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PubMed1978

Value of immune-complex assays in diagnosis and management.

Two complement-dependent assays for circulating immune complexes, the C1q-binding assay and the conglutinin binding, were used to study patients with suspected immune-complex disease. Complexes were detected most frequently in multisystem disease such as infective endocarditis (69%) and systemic lupus erythematosus (60%), and less frequently in isolated nephritis (26% of membrano-proliferative nephritis). Sequential estimations in 32 patients showed that concentrations of circulating immune complexes correlated with disease activity and were useful in monitoring therapy.

Adolescent↗
PubMed1998

Complement activation and CD59 expression in the motor facial nucleus following intracranial transection of the facial nerve in the adult rat.

Intracranial transection of the facial nerve has been shown to cause a massive neuronal cell death in the motor facial nucleus. Complement activation has been proposed to contribute to neuronal degeneration following axotomy. Using immunocytochemistry and in situ hybridization we show in the present study that there is complement activation in the facial nucleus after intracranial facial nerve transection as well as increase of the complement regulators CD59 and clusterin. We propose a neuroprotective role for the complement regulators CD59 and clusterin against homologous attack of complement to facial motor neurons.

Age Factors↗
PubMed1987

Complement activation in patients with amebic liver abscess.

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

Complement Activating Enzymes↗
PubMed1980

Evidence that C1q, a subcomponent of the first component of complement, is an Fc receptor of peritoneal and alveolar macrophages.

Guinea pig peritoneal macrophages were cultured for 24 h in the presence of two inhibitors of the biosynthesis of collagen-like molecules such as C1q : 10(-3) M 3,4-dehydroproline or 10(-4) M 2,2'-dipyridyl. Their Fc-receptor activity was measured by rosette formation, using sheep erythrocytes (E) coated with rabbit anti-sheep IgG (EAIgG). The Fc-receptor activity was decreased by 40 to 70% of control cultures depending on the amount of IgG on the E. The activity of a second receptor on the macrophages, mediating the binding of C3b coated E, was not altered by this treatment. Rat alveolar macrophages were depleted of their Fc-receptor activity by pronase treatment (1.5 mg/ml) in the presence of 2,2'-dipyridyl. After washing the cells, the EAIgG-binding activity was restored to about half of the initial level within 2 h. With 2,2'-dipyridyl also present during the second incubation, the re-expression of the Fc-receptor activity was suppressed further. Preincubation of guinea pig peritoneal macrophages with anti-C1q-F(ab')2 for 45 min at 37 degrees C caused a dose-dependent reduction of the Fc receptor activity, but not C3b receptor activity. These results support our hypothesis that C1q synthesized and secreted by macrophages serves as an Fc-receptor in the membrane during the secretion.

2,2'-Dipyridyl↗
PubMed1985

In vivo modulation of rat complement activities by infusion of anti-H antibodies.

Regulation of the activity of the alternative pathway of complement occurs by the plasma proteins I and H. H is able not only to prevent formation of the amplification convertase C3bBb but also to cause the decay-dissociation of Bb from C3bBb. The present studies have investigated the role of H in vivo. Affinity-purified goat (Fab')2-anti H was infused intravenously in rats, and its effect on C4, C3 and CH50 activities was assessed. In addition, H, C3, C4 and B were quantitated by immunochemical methods. H depletion was dependent on the dose of anti-H, and maximal consumption in vivo occurred between 5 and 15 min. A maximum of 51% and 77% hemolytic C3-consumption was seen after 15 min with 3.8 and 8.4 mg anti-H, respectively. The injection of 6.3 mg affinity-purified goat IgG anti-rat H caused 96.8 +/- 0.7% and 85.0 +/- 1.4% consumption of CH50 and C3 hemolytic activity, respectively. Using this dose of IgG anti-rat H, it was found that the clearance in rats of rat erythrocytes sensitized with 8000 molecules of guinea pig IgG2 per E was impaired as compared to the clearance of these intermediates in control rats injected with a comparable dose of normal goat IgG. The results indicate that H functions as a potent regulator of C in vivo and that infusion of anti-H can be used as a method to achieve depletion of circulating complement components.

