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PubMed2003

C3b2-IgG complexes retain dimeric C3 fragments at all levels of inactivation.

C3b2-IgG complexes are formed during complement activation in serum by attachment of two C3b molecules (the proteolytically activated form of C3) to one IgG heavy chain (IgG HC) via ester bonds. Because of the presence of two C3b molecules, these complexes are very efficient activators of the alternative complement pathway. Likewise, dimeric C3b is known to enhance complement receptor 1-dependent phagocytosis, and dimeric C3d (the smallest thioester-containing fragment of C3) linked to a protein antigen facilitates CR2-dependent B-cell proliferation. Because the efficiency of all these interactions depends on the number of C3 fragments, we investigated whether C3b2-IgG complexes retained dimeric structure upon physiological inactivation. We used two-dimensional SDS-PAGE and Western blot to study the arrangement of the C3b molecules by analyzing the fragmentation pattern after cleavage of the ester bonds. Upon inactivation with factors H and I, a 185-kDa band was generated under reducing conditions. It released IgG HC and the 65-kDa fragment of C3b alpha' chain after hydrolysis of the ester bonds with hydroxylamine. The two C3b molecules were not 65-kDa-to-40-kDa linked, because neither ester-bonded 65 kDa HC nor 65 kDa-40 kDa fragments were observed, nor was a 40-kDa peptide released after hydroxylamine cleavage. Factor I and CR1 cleaved the C3b2-IgG molecule to its final physiological product, C3dg2-IgG, which migrated as a 133-kDa fragment in reduced form. This fragment released exclusively C3dg (the final physiological product of C3b inactivation by factor I) and IgG HC. C3dg2-HC appeared as a double band on SDS-PAGE only at low gel porosity, suggesting the presence of two conformers of the same composition. Our results suggest that, upon physiological inactivation, C3b2-IgG complexes retain dimeric inactivated C3b and C3dg, which allows bivalent binding to the corresponding complement receptors.

Blood↗
PubMed1985

Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism.

L-Asparaginase (l-Asp) is widely used as an effective drug against childhood and adult acute lymphoblastic leukemia (ALL). However, it is immunogenic in humans and may lead to hypersensitivity reactions. The immunological basis of these reactions is not clear. Since the presence of l-Asp specific IgG-antibodies seems to correlate better with clinical reactions than IgE-antibodies and IgG-antibodies are known to be able to fix and activate the complement system, we speculated that the mechanism of anaphylaxis may be complement- rather than IgE-mediated. We analyzed 24 children with ALL (age 2-15 yr) for changes in the complement system during l-Asp infusions. Chemotherapy was administered according to the CoALL 82 protocol which is derived from the CoALL 80 protocol recently published. The formation of specific antibodies of IgM and IgG classes against l-Asp was monitored by a solid phase ELISA. The immunological responsiveness of individual patients varied over a wide range but both types of antibodies were induced. Anaphylactic reactions were observed on eight occasions in eight children. The infusions in the remaining 16 patients were tolerated without clinical reactions. Significant activation of complement was demonstrated in seven of eight reaction occasions and in none of the occasions without reactions. The most important complement activation parameter monitored was the C3 split product C3d measured in EDTA-plasma. We conclude that anaphylaxis to l-Asp in patients with ALL can be explained in most instances on the basis of complement activation induced by the formation of immune complexes of l-Asp and specific antibodies of IgM and IgG classes.

Adolescent↗
PubMed1986

The attachment of serum- and plasma-derived C3 to solid-phase immune aggregates and its relation to complement-mediated solubilization of immune complexes.

The interaction between immune aggregates and complement (C) was investigated. Solid-phase immune aggregates were prepared by coating microwells with heat-aggregated bovine serum albumin (BSA) followed by rabbit anti-BSA antibody. The immune aggregates were reacted with human serum or citrated plasma at 37 degrees C. The binding of C3 components was investigated with biotinylated F(ab')2 antibodies to C3c and C3d and avidin-coupled alkaline phosphatase. The form of the incorporated C3, whether C3b-iC3b or C3dg, can be deduced from the response with these two antibodies. The maximal binding of C3b-iC3b to the immune aggregates was observed within 5 min of incubation with serum or citrated plasma. The conversion to C3dg was evident by a decrease in bound anti-C3c concomitant with increasing anti-C3d reactivity within about 10 min of incubation. When the classical C pathway activation was inhibited, the binding of C3b-iC3b was delayed by 20-30 min, whereas stopping of the alternative pathway did not influence the initial kinetics of the reaction. The addition of human red blood cells had no measurable influence on the degradation of bound C3b-iC3b. 125I-labelled anti-BSA antibody bound to the solid-phase BSA was not released during the C3 incorporation. The incorporation of C3b into the immune aggregates was mediated equally well by serum and by citrated plasma. The incorporation of C3b-iC3b into immune complexes (IC) is thought to be responsible for the C-mediated solubilization (CMS) of IC. Citrated plasma, however, exerted no CMS capacity when measured by a radiometric assay. The CMS capacity of serum was inhibited by citrate, but could then be restored by adding Ca2+ and Mg2+, whereas no CMS could be demonstrated with citrated plasma to which divalent metal ions were added.

