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PubMed1992

Cold haemagglutinin disease complicating Mycoplasma pneumoniae infection in a child under cytotoxic cancer treatment.

Acute cold haemagglutinin disease, most commonly associated with underlying mycoplasma infection, is rare in children. A 3-year-old girl who developed this auto-immune disease under intensive cytotoxic treatment for rhabdomyosarcoma is presented. Clinically, a livedo reticularis skin pattern upon exposure to cold which was reversible at room temperature and a spontaneous red cell agglutination of blood samples in vitro led to the diagnosis. Together with bronchopneumonia the girl developed hyper-IgM, high antibody titres against Mycoplasma pneumoniae, as well as high titres of cold agglutinins. Laboratory signs of mild intravascular haemolysis were found. Positive direct antiglobulin test resulted from coating of red cells with C3d and C4. Three different antibodies were identified in serum: nonspecific cold agglutinins without complement activation, anti-I specific cold agglutinins with complement activation, as well as a weak biphasic Donath-Landsteiner haemolysin. Under antibiotic treatment and a short course of predisolone the clinical course was mild.

Abdominal Neoplasms↗
PubMed1984

Immunologic and biochemical studies on a patient with pyoderma gangrenosum.

A patient with pyoderma gangrenosum without associated disease was studied. Routine investigations showed several abnormalities. High ESR, high alkaline phosphatase and glutamyl transferase (gamma-GT) levels, low iron and iron binding capacity, altered protein spectrum, presence of Staphylococcus aureus and group G hemolytic streptococci in ulcer culture, higher than normal antistreptolysin titers in the serum, and perivascular infiltration in the skin. Biochemical investigations aimed at finding any excessive hydrolytic activity did not reveal the presence of neutral proteases in circulation leaked out from PMN-leukocytes or elsewhere. Lysozyme levels were higher than normal, amylase and lipase levels were normal and 5' nucleotidase levels were below normal range. TCA-soluble polypeptides were present in the serum at levels two times higher than those in normal individuals. Immunochemical investigations showed the absence of immune complexes in the serum but presence of high amounts of C-reactive protein. Total complement activity was higher than normal and so was C3c level. Clq, C4, and C3d levels were within normal range. Biologic studies showed the presence of a factor in patient serum that made guinea pig skin hard, painful, erythematous, and eventually hairless, but not necrotic. A similar factor was either absent in normal serum or present in very low concentration. After salazopyrine treatment, all the above mentioned abnormalities corrected except that 5' nucleotidase activity remained slightly lower than normal, alkaline phosphatase levels remained slightly higher than normal, and C-reactive protein levels remained very high, though lower than those during intense disease activity.

Drug Combinations↗
PubMed1982

Chronic cold haemagglutinin disease due to an anti-M-like autoantibody.

A case of chronic cold haemagglutinin disease due to an IgM monoclonal (kappa) autoantibody with anti-M-like specificity is described in a patient with the MN phenotype. The autoantibody was present in very high titre and active at body temperature, but haemolysis was only mild. The direct antiglobulin test was positive due to C3d on the patient's red cells, and the autoantibody was able to bind complement to normal MM and MN cells with a marked dosage effect.

Aged↗
PubMed1978

Membrane receptors of mouse leukocytes. I. Two types of complement receptors for different regions of C3.

Mouse leukocytes were studied for membrane receptors for the third C component by rosette formation with C coated erythrocytes (EAC). Methods were devised for the preparation of EAC complexes containing either mouse C3b or mouse C3d. EAC 1-3dmo were prepared from EA treated with whole mouse serum while EAC 1-3bmo were produced from EAC 142hu treated with whole mouse serum containing sodium suramin. The specificity of the EAC complexes for mouse leukocytes was confirmed by inhibition experiments using fluid phase human C3d. Low concentrations of fluid phase human C3d inhibited EAC1-3dmo rosettes but failed to inhibit EAC 1-3bmo rosettes. Eight-fold higher concentrations of fluid phase C3d caused partial inhibition of EAC1-3bmo rosette formation with lymphocytes, but not with other types of murine leukocytes. Thus mouse leukocytes apparently contain the same two types of C receptors as do human and guinea pig leukocytes. Mouse CR1 is specific for a non-C3d region of C3b, (possibly analogous to human C3c) whereas mouse CR2 is specific for both C3d and the C3d region of C3b.

