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PubMed1997

[Contribution of biochemical tests in the diagnosis of the nervous phase of human African trypanosomiasis].

The stage of human African trypanosomiasis (HAT) is important to define precisely as far as it is directly related to the type of treatment used. The beginning of the neurological involvement is difficult to find out because there is no known specific clinical or biological sign. This study is trying to look for a precise marker and has been realized in Congo. 70 subjects with parasitologically confirmed HAT and 70 controls are included. The stage of HAT is determined according to the classical definition on the field using the cerebrospinal fluid (CSF) cell count: less than 5 cells/microliters for the first stage (P1), more than 5 cells/microliters for the second stage (P2). The blood analysis has included: glucose, urea, creatinine, sodium, potassium, calcium, chloride, phosphorus, uric acid, total bilirubin, unconjugated bilirubin, total cholesterol, triglycerides, total proteins, aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, alkaline phosphatase, gamma-glutamyltransferase, immunoglobulins M and G, C3c fraction of complement, transferrin, seromucoid alpha 1, haptoglobin and albumin. In CSF we have analyzed IgM, IgG, protein levels and the bloodbrain barrier (BBB) impairment. The comparison between the subjects and their controls, the subjects in P1 and in P2, the CSF cell count and the other CSF alterations show the interest of the IgM level in CSF and the BBB impairment to identify subjects in P2. However there is a low gradation in the biological disturbances and not a precise threshold point. Nevertheless it seems reasonable to raise the CSF cell count level to 20 cells/microliters to define the beginning of the nervous involvement.

Blood Chemical Analysis↗
PubMed1978

[Parenteral feeding after ureterosigmoidostomy: nitron balance, free plasma amino acids and state of proteins].

The postoperative protein metabolism of 11 patients who had required either a colon conduit or ureterosigmoidostomy urinary diversion was examined. From the 3rd to 10th postoperative day day, each patient received a standard parenteral alimentation (100 g amino acids and 2000 kcal/24 h). Nitrogen balance, plasma level of the free amino acids, and the C3c-, C4-complement and transferrin fraction in plasma were determined regularly. The results showed that this substitution therapy succeeded in avoiding serious alterations in the parameters measured.

Adult↗
PubMed1994

IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA).

To study the IgG subclass distribution and complement activation ability of ANCA, 24 sera containing C-ANCA (cytoplasmatic) and 7 sera containing P-ANCA (perinuclear), as determined by a routine immunofluorescence test, were examined. The subclass distribution was tested by the use of immunofluorescence and ELISA technique and monoclonal antibodies to IgG subclasses. The complement activating activity was studied by the use of immunofluorescence technique and antibodies to C3c and the terminal complement complex (TCC, C5b-9), directed against a neoepitope on C9. For C-ANCA, IgG1 and IgG4 were the dominating subclasses. The subclass distribution differed from that of other autoantibodies tested and that of the total IgG subclass concentrations. For P-ANCA, the results were inconclusive, but the lack of IgG3 was striking. All of the C-ANCA-containing sera caused deposition of C3c, and 50% of the sera gave formation of TCC when reacting with ethanol-fixed granulocytes. P-ANCA-containing sera caused some C3c deposition, but not TCC formation. The unusual IgG subclass distribution for C-ANCA is possibly due to repeated antigenic stimulations and/or to T cell factors influencing the antibody isotype switching. Despite the high IgG4 activity, sera containing C-ANCA are often able to activate complement and are therefore potentially harmful.

Animals↗
PubMed1983

Interaction of fibronectin with complement component C3.

The activation of the complement component C3 generates C3a and C3b fragments, and the physiological cleavage of C3b further yields C3c and C3d fragments. We studied here by enzyme immunoassay the ability of human plasma fibronectin to interact with native C3 of human sera and with isolated C3c and C3d fragments of C3. C3 from sera of all six individuals tested bound to solid-phase fibronectin. Soluble fibronectin bound to solid-phase C3c and C3d, and fluid-phase C3c and C3d also bound to solid-phase fibronectin. The binding of fibronectin to solid-phase C3c and C3d could be inhibited by fluid-phase C3c and C3d. The results suggest the possibility that soluble fibronectin may attach to C3-coated particles or that C3-coated particles may adhere to fibronectin-containing structures.

Complement Activation↗
PubMed1998

Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway.

