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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↗
PubMed1987

Leukotriene C4 production by normal-density and low-density eosinophils of atopic individuals and other patients with eosinophilia.

With the use of a percoll gradient separation procedure, eosinophils of individuals with asthma and with allergy could be separated into normal- and low-density cell fractions. The presence of low-density eosinophils possibly reflects an ongoing process of activation of these cells induced by the allergic reaction. Ca-ionophore-induced leukotriene (LT) C4 production, in the absence of added substrates, demonstrated a decreased potency for LT generation by low-density eosinophils compared with the LT generation of normal-density cells (57 +/- 33 ng and 103 +/- 44 ng per 10(6) cells, respectively). In contrast with the Ca-ionophore-induced LT formation, incubations with serum-treated zymosan in the presence of glutathione demonstrated higher productions of LTC4 with the low-density eosinophilic subpopulation compared with normal-density cells. This is compatible with a possibly higher expression of complement C3b receptors on the low-density eosinophils. Total arylsulfatase contents demonstrated that low-density eosinophils are not degranulated with respect to their small granules. Although release of the large granules by low-density eosinophils cannot be excluded, electron-microscopy studies indicated that degranulation is not the only (or major) factor that determines the density of the various eosinophilic subpopulations.

Cell Count↗
PubMed1992

Immunohistochemical evidence for C3bi involvement in Graves ophthalmopathy.

PURPOSE: To determine by immunohistochemical methods if components of the complement system are present in Graves ophthalmopathy extraocular and periocular tissues compared with non-Graves ophthalmopathy ocular tissues, and, if so, whether a qualitative difference exists. METHODS: Orbital muscle, periorbital muscle, and adipose tissue from 10 Graves ophthalmopathy patients were studied with in situ assays using monoclonal antibodies for C3bi and C5b-9 (the terminal attack complex) complement components. Extraocular muscle, periocular muscle, and adipose tissue from 12 patients treated for unrelated orbital disorders were used as controls. RESULTS: All nine Graves extraocular and periocular muscle tissues exhibited C3bi positive staining in an intense, localized oval- to spindle-shaped reaction that appeared to represent cells on a diffuse staining background of the endomysial and perimysial connective tissues with no staining of the muscle fibers themselves. Some reactivity was seen in 6 of the 12 control muscles, but this was much less intense than that of Graves ocular muscle tissue. Only two Graves muscle samples stained minimally with the monoclonal antibody for the C5b-9 terminal attack complex while none of the control muscle samples demonstrated reactivity. Orbital fat from Graves and control patients did not demonstrate any reactivity for C3bi or C5b-9. CONCLUSION: C3bi and not C5b-9 (the terminal attack complex) is present in Graves ophthalmopathy extraocular and periocular tissues in a qualitatively greater way than in control non-Graves ophthalmopathy ocular tissue. Consequently, C3bi may contribute to the pathophysiology of Graves ophthalmopathy.

Adult↗
PubMed1984

Covalent binding efficiency of the third and fourth complement proteins in relation to pH, nucleophilicity, and availability of hydroxyl groups.

The binding of [3H]glycerol and [3H]putrescine to C3 was studied in a fluid-phase system using trypsin as the C3 convertase. The binding of glycerol showed little variation in the pH range between 6.0 and 10.0. The binding of putrescine (pKa = 9.0) is rather ineffective below pH 7.5 but becomes more efficient as the pH of the reaction mixture increases. These results agree with the contention that the final step of the binding reaction is the transfer of the acyl group of the exposed thio ester of C3 to a nucleophile since the nucleophilicity of hydroxyl groups is rather independent of pH whereas only the unprotonated form of amino groups is nucleophilic. The inefficient reaction of amino groups with the exposed thio ester of C3 is also supported by the study of the inhibitory activity of serine and its two derivatives, N-acetylserine and O-methylserine, to the binding of [3H]glycerol to C3. N-Acetylserine showed an inhibitory activity equivalent to that of serine, whereas O-methylated serine showed only minimal activity. It can be concluded, therefore, that serine reacts with the thio ester of C3 by its hydroxyl group but not by its alpha-amino group. The ability of the alcohol group of various alkanes to inhibit the binding of [3H]glycerol to C3 was also studied. The primary alcohols inhibit the binding reaction with an efficiency that is similar to glycerol, and there are no significant differences in the binding efficiencies of methanol, ethanol, 1-propanol, and 1-butanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
PubMed1987

Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis.