Animals↗
PubMed1987

Characterization of the C3 receptor induced by herpes simplex virus type 1 infection of human epidermal, endothelial, and A431 cells.

Herpes simplex virus type 1 (HSV-1) infection induces the appearance of viral analogues of human Fc IgG and C3 receptors on the surface of human cells. The virally induced C3 receptor(s) has been broadly defined as a C3b receptor, but its ligand binding characteristics have not been rigorously defined. In this study, human epidermal cells, A431 cells, and human umbilical vein endothelial cells infected with HSV-1 demonstrated rosetting with sheep erythrocytes (E) coated with IgG (E-IgG) or the complement components C3b (EAC3b) or iC3b (EAC3bi), but not with E-IgM, C4 (EAC14), C3d (EAC3d), or E alone. Rosetting was markedly enhanced by pretreatment of HSV-1-infected cells with neuraminidase. Unlike human C3 receptors, the HSV-1-induced C3 receptor was found to be trypsin resistant. To determine whether HSV-1 induced CR1-like receptors or CR3-like receptors, infected cells were pretreated with EDTA, which is known to inhibit native CR3 function. EDTA failed to prevent rosetting with EAC3bi. Furthermore, blocking studies using monoclonal antibodies against CR1 and CR3 revealed that the anti-CR1 antibody 5C11 consistently blocked EAC3b and EAC3bi rosetting with HSV-1-infected cells in a dose dependent manner, but monoclonal antibodies against CR3 did not. This study indicates that the HSV-1-induced C3 receptor is an analogue of CR1.

Antibodies, Monoclonal↗
PubMed2004

Identification and characterization of the C3 binding domain of the Staphylococcus aureus extracellular fibrinogen-binding protein (Efb).

The secreted Staphylococcus aureus extracellular fibrinogen-binding protein (Efb) is a virulence factor that binds to both the complement component C3b and fibrinogen. Our laboratory previously reported that by binding to C3b, Efb inhibited complement activation and blocked opsonophagocytosis. We have now located the Efb binding domain in C3b to the C3d fragment and determined a disassociation constant (Kd) of 0.24 microM for the Efb-C3d binding using intrinsic fluorescence quenching assays. Using truncated, recombinant forms of Efb, we also demonstrate that the C3b binding region of Efb is located within the C terminus, in contrast to the fibrinogen binding domains that are located at the N-terminal end of the protein. Enzyme-linked immunosorbent assay-type binding assays demonstrated that recombinant Efb could bind to both C3b and fibrinogen simultaneously, forming a trimolecular complex and that the C-terminal region of Efb could inhibit complement activity in vitro. In addition, secondary structure analysis using circular dichroism spectroscopy revealed that the C-terminal, C3b binding region of Efb is composed primarily of alpha-helices, suggesting that this domain of Efb represents a novel type of C3b-binding protein.

Amino Acid Motifs↗
PubMed1979

Complement activation in pneumonia.

Complement analyses performed on serially collected plasma samples from 10 patients during acute infectious pneumonia or bronchopneumonia showed normal or increased values for hemolytic activity and Clq, C4, C3, and factor B levels. However, the levels of C3 breakdown products (C3d) were significantly (greater than 2 SD) increased in six patients during the first three days of observation, suggesting that hypercatabolism of complement components may occur during the acute phase of infectious pneumonia concomitant with a hypersynthesis of some complement components. Evidence of circulating immune complexes was obtained only in two patients with the 125I-Clq Binding Test.

Acute Disease↗
PubMed1977

[Anticomplement activity of a polyanion: pentosan sulfuric polyester. III. Mechanism of functional inactivation of the different properdin and complement system fractions].