Antibodies↗
PubMed1976

Studies of the presence of membrane receptors for complement, IgG and the sheep erythrocyte rosetting capacity on the same human lymphocytes.

Normal peripheral blood lymphocytes were tested by a mixed rosette method, employing different sized erythrocytes as indicators to identify lymphocytes simultaneously possessing membrane markers found commonly on B and T cells. Only small populations of these lymphocytes were detected regularly in normal lymphocyte preparations. One type of lymphocyte (ranged from 0.5%-8%) was shown to possess the following markers: receptors for human and rabbit IgG, receptors for the third complement component C3b and C3b inactivator-cleaved C3b (C3d), and the capacity to rosette spontaneously with uncoated sheep erythrocytes (SRBC). Another lymphocyte cell type was shown to possess both SRBC and IgG receptors but lack membrane immunoglobulins and complement receptors. This population was detected in lymphocyte preparations depleted of complement receptor cells, and an increased number of these cells was found in rosette preparations incubated with human serum. The possible presence of some lymphocytes possessing both complement and SRBC receptors and lacking other markers was considered. The possibility that these small populations of human lymphocytes are sub-populations of T cells with certain cytotoxic function is postulated.

Adolescent↗
PubMed1999

The direct antiglobulin test: still a place for the tube technique?

OBJECTIVES: Antibodies of different immunoglobulin isotypes, or complement, may coat red blood cells in vivo. They are detected by the direct antiglobulin test (DAT), usually performed by the conventional tube technique. The purpose of this study was to compare the latter technique with the gel test. METHODS: Three hundred and ninety-eight consecutive samples, sent to our laboratory for direct antiglobulin testing, were analyzed with the tube technique and the gel test, using reagents from different manufacturers. Eighty-seven samples had been collected from newborns and 23 from fetuses. Results were expressed as positive or negative. RESULTS: In 162 out of 398 cases, the DAT was negative with both methods, whereas in 178 out of 398 cases, the DAT was positive with both techniques using polyspecific antibodies (observed agreement: 84.5%; kappa = 0.71). Discrepancies between the two methods were observed in 58 cases: 51 samples appeared as DAT positive using the tube method and negative with the gel test, whereas only 7 were positive exclusively with the gel test. Among the 178 samples that were positive with both techniques, 93 samples showed discordant results when evaluated with monospecific antisera (11 with anti-IgG and 82 with anti-C3d, respectively). The sensitivity of the DAT performed by the gel test, in comparison with the conventional tube technique, was 75.4% (95% confidence interval (CI): 69.4-80.8). 96. 8% (95% CI: 92.8-99.0), and 16.3% (95% CI: 9.8-24.9) with polyspecific, anti-IgG and anti-Cd3 reagents, respectively. CONCLUSIONS: The gel test appeared to be less sensitive than the conventional tube technique when utilized for DAT, particularly when C3d was present on red blood cells. These results emphasize that before implementing a new technique in the laboratory, comparison with existing techniques, using different reagents, is mandatory.

ABO Blood-Group System↗
PubMed1990

Complement components in neonatal sepsis.

Complement components C3, C1q, factor B and breakdown products of C3, i.e. C3c and C3d, were evaluated in the diagnosis and prognosis of sepsis in 24 neonates with proven sepsis. The complement components were measured by electroimmunodiffusion and breakdown products by counterimmunoelectrophoresis (CIEP). The babies with sepsis were found to have decreased levels of C1q and factor B as compared with suitably matched healthy controls. No statistically significant depression was observed in C3 levels of infected babies. However, breakdown products of C3, i.e. C3c and C3d, were detected in 58.3% of these babies. The breakdown products of C3 were not present in any of the healthy controls. The degree of depression of complement components was of no prognostic significance in neonatal sepsis.

Bacterial Infections↗
PubMed2002

Purification and characterization of soluble CD21 from human plasma by affinity chromatography and density gradient centrifugation.