Antigens of the membrane attack complex of complement (MAC), such as C5, C6, C9 and MAC-related neoantigen(s), were demonstrated in the mesangium of 23 cases with IgA-glomerulonephritis (IgA-GN) and two cases with Henoch-Schönlein purpura nephritis (HSP). High specificity of the polyclonal antibodies was verified by dot-blot analysis. Control specimens lacking immunoglobulin deposits were negative for MAC-related antigens. Markers of classical pathway activation (Clq and C4) were observed only in two of 24 and one of 23 cases of IgA-GN and HSP, respectively. Glomerular distribution patterns (mesangial vs. mesangio-peripheral) of immunoglobulin or complement deposits were correlated for IgA and C3b/iC3b (P less than 0.002), for IgA and properdin (P less than 0.002) and for IgA and MAC neoantigens (P less than 0.01). Double immunostaining experiments revealed co-localization of IgA and MAC neoantigens at identical mesangial and capillary sites. Glomerular distribution of the less pronounced IgG or IgM deposits did not correlate with that of any complement-derived antigen. The pattern of MAC-related antigens was found to be uniformly either mesangial or mesangio-peripheral. Staining for MAC-related antigens was less intense in IgA-GN cases with minimal glomerular lesions than in cases with more advanced non-sclerosing lesions. IgA, C3d, and MAC localized in corresponding glomerular sites. This is consistent with complete local activation of complement by glomerular IgA deposits via the alternative pathway. The possibility exists that MAC plays a pathogenetic role, such as by irritation of bystander cells, in IGA-GN and HSP.

Adolescent↗
PubMed1991

Elevated plasma levels of the immunosuppressive complement fragment Ba in renal failure.

The complement fragment Ba is a 33 kD activation product of factor B which suppresses human B-lymphocyte functions in vitro. We report that plasma levels of Ba are highly elevated in patients with chronic renal failure (4.84 +/- 3.58 micrograms/ml) and in patients with end-stage renal disease undergoing regular hemodialysis (16.1 +/- 6.1 micrograms/ml) as compared to normals (1.01 +/- 0.30 micrograms/ml). Ba levels were strictly correlated with the creatinine clearance. The urinary excretion of Ba was 165-fold higher in patients with tubular proteinuria than in normals. These results indicate that the kidney is the major catabolic site for Ba. In addition, direct evidence was obtained for an enhanced turnover of the alternative pathway of complement in renal failure that, although it appears to be less important than the renal retention of Ba, contributes to elevated Ba plasma levels in these patients. Ba concentrations in dialysis patients who responded to hepatitis B vaccination were significantly lower than in non-responders. Furthermore, the in vitro IgM synthesis by purified mononuclear cells was negatively correlated with Ba concentrations determined in the plasma of these patients. These results suggest that the accumulation of Ba contributes to the defective immune response in patients with renal failure.

Adult↗
PubMed1987

Resolution and analysis of 'native' and 'activated' properdin.

A rapid and reproducible procedure for the resolution of 'native' and 'activated' forms of properdin (a component of the alternative activation pathway of complement), by gel filtration on the polyvinyl matrix Fractogel TSK HW-55(S), is reported. This fractionation permitted effective screening of samples for conditions that cause activation. Only 'native' properdin was detected in serum, even after activation of the alternative pathway by yeast cell walls. Transformation of 'native' into 'activated' properdin in vitro was produced by freeze-thawing of the protein, but not upon binding to and dissociation from the C3 convertase, C3bBb. Electron microscopy showed that only the 'native' population contained the discrete cyclic structures described previously by Smith, Pangburn, Vogel & Müller-Eberhard [(1984) J. Biol. Chem. 259, 4582-4588]. 'Activated' properdin, which was eluted from the gel-filtration column close to the breakthrough peak, was mainly composed of large amorphous aggregates. We therefore conclude that properdin 'activation' is not a physiological event that occurs in serum on complement activation, but is an artifact of isolation. Fractionation of properdin on Fractogel TSK HW-55(S) has, however, enabled detailed analysis of functional heterogeneity within the 'native' population.

Cell Wall↗
PubMed1991

The principal site of glycation of human complement factor B.