In vitro, the drug pentosan-poly-sulfoester (PPS) changes the electrophoretic migration of different proteins from the complement and properdin systems, such as native C3 (beta 1C globulin), C3c (beta-1A globulin), C3d (alpha-2D globulin), C1s inactivator (ClsINA), Clq and properdin factor B (B). Their more anodal migration is the consequence of a molecular alteration and persists after prolonged dialysis. These structural changes, yet undefined, explain the loss of functional activity of these proteins, and the anticomplementary activity of this drug. Moreover, PPS is able to block the alternate pathway activation by its action on properdin factor B (C3 proactivator). In fact, in presence of PPS, the activators of the properdin systems such as C3 nephritic factor are inactive. These altered mobilities are also responsible for the overestimation in the antigenic concentration of B (+ 45%), C4 (+27%) and C3/C3c (+ 14%), found in human serum containing 50 mg/ml of PPS. PPS has an original action upon the complement and properdin systems, which allows its clinical use as a potent inhibitor of the humoral mediators of inflammation.

Binding Sites↗
PubMed1991

Human serum induced opsonization of immunoglobulin G-coated polystyrene microspheres with complement components C3 and C4 as measured by flow cytometry.

Human IgG-coated polystyrene microspheres (IgG-ms) were incubated with human serum followed by biotinylated monoclonal anti-C3d or anti-C4d antibody, and phycoerythrin-streptavidin. The intensity of fluorescence was measured by flow cytometry and corresponds to the amount of deposited C3 and C4. Binding of C3 and C4 was dependent on the activation of the classical pathway of complement and on the amount of IgG adsorbed to the particles. No deposition was observed on control particles coated with bovine serum albumin or ovalbumin. Incubation of constant amounts of IgG-ms with increasing amounts of normal human serum (NHS) resulted in a dose-dependent increase in C3 deposition. The same result was found for C4 deposition at moderate NHS dilutions, but less C4 was detectable using a higher input of NHS. Half-maximum C3 and C4 deposition was observed at a mean serum dilution of 1/114 and 1/520, respectively (n = 26). No correlation was found between C4 or C3 deposition and either total C4 and C3 serum concentrations as measured by nephelometry or complement-mediated lysis of antibody-coated sheep red blood cells. Reduced or absent C4 or C3 deposition was found in the sera of patients with low amounts or deficiencies of components involved early in classical complement pathway activation whereas essentially normal C4 or C3 deposition was obtained with the sera of patients with deficiencies in components of the membrane attack complex. With this simple and specific functional assay using stable reagents an altered function of early components of the classical pathway of complement may be quickly and reliably detected in routine diagnostic laboratories. Moreover, such opsonized and well characterized particles may be useful in assays of phagocytic cell function.

Complement C3↗
PubMed1995

C3d and Epstein-Barr virus (CR2/CD21 ligands) stimulate cells of an HTLV-I line, MT-2.

We studied the physiological role of complement receptor type II (CR2, C3d/EBV receptor) expressed on T cells using MT-2 cells. First, we confirmed CR2 expression on MT-2 cells by flow cytometry and found that the MW of CR2 molecules on these cells and Raji B cells were the same by SDS-PAGE analysis. When MT-2 lysates were incubated with anti-CR2 mAb HB5 and thereafter with 32P-labeled ATP, 52- and 74-kDa proteins were phosphorylated, suggesting the activation of MT-2 cells through the complex of CR2 with these proteins. In this respect, we measured lymphotoxin production by MT-2 cells when incubated with C3d or EBV. The cytotoxicity of the MT-2 supernatant against L929 cells was elevated in a dose- and time-dependent manner. Next, we confirmed EBNA expression on EBV-infected MT-2 cells and attempted to establish an EBV-positive MT-2 clone by in vitro EBV infection. However, these clones disappeared during cloning. To clarify this mechanism, we examined the EBV genome in MT-2 cells. By Southern blot analysis, BamHI digestion of DNA extracts from MT-2 cells 3 days after EBV treatment gave a 3.0-kb signal which comigrated with the EBV BamHI-W probe. The 3.0-kb signal of genomic EBV-DNA was detected at 1, 2, 3, 5, and 7 days after EBV treatment, but could not be detected at 14 days. Thus, natural ligands of CR2 stimulate CR2-positive MT-2 cells through their functionally active CR2 molecules and in vitro EBV infection of MT-2 cells might be transient.