Vaccinia virus complement control protein (VCP) is a virulence determinant of vaccinia virus that helps protect the virus from the complement attack of the host. To characterize the interaction of VCP with C3 and C4 and understand the mechanism by which VCP inactivates complement, we have expressed VCP in a yeast expression system and compared the biologic activity of the purified protein to that of human factor H and complement receptor 1 (CR1). Recombinant VCP bound to C3 and the proteolytically cleaved form of C3 (C3b), but not to the 135,300-m.w. fragment of C3 generated using elastase (C3c) and the 35,000-m.w. fragment of C3 generated using elastase (C3d) and inhibited both the classical and alternative pathways of complement activation. Although rVCP was less effective at inhibiting the alternative pathway than factor H or CR1, it was more effective than factor H at inhibiting the classical pathway. Unlike factor H, rVCP was unable discriminate between alternative pathway-mediated lysis of rabbit and sheep E. A comparison of the cofactor activity in factor I-mediated cleavage of C3b suggested that in contrast to factor H and CR1, which displayed cofactor activity for the three sites, rVCP displayed cofactor activity primarily for the first site, leading to generation of C3b cleaved by factor I between Arg1281-Ser1282 (iC3b1). Its cofactor activity for C4b cleavages was similar to that of soluble complement receptor type 1. Purification and functional analysis of iC3b1 showed that it was unable to interact with factor B to form the alternative pathway C3 convertase, C3b,Bb. These results suggest that the interaction of VCP with C3 is different from that of factor H and CR1 and that VCP-supported first cleavage of C3b by factor I is sufficient to render C3b nonfunctional.

Arginine↗
PubMed1984

Physiologic inactivation of fluid phase C3b: isolation and structural analysis of C3c, C3d,g (alpha 2D), and C3g.

The fragments that result from the inactivation of C3b have not been completely characterized. Initial inactivation is catalyzed by the protease factor I, which, in the presence of its cofactor (factor H), cleaves two peptide bonds in the alpha'-chain of C3b. This results in the release of a small peptide (C3f, Mr 3000) from iC3b, which consists of the C3 beta chain covalently bonded to two alpha'-chain-derived peptides (Mr 68,000 and Mr 43,000). Surface-bound iC3b is cleaved at a third site by factor I to produce C3c and C3d,g (or alpha 2D). The factor I cofactor for this cleavage is the C3b receptor that is present on erythrocyte and leukocyte membranes. This report describes the isolation and initial structural characterization of C3c and C3d,g generated in whole blood after complement activation with cobra venom factor. These fragments were compared with the C3 fragments isolated from the serum and plasma of a patient with complement activation in vivo. The fragments were isolated with two solid phase monoclonal antibodies, one of which recognizes a determinant on C3g (clone 9) and one of which recognizes a determinant on C3c (clone 4). C3c isolated from normal blood showed three polypeptides that had apparent m.w. of 75,000, 43,000, and 27,000. The C3d,g consisted of a single polypeptide chain with a m.w. of 40,000. Amino terminal sequence analysis showed that the Mr 27,000 peptide from C3c is derived from the amino terminal portion of the alpha'-chain of C3b, whereas the Mr 43,000 peptide is derived from the carboxy terminus of the same chain. Amino terminal sequence analysis showed also that C3g is derived from the amino terminus of C3d,g. The C3 fragments isolated from a patient with partial lipodystrophy, nephritic factor activity, low serum C3 levels, and circulating C3 cleavage products showed a more complicated pattern on SDS-PAGE. The fragment isolated with clone 9 had an apparent m.w. of 40,000, identical to C3d,g generated in vitro, and it had the same amino terminal sequence as C3d,g generated in vitro. The eluate from insolubilized clone 4, however, showed prominent bands with Mr of 75,000, 56,000, 43,000, and 27,000, together with a triple-banded pattern at 68,000 and a minor band at 80,000. This eluate thus appears to contain C3c, and iC3b or an iC3b-like product. The origin of the Mr 56,000 and Mr 80,000 peptides have not yet been determined. These studies, with previous data, definitively order the C3c and C3d,g peptides in the alpha-chain of C3.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1997

Cleavage of the complement system C3 component by HIV-1 proteinase.

The C3 factor of the complement system and its C3b fragment are cleaved in vitro by the proteinase of the human immunodeficiency virus, type 1 (HIV PR). The cleavage occurs in the alpha-chain of both substrates at multiple sites yielding a 100 kDa fragment of the C3 alpha-chain and multiple fragments of the C3b alpha-chain. The scissile bonds are: Ala86-Glu87, Leu310-Leu311, His641-Trp642 and Arg649-Ser650. The resulting fragments resemble the physiologically occurring inactive fragments of C3: C3c and C3d, suggesting a possible biological role of the HIV-proteinase in the complement inactivation process.