Complement receptor II (CD21) is the receptor for C3d fragments on immune complexes. It also serves as a receptor for Epstein-Barr virus (EBV) and on B-lymphocytes CD21 amplifies signalling through the B cell receptor. CD21 is shed from the surface of the cell and is found circulating in plasma. There, soluble CD21 (sCD21) binds to CD23 and complement fragments, thereby modulating the immune response. sCD21 activates monocytes through binding to membrane CD23. The clinical significance of sCD21 is shown by the increased levels found in the sera of patients with B lymphomas, EBV infections and other lymphoblastoid tumors. In this paper, we report the isolation of soluble CD21 from human plasma using affinity chromatography and density gradient centrifugation. sCD21 was found to be a single 126 kDa molecular species. By determining the sedimentation coefficient, we have calculated the partial specific volume, diffusion coefficient and frictional coefficient of the protein. These values show that the sCD21 isolated from human plasma is an elongated rod-shaped molecule.

Cell Line↗
PubMed1985

Complement activation associated with active cytomegalovirus infection in renal transplant patients, and its absence in transplant rejection episodes.

In 20 patients with a cadaveric renal allograft, serial measurements were made of the serum complement factors C3, C4, factor B (FB), and C3d, the stable conversion product of C3. Measurements were started immediately before transplantation and continued thereafter once a week to investigate whether these assays help to differentiate between acute allograft rejection (R) and an active cytomegalovirus (CMV) infection. Fifteen patients had one or more R episodes, and 9 patients suffered from an active CMV infection. Six patients had an R episode and subsequently a CMV infection 13-64 days after R. No significant changes were found in the levels of C3, C4, and FB during R or CMV infection. C3d levels remained unchanged or decreased slightly during R. However, there was a 43-500% increase in the C3d level during CMV infection. This difference in the behavior of levels of C3d during R and CMV infection is significant (P less than 0.01), and suggests that serial measurements of C3d may be useful in differentiating CMV infection from R after renal transplantation.

Adult↗
PubMed1991

Complement activation by house dust: reduced reactivity of serum complement in patients with bronchial asthma.

Among ten different allergens, house-dust extract proved to be the most potent complement activator. It was therefore chosen to investigate the susceptibility of complement in the serum and bronchoalveolar lavage fluid of patients with extrinsic asthma and control persons. Complement activation in serum was assessed by the appearance of C3d as well as the activation-specific protein-protein complexes C1rs-C1inhibitor (classical pathway) and C3b(Bb)P (alternative pathway). Complement was activated via both the classical and the alternative pathway in a dose- and time-dependent manner. In contrast to earlier observations, however, complement was less affected in the serum of asthmatics than in the serum of normal individuals. Differences were restricted to alternative-pathway activation, probably due to preactivation and/or a significantly higher serum concentration of the regulatory protein factor H in asthmatic patients. In vitro generation of C3a in bronchoalveolar lavage fluid could not be achieved, although the presence of alternative pathway proteins C3, B and D was demonstrated.

Allergens↗
PubMed1987

Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis.

The type 2 complement receptor, CR2, a B lymphocyte surface glycoprotein, is known to be a component of the EBV receptor. We now demonstrate that the major EBV outer membrane glycoprotein, gp350/220, is a highly specific ligand for CR2. EBV or beads coated with purified recombinant gp350/220 adsorb to normal B lymphocytes, cap with CR2, become endocytosed into vesicles, and are released into the cytoplasm. This is the first demonstration of herpesvirus glycoprotein-cell glycoprotein receptor interaction in viral adsorption and penetration. The capping of CR2 in response to virus, gp350/220-coated beads, or anti-CR2 monoclonal antibodies is associated with cocapping of surface immunoglobulin. Interaction between CR2 and surface immunoglobulin may be important in modulating the B cell activation that normally follows EBV infection or exposure to antigen.

Adsorption↗
PubMed1989

Lymphocyte autoantibodies and alloantibodies in HIV-positive haemophilia patients.

