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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↗
PubMed1993

Complement activation by polymethyl methacrylate minimized by end-point heparin attachment.

After intraocular lens implantation, despite good clinical results, many cataract patients develop a chronic uveitis, caused by an inflammatory response to the implant. One way to improve the biocompatibility of the intraocular lens is to modify the surface by end-point heparin attachment. This study shows that complement activation caused by poly(methyl methacrylate) can be diminished by end-point heparin attachment, as demonstrated by a significant reduction in the generation of C3a and fluid phase terminal complement complexes. It suggests that assessment of complement activation is a good indicator of the biocompatibility of intraocular lenses.

Biocompatible Materials↗
PubMed1993

Specific interactions of polystyrene biomaterials with factor D of human complement.

The contact of blood with some biomaterials results in complement activation, primarily by the alternative pathway (AP). Insoluble polystyrene derivatives bearing isolated sulphonate groups (PSSO3) deplete complement, whereas identical surfaces substituted with both sulphonate and hydroxymethyl groups (PSCH2OH-SO3) are non-activators. Polystyrene sulphonate derivatives possess high adsorptive properties, particularly for serine proteases of the coagulation cascade. Thus, we studied the interactions between polystyrene derivatives and factor D, an enzyme essential for AP activation. C3 was activated when normal human serum (NHS) was incubated with PSSO3, whereas PSCH2OH-SO3 did not induce any specific C3 activation. Both polymers adsorbed factor D from serum, as shown by the loss of haemolytic factor D from NHS incubated with the polymers and by the specific adsorption of radiolabelled factor D. When bound to the polymers, factor D was not functional. The disappearance of factor D was in contradiction to the observed complement activation induced by PSSO3. When other AP components were studied, it was evident that PSSO3 adsorbed factor H even more rapidly and efficiently than factor D. Thus, the net effect was an immediate deregulation of the AP resulting in C3 activation, followed by inhibition of the AP when factor D was finally depleted. Pre-exposure of PSSO3 to NHS prevented any complement activation because the polymer was saturated with factor H, but still adsorbed factor D. Such properties could be beneficial during haemodialysis with membranes for uremic patients who have increased levels of factor D in their serum.

Biocompatible Materials↗
PubMed1993

Estimation of the genetic variation in complement activity of common carp (Cyprinus carpio L.).

The complement status of hybrid, laboratory raised carp was determined by an in vitro approach of the alternate complement activity (ACH50) and total haemolytic activity (CH50), and by measurement of serum C3 levels. The lysis of target sheep red blood cells (RBC) in the haemolytic assay for CH50 activity depended, amongst others, on the haemolysin concentration in the assay. Rocket electrophoresis showed a mean serum C3 concentration of 0.95 mg ml-1. The variation for both ACH50 and CH50 haemolytic activity was approximately 30%. The degree of genetic determination of the parameters was investigated by estimation of their repeatabilities, which were relatively high for CH50 (0.71) and ACH50 activity (0.72), but lower for C3 levels (0.54). Correlations between ACH50 values and C3 levels were significant, but moderate (0.54-0.58).

Animals↗
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↗
PubMed1983

Imipramine serum protein binding in healthy subjects.

Imipramine serum protein binding was measured by equilibrium dialysis in healthy subjects (88 women and 57 men; age 21 to 79 yr) who were relatively evenly distributed according to age, sex, smoking habits, and oral contraceptive use. Average free fraction was 10.9 +/- 1.4%. Interindividual variation in degree of binding was less than 100%, the free fraction varying from 8% to 14.7%. Women age 30 to 39 yr had significantly lower binding than all other female age groups and lower binding than men age 30 to 39 yr. Oral contraceptive use and smoking habits did not correlate to degree of binding. Serum concentrations of 12 proteins were measured in subjects with the highest binding (n = 17) and lower binding (n = 18). The concentration of orosomucoid, complement C3c, and apolipoprotein B was higher in the high-binding group than in the low-binding group. Since covariation among concentrations of these three proteins was modest, the data indicate a separate significance of the three proteins. The binding of 3H-imipramine did not correlate with the albumin concentration.

Adult↗
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↗
PubMed1996

Human nasal epithelium adsorbs complement C3-related fragments and expresses cell membrane complement regulatory proteins.

Recent evidence suggests that complement is activated in human nasal airways in inflammatory states. Activated complement protects the nasal mucosa against microorganisms, but also has the potential to lyse the host's normal cells. Complement-mediated cell lysis depends on adsorption of complement to the cell membrane and on uninterrupted activation of the complement cascade upon the same cell membrane. In the present study, the authors investigated first whether key complement components, C3-related fragments, are adsorbed to nasal epithelial cell membrane. Second, we investigated whether nasal epithelium expresses cell membrane complement regulatory proteins that are known as interruptors of complement activation. Studies were done using fresh nasal mucosa obtained at turbinectomies from allergic rhinitis and vasomotor rhinitis patients. In addition, in order to establish an in vitro model, studies were also done using primary cell cultures of nasal epithelium. We have found that complement C3-related fragments are present on cell membranes of fresh nasal epithelium and that C3-related fragments are adsorbed to the epithelial cell membrane in nasal mucosa tissue segments and in cell cultures that were incubated with autologous serum. Adsorption of C3-related fragments to the cell membrane of cultured nasal epithelial cells was found by flow cytometry analysis to be concentration-dependent. In addition, we found that nasal epithelium in fresh tissue and in cell culture express three cell membrane complement regulatory proteins: membrane cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and CD59. Our findings in fresh nasal epithelium suggest that complement activation may occur upon the nasal epithelial cell membrane during inflammation in vivo and that nasal epithelium might regulate this complement activation. Our in vitro cell culture model will allow further investigations of complement activation and regulation upon the human nasal epithelial cell membrane.

Adolescent↗
PubMed1983

In vitro complement binding in human skin cells with altered differentiation.

Exposure of cytoskeletal intermediate-sized filaments (ISF) of various cell populations in normal human skin to normal human serum (NHS) results in the deposition of C3 upon these structures; this phenomenon most likely occurs antibody-independently, is initiated by Clq binding to ISF, and is followed by the activation of the classical complement pathway. In the present study we investigated the cytoplasmic C3-binding properties of skin cells undergoing altered differentiation. Incubation of cryostat skin sections of dermal melanocytic nevi with NHS and, subsequently, with fluorescein isothiocyanate-conjugated rabbit antihuman C3 resulted in a bright cytoplasmic staining of the vast majority of nevus cells. Immunoelectron microscopic studies demonstrated that ISF within nevus cells represented the only cytoplasmic C3-binding structures. In contrast, ISF within melanoma cells, basal cell carcinoma cells, and keratinocytes constituting psoriatic lesions lacked C3-binding properties. We propose that changes in structure and subunit protein composition of ISF in certain cells undergoing altered differentiation results in a decrease or loss of their C3-binding capacity.

Basal Cell Carcinoma↗
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↗