Animals↗
PubMed1989

Chronic urticaria and macroglobulinemia (Schnitzler's syndrome): report of two cases.

Two cases of chronic urticaria associated with macroglobulinemia are reported, and the characteristics of 13 other cases are reviewed. This entity was described by Schnitzler in 1974 and has the following characteristics: chronic nonpruritic urticaria with leukocytoclastic vasculitis, bone pains with hyperostosis, intermittent fever, and a monoclonal IgM gammopathy. Liver, lymph node, and spleen enlargement may occur. Criteria for the diagnosis of Waldenström's disease are lacking (IgM level less than 10 gm/L, no overt lymphoid proliferation in bone marrow). Other immunologic findings (complement, C1 inhibitor, cryoglobulin, rheumatoid factor, antinuclear antibodies) are negative or normal. Evolution is long-term with a long follow-up period. In one case a lymphoplasmocytic lymphoma developed. No adequate treatment has yet been found. Pathogenesis is unclear but seems to be caused by skin deposits of the IgM paraprotein, as attested to by the direct cutaneous immunofluorescent findings in some cases.

Bone Diseases↗
PubMed1984

Ultrastructural immunohistochemistry of glomerulonephritis in needle biopsy.

In two patients with glomerulonephritis (GN) IgG and C 3 were visualized in ultrastructure by means of HRP-conjugated antisera. The first patient had an acute postinfectious extra-intracapillary GN lasting for about two months with granular fluorescence of anti-IgG, -C 3, and -C 1q. Electron microscopy revealed widespread endothelial defects, a well-pronounced polymorphonuclear stasis, and typical perimembranous "humps". These deposits reacted with HRP-anti-C 3 but the ultrastructural proof of IgG was negative. A weak and sporadic reaction of both these conjugates was seen in the swollen mesangial matrix while intraluminal plugs of coagulated plasma and extracapillary exudates yielded a dense coarse reaction product. In the second patient (allograft, three years after transplantation) the membranous and proliferative probably recurrent GN with nephrotic syndrome showed massive perimembranous deposits in the late involution stage. Granular fluorescence of the main Ig classes and of C 3 was sporadic or absent. In the ultrastructural immunoenzyme assay, too, the residues of deposits failed to react with HRP-anti-IgG or -C 3 and the mesangial matrix harboured only sporadic foci of faint positivity; however, dense product was again seen in capillary plasmatic "microthrombi". The discrepancy between immunofluorescence microscopy and immunoenzyme histochemistry, noted also by others in experimental glomerulopathies, may reflect the instability and dynamic properties of immune deposits with an early loss of antibody reactivity and a more protracted though not persistent local activation of complement. In light microscopy, fluorescent granules may correspond not only to the sites of immune deposition but also to accidental intracapillary plasma precipitates.

Adult↗
PubMed1989

The effect of a bolus injection of unfractionated or low molecular weight heparin during aortobifemoral bypass grafting.

Eighteen patients undergoing aortobifemoral graft surgery for severe aortoiliac atherosclerotic disease received a bolus injection of 10,000 anti-Xa units of either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) into the distal aorta as prophylaxis against thromboembolic complications related to clamping. Heparin activity was measured by factor Xa inhibition and by prolongation of the APTT. In both groups there was a delay before peak levels of heparin were observed. In the LMWH group, this amounted to 30 min. In the UFH group, APTT was prolonged by 46 s, 7 min after injection but only by 5 s at the end of the operation. In contrast, in the LMWH group, the prolongation in APTT 7 min after injection was less (34 s) but more sustained since a 12.5 s prolongation was still present at the end of the operation. During surgery, heparin activity exceeded 0.7 U/ml in the LMWH group, compared to significantly lower levels in the UFH group (less than or equal to 0.20 U/ml). By the end of the operation no heparin activity was detectable in the UFH group. Protein C antigen decreased after heparin injection and this fall was more pronounced in the UFH group. The level of C1q (a subcomponent of the first component of the complement system) was decreased in the UFH group (P less than 0.04), whereas in the LMWH group C1q levels increased. Platelet aggregation with collagen was inhibited to a significantly greater degree in the LMWH group than the UFH group (54% compared with 23%) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

Complete cDNA sequence of human complement Cls and close physical linkage of the homologous genes Cls and Clr.