Immune parameters were studied in 86 haemophilia patients (six with AIDS) and 87 healthy controls. We found lymphocytotoxic alloantibodies in HIV-positive (HIV+) sera which reacted preferentially with B lymphocytes but also with T lymphocytes, and which reacted more frequently at 4 degrees C than at 37 degrees C. The antibodies were not directed against HIV-induced structures on T lymphocytes and they were reactive with both CD4+ and CD8+ lymphocytes. In addition to cytotoxic alloantibodies, cytotoxic autoantibodies were detected which coated patient lymphocytes in vivo. Increased proportions of in vivo-antibody-coated-cells were found in 37 of 86 haemophilia patients. Antibody binding was labile so that the immunoglobulins were partially removed from the lymphocyte surface by washing. The autoreactive antibodies were of IgG and IgM type, fixed complement as demonstrated by increased anti-C3d+ cells in the patients' blood, and reacted with CD4+ as well as CD8+ lymphocytes. There was a statistically significant correlation of increased Ig+ cells with HIV infection, decreased CD4/CD8 ratios, increased serum neopterin levels, and abnormal in-vitro responses to pooled allogeneic stimulator cells or CD3 monoclonal antibody. Patients with increased Ig+ cells were lymphopenic, had decreased absolute counts of CD4+, CD25+, CD21+ and OKM5+ cells, and higher percentages of CD8+ and OKIa1+ cells in their blood than patients with normal levels of Ig+ cells. Our data suggest a role of autoreactive anti-lymphocyte antibodies in the pathogenesis of acquired immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1988

The esterase-like activity of covalently bound human third complement protein.

The acyl ester bond between the third complement protein, C3, and a variety of molecules is hydrolyzed spontaneously at neutral pH (Venkatesh et al., 1984). Modification of the free, single sulfhydryl group of bound C3 by thiol reagents suggested that a functional group other than the -SH acts as a "catalytic" group in this intramolecular hydrolytic reaction. Complete inhibition of the esterase-like activity is observed with stoichiometric amounts of mercuric chloride, palladium chloride, and the bifunctional organic mercurial, 3,6-bis-(acetoxymercuri)-o-toluidine [BAMT]. Since alkyl and aryl mercuric ions do not inhibit the esterase-like activity of C3-[3H]glycerol, it is conjectured that divalent mercury, palladium, and BAMT will form a complex with the -SH group and an atom of the "catalytic" group X having a lone pair of electrons. The structural features of C3 that are essential for the esterase-like activity remain intact after subjecting C3-[3H]glycerol to covalent chromatography on organomercurial agarose. Based on the observed effects of chemical reagents and the kinetic deuterium solvent isotope effect on the esterase-like activity, a general-base mechanism is proposed for the intramolecular hydrolysis of the acyl ester bond in covalently bound C3. The "catalytic" group X is located in the C3d region (residues 317-632 of the alpha chain), since C3d-[3H]glycerol also has esterase-like activity. A general-base mechanism mediated by the same "catalytic" group X may also apply to the formation of acyl ester bonds following the hydrolysis of the internal thiolester bond in native C3.

Chemical Phenomena↗
PubMed1990

Effect of amnionitis on the complement system of preterm infants.

The development of the complement system was studied by quantitation of total hemolytic complement activity (CH50), C1q, C3, C4, and C3 split product (C3d) in cord plasma of nine human fetuses (17-22 weeks of gestation), 110 preterm (24-36 weeks of gestation) and 30 term neonates. The complement levels were analyzed in relation to various illnesses of preterm infants. Histological examination of the placenta revealed a higher incidence of amnionitis in the placenta of less than 34 gestational weeks. In cases without amnionitis, there were significant correlations between complement levels and gestational age. In cases with amnionitis, the complement system was activated even in infants of less than 28 weeks gestation. The complement levels correlated with the extent of the inflammation in the placentas and umbilical cords except for C1q. In infants with Wilson-Mikity syndrome, complement levels other than C1q were significantly elevated in comparison with those of infants with respiratory distress syndrome. In the group of preterm infants without amnionitis, no differences were found between infants with intrauterine growth retardation and those with growth appropriate for gestational age.

Chorioamnionitis↗
PubMed1976

Surface markers of human eosinophils.

Peripheral blood eosinophils from patients with eosinophilia and from healthy subjects were studied for surface immunoglobulins, receptors for the Fc region of IgG, complement receptors, and spontaneous rosette formation with sheep and mouse erythrocytes. Eosinophils were found to have receptors for complement and for aggregated IgG, and to have the same two types of complement receptors as do lymphocytes and monocytes. Immune adherence type receptors were specific for C4 or C3b, while C3d receptors were specific for C3d but unreactive with C4. Eosinophils differed from fully mature neutrophils in that the former had C3d receptors and relatively weak immune adherence (C4 or C3b) receptors, while the later did not have the C3d receptors and had strong immune adherence receptors. Eosinophil phagocytosis of complement-receptor bound erythrocytes was dependent on the presence of IgG in the antibody coating the red blood cells; this requirement for IgG resembled that found in neutrophil phagocytosis. No surface Ig or spontaneous erythrocyte rosette formation was observed with eosinophils.

Binding Sites, Antibody↗
PubMed1987

Immunohistochemical study of intrathyroidal lymph follicles.