Animals↗
PubMed1990

Immune complex binding to erythrocyte-CR1 (CD 35), CR1 expression and levels of erythrocyte-fixed C3 fragments in SLE outpatients.

Erythrocytes (E) from a cross-sectional group of 22 outpatients with systemic lupus erythematosus (SLE) and/or mixed connective tissue disease (MCTD), the majority without active disease (n = 14), were analyzed for CR1 antigen expression and capacity to bind complement opsonized, radiolabelled immune complexes (IC). Furthermore, E-bound C3 fragments and the plasma C3d concentration were determined. E-bound C3b/iC3b fragments were not elevated in patients with SLE, whereas E from 11 out of 22 SLE patients had increased C3d levels which correlated with the plasma C3d concentration (Rs 0.73, p less than 0.001). E-fixed C3d fragments did not affect the binding of Mab or preopsonized IC to E-CR1 and were not correlated with disease activity or medical treatment. Antigen expression of E-CR1 measured by ELISA or agglutination showed positive correlation with the IC binding capacity of E-CR1 (Rs 0.92 and 0.72 respectively, p less than 001). The IC binding capacity of E-CR1 from SLE patients was significantly reduced (p less than 0.005), whereas the antigen expression of CR1 (ELISA) on E from the patients did not differ from that of E from healthy donors (p greater than 0.1). E-CR1 antigen was measured by Mab reacting with an epitope outside the IC-binding site of E-CR1. E-CR1 antigen expression or IC binding showed no correlation either with disease activity or prednisolone treatment. However, 4 og 5 patients with MCTD and 4 of 5 patients receiving Imurel were found to have low E-CR1 expression and capacity to bind IC. Thus, measurement of antigenic E-CR1 in a cross-sectional group of SLE outpatients by use of Mab reacting with an epitope outside the ligand-binding region of CR1 did not reveal a significantly reduced CR1 expression. However, an assay for CR1-mediated IC binding showed a clearly reduced E-CR1 function.

Antigen-Antibody Complex↗
PubMed1989

Expression of the binding molecules for factor B and its fragment, Bb, of human complement on human monocytes after in vitro cultivation.

We have examined the expression of the binding molecules for Bb of human complement on the surface of resting and cultured human monocytes. Flow cytometry using biotinylated anti-B antibodies and phycoerythrin-avidin showed that although resting monocytes did not bind Bb significantly, monocytes cultivated for 24 h in the presence of fetal calf serum were capable of binding with Bb and its precursor B, but not with Ba fragment. The Bb-binding molecules were pronase-sensitive, suggesting that membrane proteins are associated with the Bb-binding molecules. In addition to human monocytes, liquid paraffin-induced guinea pig inflammatory macrophages were also found to express Bb-binding molecules on their surface. This implies that Bb receptor-like molecules become expressed during activation and differentiation of monocytes, just as observed with the C3d-receptor of monocytes.

Animals↗
PubMed1990

Peripheral nerve CR1 express in situ cofactor activity for degradation of C3b.

Adsorption of sheep erythrocytes (E) sensitized with IgM antibodies (A) and C3b (EAC3b) to C3b/C4b receptors (CR1) in cryostat sections of human myelinated nerves was studied using the closed chamber technique. The adsorption was stable for at least 3 h at 37 degrees C. In the presence of purified factor I, the indicator cells detached from the sections after 40 min at 37 degrees C. Factor H was not required. The release was not due to loss of CR1 activity in the sections. The detached indicator cells were negative in the immune adherence test and were agglutinated by antibody to C3d, but not by antibody to C3c. Western blot of the detached indicator cells revealed the presence of C3d and C3c was found in the chamber fluid. Accordingly, detachment of the indicator cells was due to degradation of C3b to C3d with the release of C3c into the chamber fluid. Protease inhibitors did not prevent the detachment of the indicator cells. EAC3b incubated with sections of myelinated nerves pre-incubated with anti-CR1 antibody or with sections of unmyelinated nerves which contain functionally inactive CR1 were not degraded. The results therefore indicate that CR1 in situ in myelinated nerves can provide the necessary cofactor activity for factor I-mediated degradation of C3b to C3d and C3c.