Overlapping molecular clones encoding the complement subcomponent Cls were isolated from a human liver cDNA library. The nucleotide sequence reconstructed from these clones spans about 85% of the length of the liver Cls messenger RNAs, which occur in three distinct size classes around 3 kilobases in length. Comparisons with the sequence of Clr, the other enzymatic subcomponent of Cl, reveal 40% amino acid identity and conservation of all the cysteine residues. Beside the serine protease domain, the following sequence motifs, previously described in Clr, were also found in Cls: (a) two repeats of the type found in the Ba fragment of complement factor B and in several other complement but also noncomplement proteins, (b) a cysteine-rich segment homologous to the repeats of epidermal growth factor precursor, and (c) a duplicated segment found only in Clr and Cls. Differences in each of these structural motifs provide significant clues for the interpretation of the functional divergence of these interacting serine protease zymogens. Hybridizations of Clr and Cls probes to restriction endonuclease fragments of genomic DNA demonstrate close physical linkage of the corresponding genes. The implications of this finding are discussed with respect to the evolution of Clr and Cls after their origin by tandem gene duplication and to the previously observed combined hereditary deficiencies of Clr and Cls.

Amino Acid Sequence↗
PubMed1988

C1q component of complement binds to fibrinogen and fibrin.

The interaction of complement component C1q with fibrinogen and fibrin was studied by using a solid-phase direct binding assay. Scatchard analysis of radioiodinated fibrinogen binding to C1q indicated at least two high-affinity binding constants (Kd) calculated as 8.5 and 120 nM. In contrast, binding of radioiodinated fibrin to C1q showed only a single class of binding sites with a calculated Kd of 600 nM. Fibrinogen-C1q binding was shown to decrease as a function of increasing salt concentrations, indicating either the presence of charged amino acids in the binding sites or an ionic strength induced conformational dependency of the binding. In direct binding studies using isolated fragments of C1q, both the collagen-like domain of C1q and the globular domains of C1q were shown to bind fibrinogen, indicating at least one binding site for fibrinogen is located in each of the major domains of C1q. Addition of the thrombin-generated peptides of fibrinogen, fibrinopeptides A and B, enhanced C1q-fibrinogen binding, again indicating a complex binding interaction. These results indicate that C1q and fibrinogen are capable of high-affinity interactions that may serve to sequester these complexes in areas of tumors, immune complex deposition, or wounds.

Binding Sites↗
PubMed1977

Correlation between the exposure of aromatic chromophores at the surface of the Fc domains of immunoglobulin G and their ability to bind complement.

The recognition that certain biological effector functions associated with the Fc region of human IgG are mediated exclusively by either the Cgamma2 or Cgamma3 domains prompted a study of some of the physical properties of the isolated domains in an attempt to correlate these with functional differentiation. The degree of aromatic chromophore exposure of intact Fc and fragments corresponding to the Cgamma2 and Cgamma3 domains were determined by solvent perturbation difference spectroscopy using 20% ethylene glycol. For the monomeric Cgamma2 fragment one of the two tryptophans and all four of the tyrosines were exposed to solvent. In the pFc' fragment, which represented a dimer of two intact Cgamma3 domains, an average of 0.4 of the two tryptophans of 3.3 of the five tyrosines per chain were exposed. These data were consistent with the suggested involvement of tryptophan in complement fixation since Cgamma2 binds C1q but pFc' does not. Several fragments derived from the Cgamma3 region had previously been shown to have differing environments for their aromatic side chains from circular dichroism studies. These fragments have now been shown to exhibit different degrees of chromophore exposure to solvent. Removal of the carboxy-termimal heptapeptide from the intact, Cgamma3 domain resulted in a fragment not only showing a greater exposure of aromatic residues but also having the ability to bind Clq. Our data suggest that the structural requirements for C1Q binding may be quite commonplace within Fc, but tertiary folding limits their expression except in Cgamma2 in the native molecule. The solvent perturbation observed with Fc was somewhat lower than would have been expected from the results with the isolated domains, suggesting that interdomain interactions may result in burial of aromatic residues.