Tissue samples from 76 cases of thyroid disease containing germinal centers (GCs) were selected from 396 cases of various thyroid diseases for immunohistochemical analysis of the GC and follicular dendritic cell (FDC). These 76 cases included 28 cases of thyroid cancer, 23 of chronic thyroiditis, 12 of nontoxic goiter, 8 of adenoma, and 5 of Graves' disease. In many lymphoid GCs IgG, IgM and kappa and lambda light chains were detected with a lacy dendritic pattern. Only thyroglobulin (Tg), among the various thyroid-associated antigens sought, was stained in GCs and was found in the same distribution as immunoglobulins. Tg was found in all of the disease categories studied. Moreover, early components in the classical complement (C) pathway, that is, C1q, C4, C3c, C3d, and C5, were detected in almost all GCs in the thyroid tissues in a lacy dendritic pattern. C3d was intensely positive and was seen also by immunoelectron microscopy on the cell surface of FDCs. It is concluded that not only immunoglobulins but also Tg and early C components are closely related to the GC and FDC in the intrathyroidal lymph follicle.

Antigens↗
PubMed1981

Plasma haemoglobin and complement activation in sickle cell disease.

The role of haemolysis in producing deficient complement function in homozygous sickle cell disease was studied by measuring indices of complement activation and of haemolysis in 30 asymptomatic patients. Plasma concentration of C3d (an index of increased C3 turnover) was elevated in 40% of patients, and modest decreases in serum concentration of C3 and functionally (haemolytically) active factor B were found. There was a positive correlation between C3d and plasma haemoglobin concentration (r = 0.56, p less than 0.005). Reticulocyte count and foetal haemoglobin concentration also contributed to variation in C3d, though to a lesser extent than plasma haemoglobin. Intravascular haemolysis in sickle cell disease may produce activation of complement and thus cause partial depletion of functional factor B and C3. This may reduce the immune function of the alternative pathway.

Adolescent↗
PubMed1982

Circulating immune complexes in paroxysmal nocturnal hemoglobinuria.

Circulating immune complexes were investigated in sera of 13 patients with paroxysmal nocturnal hemoglobinuria. A significant inhibition was observed in the complement-dependent rosette formation (EAC) in 6 cases; 2 patients presented an increased anticomplementary activity; antilymphocyte antibodies were demonstrated in 2 patients. The levels of C3d and immunoconglutinins were also increased; there were no differences in the total hemolytic complement between patients and normal controls. There was a significant correlation between C3d and immunoconglutinins with the inhibition of the EAC rosette formation test. These results provide evidence for the presence of circulating immune complexes in paroxysmal nocturnal hemoglobinuria.

Adult↗
PubMed1995

Complement in serum and dialysate in children on continuous ambulatory peritoneal dialysis.

OBJECTIVE: During continuous ambulatory peritoneal dialysis (CAPD), activation of complement in the peritoneal cavity may theoretically occur, with inappropriately high or low levels of certain complement factors in dialysate as a consequence. In a group of children on CAPD, it was tested whether levels of a number of complement factors in dialysate were in the range that was predicted on the basis of their molecular weight. DESIGN: Serum and dialysate levels of C1q, C3, C4, C3d, B, D, and P were measured after a night dwell in children on CAPD. Simultaneously, four non-complement proteins (beta 2-microglobulin, albumin, IgG, and alpha 2-macroglobulin) were also measured in dialysate and serum. Assuming a linear relationship between the log base 10 of the dialysate/serum ratio of these non-complement proteins and the log base 10 of their molecular weight, the expected ratios of all complement factors were determined. The differences between actual and predicted ratios were tested using a modified t-test, taking into account the inaccuracy of the estimate. SETTING: University hospital. PATIENTS: A group of 14 children on CAPD, with a median age of 7.8 years (range 2.1 - 13.2). These children had been on CAPD for a median period of 42.4 months (range 0.4 - 89.1). RESULTS: The ratios of factor D (p < 0.001) and C3d (p = 0.035) were elevated, whereas those of C3 (p < 0.001), C4 (p < 0.001), and factor P (p = 0.012) were decreased. CONCLUSIONS: Relatively low dialysate/serum ratios of C4, C3, and factor P could be caused by intraperitoneal consumption of complement. High levels of C3d are compatible with this. High dialysate/serum ratios of factor D indicate intraperitoneal production of factor D. These results provide evidence for activation of complement in the peritoneal cavity in children on CAPD. A further reduction of already low levels of complement factors in dialysate as a result of this may impair host defense.

Albumins↗