Animals↗
PubMed1982

Immunological characterization of mononuclear cells in thyroid gland and blood in Graves' disease, multinodular goiter and papillary carcinoma.

Mononuclear cell infiltrates in thyroid gland tissue sections from patients with drug-treated Graves' disease (n = 5), non-toxic nodular goiter (n = 12) and papillary carcinoma (n = 5) were characterized by immunological membrane receptors. T lymphocytes were identified using 2-aminoethylisothiouronium bromide hydrobromide (AET)-treated sheep erythrocytes (E) (E-AET). E sensitized with rabbit IgM antibodies (A) and human complement (C) (EAC) were used to detect receptors for C3b (B lymphocytes and monocytes) or C3d (B lymphocytes). E sensitized with rabbit IgG antibodies were used to detect receptors for the Fc portion of IgG (FcR; lymphocytes and monocytes). The results indicate that T and B lymphocytes infiltrate the thyroid gland in Graves' disease as well as in nodular goiter. T lymphocytes seemed to predominate in both disorders. In thyroid papillary carcinoma the number of B and T lymphocytes was negligible. However, EA absorbed strongly to sections from 3 of the 5 tumors studied, indicating the presence of FcR on tumor cells or infiltrating host cells. The percentage of active and total T lymphocytes in peripheral blood from the patients with drug-treated Graves' disease was markedly reduced (9 +/- 5 and 28 +/- 11%, controls 22 +/- 9 and 68 +/- 11%; p less than 0.01 and less than 0.001). In patients with nodular goiter the percentage of total T lymphocytes was slightly, but significantly decreased (p less than 0.05). We suggest that the marked decrease in blood T lymphocytes observed in Graves' disease might be caused by the drug therapy. In nodular goiter the predominance of T lymphocyte infiltration together with a slight decrease in blood T lymphocytes suggest that autoimmune mechanisms are involved in the pathogenesis.

Adult↗
PubMed1989

Complement activation in human lymphoid germinal centres.

The presence of complement activation products has been studied in morphologically normal human lymphatic tissue from tonsil, spleen and lymph node. Newly established monoclonal antibodies (mAbs) with reactivity against the C4 cleavage fragments C4a, C4b, C4c and C4d were applied on cyrostat sections in the indirect immunoperoxidase staining technique. Irrespective of organ type, C4d activation product could be detected in germinal centres of all secondary lymphoid follicles. To substantiate this finding, the complete sequence of complement activation products was investigated by a series of mono- and polyclonal antibodies to the complement proteins C1, C2, C3, factor B, C5, C9 to C5b-9 neoantigens and to the regulatory complement proteins C4 binding protein (C4bp), factor I, factor H and properdin. Similar to C4d, all secondary follicles exhibited a strong staining reaction for C3d antigens restricted to germinal centres. At the same site, albeit with distinctly weaker intensity, components of the membrane attack complex (MAC) C5b-9 were found. The simultaneous deposition of C1, C4b and C4bp in certain germinal centres indicates that complement activation is induced via the classical pathway. Concomitant deposition of IgM suggests IgM-antigen complexes that have been trapped on follicular dendritic cells (FDC) during normal immune response as the most likely candidates for activators of the classical pathway. Our data demonstrate that human lymphoid germinal centres as important sites of immune regulation closely interrelate with the complete cascade of complement-activation products, including the membrane attack complex (MAC).

Antigen-Antibody Complex↗
PubMed1985

Sequential studies of complement activation in systemic lupus erythematosus.

