervals from birth (presuckling) until 30 days of age. Findings were compared with circulating immunoglobulin concentrations in each age group. Immunoglobulins were undetectable in immature kidneys of newborn rats. However, as early as 5 days, scanty IgA and IgM deposits were observed predominantly in mesangial areas of mature glomeruli, corresponding to low circulating concentrations of these immunoglobulins. By contrast, glomerular IgG deposits were not observed until 21 days, despite relatively high concentrations of circulating maternal IgG from birth. Mesangial deposition of immunoglobulins increased with age. Absence of complement C3c or electron dense deposits associated with this mesangial localization suggests that immunoglobulins were not deposited as immune complexes. Accumulation of non-phlogogenic immunoglobulins in the mesangium of normal rats supports the concept that the mesangium is constantly perfused by circulating macromolecules and filtration residues. The results indicate problems of interpretation of the significance of endogenous immunoglobulin deposition in models of experimental glomerulonephritis, even in studies involving weanling rats.

Animals↗
PubMed1989

Serum immunoglobulins, complement levels and lymphocyte subpopulations in phenytoin-treated epileptic patients.

The peripheral blood lymphocytes, serum immunoglobulins, C3 and C4 complement protein concentrations of 20 patients with idiopathic epilepsy who were receiving phenytoin were examined and compared with 30 healthy controls in order to obtain a detailed profile of the effects of the drug on the humoral and cellular immune systems. The T-lymphocyte subsets were identified using monoclonal antibodies. A significant decrease in suppressor T-cells (p less than 0.05) and an increase in the ratio of T-helper to T-suppressor lymphocytes (p less than 0.01) have been found. Furthermore, an increase in B-lymphocytes (p less than 0.01) and a significant rise in serum Ig M concentrations (p less than 0.05) have been observed. No significant changes in serum concentrations of Ig G, Ig A and complement proteins were detected.

Adolescent↗
PubMed1977

Immunoproteins in human brain tumor cyst fluids.

Quantitation of the concentration of immunoproteins in serum, and cystic fluids from six patients (three with cerebral astrocytoma and three with cerebellar hemangioblastoma) has been determined. The values for total protein, albumin, immunoproteins IgG, IgA, and IgM, and C3C (complement) in cyst fluid more closely correspond to serum than to cerebrospinal fluid values. Values for cyst fluid, cerebrospinal fluid, and serum were determined using albumin ratios in order to compare relative differences between fluids from these three compartments. Our data suggests that: 1) the major protein content of brain tumor cyst fluid is consequential to a transudative process from serum, and 2) that immunoglobulins IgG and IgA are present in higher concentrations in human brain tumor cyst fluids in comparison to IgM concentrations. These studies further question the concept of the brain as an "immunological privileged site", and may be of direct relevance to the investigation of the use of immunotherapeutic modalities as an adjunct after surgical tumor removal.

Adolescent↗