Accumulating amino acid sequence data have made it increasingly evident that many essential complement proteins have potentially modifiable lysine residues in putative critical functional regions. Evidence is now presented that glucose is covalently attached to lysine-266 of purified human complement Factor B as a result of glycation. Purified B was treated with NaB3H4, which reduces such bound glucose to a mixture of radiolabelled hexitols. Amino acid analysis revealed the expected radiolabelled hexitol-lysine epimers. In addition, fluorography of dried gels resolving the major high-molecular-mass h.p.l.c.-fractionated CNBr-cleavage peptides of NaB3H4-reduced B indicated that this radioactivity was specifically associated with the 15 kDa fragment derived from the N-terminal region of fragment Bb. Amino acid sequence analysis suggested that the C-terminal lysine (residue 266 of B) of the N-terminal Lys-Lys doublet of this peptide is preferentially modified. If such glycation can subsequently be shown to occur in vivo, then perhaps this modification might also be found to affect the functional activity of B and offer a potential explanation for some of the immunopathological complications of diseases exposing key plasma proteins, such as this active-site-containing proteinase of the multimeric alternative-complement-pathway C3/C5 convertases, to long-term high concentrations of glucose, such as the decreased resistance to infection and impaired chemotaxis and phagocytosis characteristic of diabetes.

Amino Acid Sequence↗
PubMed1990

Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.

1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

Complement Activation↗
PubMedDate not supplied

[In-vivo activation of the 4th component of the complement system (C4) in premature and term infants with generalized bacterial infections].

The concentrations of the complement components C3 and C4 and their activation products C3dg and C4d were determined in EDTA-stabilized serum of 25 premature and term infants. EDTA plasma and EDTA serum obtained from 30 normal blood donors were used as controls. According to clinical, laboratory and/or microbiological findings, six of the 25 children had infections. The mean scatter range of the C3 and C4 values was from 30% (in the 30th week of pregnancy) to 80% (in term infants) of the normal value for adults. In all the children, irrespective of gestational age, the C3dg concentrations were of the same order of magnitude as in healthy adults. As regards the C3, C4, and C3dg values, there was no difference between the newborns with and without infections. The C4d values of the newborns without infections, on the other hand, (range 0.1-1.4 mg/dl, mean 0.8 mg/dl, n = 19) were significantly lower than those of the newborns with infections (range 1.3-2.4 mg/dl, mean 1.95 mg/dl, n = 6). Observation of the course and comparison with CrP showed that elevated C4d values may occur earlier. In the authors' view, these findings indicate that in bacterial infections of premature and term infants the fourth complement component is activated, while the extent to which the third complement component is involved in the activation process is not measurable. Further studies are needed to establish whether early diagnosis of neonatal sepsis can be improved by determining C4d.

Bacterial Infections↗
PubMed1981

Opsonic requirements for intravascular clearance after splenectomy.

We investigated the opsonic requirements for intravascular clearance of pneumococci in guinea pigs and of sensitized erythrocytes in human beings after splenectomy. The impaired clearance of injected pneumococci in splenectomized guinea pigs was corrected by immunization. This improvement in clearance was due to increased hepatic sequestration of organisms. There was a significant delay in antibody-mediated clearance of autologous erythrocytes sensitized with IgG (P < 0.001), although the rate of complement-mediated clearance in splenectomized patients was normal. A fourfold increase in sensitizing antibody resulted in a significant improvement in clearance that was due to increased hepatic sequestration (P < 0.005). One patient who had an intact spleen and who had previously received Thorotrast (thorium oxide) had impaired antibody-mediated clearance despite increased sensitization. These observations suggest that, after splenectomy the remaining macrophages of the reticuloendothelial system require increased amounts of antibody to mediate efficient intravascular clearance of opsonized particles.

Animals↗
PubMedDate not supplied

Complement activation by cigarette smoke condensate and tobacco infusion.

The capacity of tobacco infusion and cigarette smoke condensate to activate the complement pathway was investigated in vitro by hemolytic and immunological assays. Complement activity was studied using samples of normal human serum incubated at 37 degrees C with different dilutions of tobacco infusion and cigarette smoke condensate. In all mixtures containing tobacco infusion or cigarette smoke condensate at a concentration of 0.1: 1, total hemolytic complement showed an average progressive decrease of 90% and 50%, respectively, after 60 min of incubation. This decrease was associated with a decrease of both classical and alternative pathway activities. In addition, cleavage fragments of C3, C4, and factor B were identified with immunochemical analyses. This study suggests that tobacco infusion and cigarette smoke condensate are activators of complement either through the classical or alternative pathway.

Blood↗