C1 and C3 activation, measured as C1r-C1s-C1 inactivator C1s-C1r-C1IA complexes in serum and circulating C3d were studied in serial samples from 33 patients with SLE. All patients demonstrated exacerbations during observation periods of 10-30 months and were divided into groups according to principal clincal features (mild SLE, severe extra-renal SLE, and lupus glomerulonephritis). Increased C1 activation was consistently found during exacerbation. C3d in plasma was a feature associated with severe disease flares. Activation of C1, but not of C3, was documented before flare-ups of disease activity, but such predictive information was mostly restricted to patients with extra-renal disease. C2 cleavage in plasma, studied serially in a few patients, appeared to be closely associated with C1 activation. Circulating immune complexes, measured with solid-phase C1q assay, did not always increase before development of clinical manifestations. Remission of symptoms was paralleled by decreasing concentrations of C1r-C1s-C1IA and of, when present, C3d. Similar findings were made for immune complexes but only in severe disease. Persisting C3d was observed in 3 patients, who subsequently developed renal failure. C1q levels were transiently low during flare-ups of lupus glomerulonephritis, but otherwise the concentrations of C1q, C4 and C3 did not show consistent patterns of variation in relation to disease activity.

Adolescent↗
PubMed1974

Studies on the in vivo effects of antibody. Interaction of IgM antibody and complement in the immune clearance and destruction of erythrocytes in man.

Purified human IgM isoagglutinins were utilized to sensitize (51)Cr-labeled erythrocytes so as to produce a known number of complement-fixing sites. These cells were then reinfused into the erythrocyte donor. A minimum of 20 C1-fixing sites/erythrocyte were required for decreased survival. As the amount of antibody coating the erythrocytes was increased, a larger percentage was sequestered. With 80 C1-fixing sites, more than 75% of the injected erythrocytes were removed from the circulation within 10 min. In each case, the clearance pattern consisted of rapid hepatic sequestration followed by a gradual return of a portion of the erythrocytes into the circulation where they survived normally. Clearance was shown to be dependent upon activation of the classical complement pathway, since sensitized cells survived normally in hereditary angioedema patients with low levels of C4 and no detectable C2. Exposure of sensitized cells to fresh serum for 15 min led to the deposition of 550-800 C3 molecules/C1-fixing site. Such cells were immune adherence positive, were agglutinated by anti-C3b, formed rosettes with human alveolar macrophages, and were sequestered in vivo, presumably because of the interaction of cell-bound C3b with the C3b receptor on hepatic macrophages. After exposure to heated serum as a source of the C3b inactivator, the cells were immune adherence negative, were agglutinated only by anti-C3d, did not form rosettes with macrophages, and survived normally in vivo despite, being Coombs positive. Cleavage of cell-bound C3b to C3d may explain the release phase of the IgM clearance pattern. Whereas erythrocytes coated with IgM antibody and complement were previously thought to be sequestered in the liver because of extensive membrane damage, these experiments suggest that clearance is determined by the interaction of erythrocyte-bound complement fragments with specific receptors on hepatic macrophages.

Adolescent↗
PubMed1991

Localisation of complement components in association with glomerular extracellular particles in various renal diseases.

Intraglomerular extracellular microparticles including so-called virus-like particles and striated membranous structures have been observed in various renal diseases. The presence and localisation of complement components in these extracellular bodies was studied using the protein A-gold electron microscopy method. Ultrastructurally these particles were differentiated into microspherical structures (MSS) and thread-like structures (TS). Both structures showed weak to moderate diffuse labelling with C1s, whilst the intense labelling found with C3d and C9 was confined to individual membrane-like structures of both MSS and TS. Labelling with IgA, IgG, fibrinogen and the complement components C1q, C1r, C3c C4 and C5 showed negative or trace results. There were no differences between the immunolabelling patterns of MSS and TS, nor among different renal diseases in which these structures were found. These findings raise the possibility that formation of so-called virus-like particles such as MSS and TS may be associated with complement activation.

Complement System Proteins↗