Binding Sites↗
PubMed1976

Ultracentifuge studies of the binding of IgG of different subclasses to the Clq subunit of the first component of complement.

Normal IgG and myeloma proteins of the IgG1, 2, 3,and 4 subclasses were mixed with human Clq and studied in the analytical ultracentrifuge for complex formation. Binding of IgG to Clq is apparent both from the enlargement of area and from the increase in sedimentation rate of the well-separated schlieren peak of Clq. The accurate determination of binding parameters requires that sedimentation rates be corrected for hydrodynamic interaction, and area measurements corrected for the Johnston-Ogston effect. At the highest immunoglobulin concentrations employed in these studies more than ten IgG molecules are bound to each Clq. If we assume that the number of binding sites must be an integral multiple of 6, then the data best support a 12 binding site model, although an 18 site model cannot be rule out. Myeloma IgG proteins of all subclasses bind to Clq, with affinities decreasing in the order G3 greater than G1 greater than G2 greater than G4. No binding of IgA to Clq could be detected.

Binding Sites↗
PubMed2003

Importance of the prime subsites of the C1s protease of the classical complement pathway for recognition of substrates.

The classical complement pathway, which plays a vital role in preventing infection, is initiated by the action of the serine proteases C1r and C1s. We have examined the hydrolysis of substrates representing cleavage sequences in the physiological substrates for C1s, C2 and C4. These studies showed that the P(1)'-P(4)' substrate residues of C2 and C4 conferred greater affinity of substrate for enzyme and also induced a sigmoidal dependence of enzyme velocity on substrate concentration. This indicates that the substrate gave rise to homotropic positive cooperative behavior in the enzyme. When C1s was in complex with C1q and C1r, as would occur under physiological conditions, the same behavior was observed, indicating that this mechanism is relevant in the complement pathway in vivo. We further investigated the requirements of C1s for prime side amino acids by examining a substrate library in which each of the P(1)'-P(4)' positions had been substituted by different classes of amino acids. This revealed that the P(1)' position was a major determinant of the selectivity of the enzyme, while certain substitutions at the P(1)'-P(4)' positions abolished the allosteric behavior, indicating that contact residues at these positions in the C1s enzyme must mediate the cooperativity. The studies reported here highlight the importance of prime subsites in C1s for interaction with its cognate substrates in the complement pathway and therefore yield greater understanding of the mechanism of interaction between this vital protease and its physiological substrates.

Amino Acid Substitution↗
PubMed2001

Inhibitory effects of S-(-) and R-(+) bupivacaine on neutrophil function.

BACKGROUND: Local anesthetics inhibit migration, enzyme release and superoxide anion generation of polymorphonuclear leukocytes (PMN). Due to their ability to phagocytose and kill bacteria PMN represent a major defense mechanism in the circulating blood. In this study we determined the influence of racemic bupivacaine and its enantiomers on neutrophil phagocytic activity, oxidative burst as well as surface expression of complement and Fcgamma receptors. METHODS: Venous blood was pre-incubated with different concentrations of either racemic bupivacaine, R-(+) or S-(-) bupivacaine. Fluoresceine isothiocyanate (FITC)-labeled antibodies against Fcgamma receptor III (CD16), complement receptor 1 (CD35) and complement receptor 3 (CD11b) were used to determine surface receptor expression. Phagocytic activity was measured by ingestion of FITC-labeled vital Staphylococcus aureus. Oxidative burst was determined by conversion of nonfluorescent dihydrorhodamine 123 into fluorescent rhodamine 123. Fluorescent intensity of each sample was determined by flow cytometry. RESULTS: Racemic bupivacaine inhibited surface receptor expression, phagocytosis, and oxidative burst in a time- and concentration-dependent manner. Although the S-(-) enantiomer exerted significantly less inhibitory action on neutrophil function compared to R-(+) and racemic bupivacaine, these effects were small compared to the overall changes. CONCLUSION: These findings suggest that bupivacaine impairs surface receptor expression and may thereby contribute to reduced phagocytic activity and oxidative burst. Enantiomer-specific effects of bupivacaine may play a minor role in the inhibition of these leukocyte functions.

Adult↗