Amino Acids↗
PubMed1991

Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process.

Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer's disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer's disease. Cerebral amyloid plaques in scrapie-affected mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive inflammatory process by beta/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer's disease.

Aged↗
PubMed1986

Molecular modelling of human complement component C3 and its fragments by solution scattering.

Solution scattering experiments using both X-rays and neutrons are reported for human complement component C3 and up to six other glycoprotein fragments that are derived from C3. The X-ray and neutron molecular masses and neutron matchpoints are in agreement with the known primary sequence of C3. The X-ray radius of gyration RG of C3 is 5.2 nm and is similar for the related forms C3u, C3(a + b) and C3b. The X-ray cross-sectional radius of gyration RXS of C3b is however less than that of C3, C3u and C3(a + b). The major fragments of C3b, namely C3c and C3dg, were studied. The RG of C3c is 4.7 nm and for C3dg is 2.9 nm. C3c and C3dg do not interact when they coexist in solution in equimolar amounts. When C3u is cleaved into iC3u, the RG of iC3u increases to 5.9 nm and its RXS decreases, showing that C3c and C3dg behave as independent entities within the parent glycoprotein. Analyses of the neutron RG and RXS values by contrast variation techniques confirm the X-ray analyses, and show no evidence for significant hydrophobic or hydrophilic domains within C3 or any of its fragments. Shape analyses show that C3, C3c and C3dg are elongated particles. Debye models were developed using the scattering curve out to Q = 1.6 nm-1. These show that C3 and C3c resemble oblate ellipsoids while C3dg resembles a prolate ellipsoid. C3dg lies on the long edge of C3c within C3. The dimensions of the models are 18 nm X 2 nm X 10 nm for C3, 18 nm X 2 nm X 7 nm for C3c and 10 nm X 2 nm X 3 nm for C3dg. These models are compatible with analyses of the scattering curve RG and RXS values, data from sedimentation coefficients, and images of C3 and C3c seen by electron microscopy.

Complement C3↗
PubMed1984

The third complement factor (C3) and its in vivo cleavage products: interaction with lectins and precipitation with polyethylene glycol.

Five molecular forms of C3 expressing D but not C epitopes were identified following in vivo activation of the complement system. Examination of concanavalin A (Con-A) reactivity in crossed immunoelectrophoresis revealed that native C3, C3c and the beta mobile form 4 of C3d were completely precipitated by 100 micrograms Con A/cm2. The alpha-1 mobile form 1 of C3d did not interact with Con A, whereas the alpha-2 mobile forms 2 and 3 were retarded in electrophoretic migration by Con A. Native C3, C3c, and forms 4 and 5 of C3d were precipitated by 12% (w/v) polyethylene glycol (PEG). Form 1 of C3d was soluble in these PEG concentrations, whereas forms 2 and 3 were partially precipitated.

Antigen-Antibody Reactions↗
PubMedDate not supplied

Report of studies on monoclonal antibodies (MABS) to complement components.

Twenty-five monoclonal antibodies (MABS) to complement components were evaluated according to the ISBT/ICSH protocol by twelve laboratories. Seven detected some form of C3c, but one of them, 174, did not react with EiC3b, although it was positive with 'EC3b' (Fruitstone). 174 may detect some form of enzyme sensitive C3b antigen, but C3a was not evaluated (present on 'EC3b' Fruitstone). Twelve of the antibodies were anti-C3d, one was an anti-C3g and five were anti-C4c.

Antibodies, Monoclonal↗
PubMed1991

Atypical structured glomerular deposits: an immunohistochemical study.

Atypical structured glomerular deposits were identified in sub-epithelial, sub-endothelial and mesangial areas in biopsy tissue from a female, aged 33, who presented with anaemia and was found to have proteinuria and microscopic haematuria. Histological examination showed that the deposits were periodic acid Schiff positive and silver negative whilst stains for amyloid were negative. Immunofluorescent staining for all immunoglobulins was negative, and only C3 showed moderate labelling. Conventional electron microscopy revealed that all deposits contained microtubular structures of variable length but with an average diameter of 25 nm and a periodicity of approximately 16 nm. The glomerular basement membrane was interrupted in many areas by deposits, and also contained 'myelin-like' structures. Free microtubular structures were also seen in the urinary space. Immunoelectron microscopy using protein-A-gold confirmed the immunofluorescent findings with immunoglobulins and fibrinogen, showed marked positive labelling of deposits with C1s and C3d and also intense labelling of coiled microtubular structures with C9. Other complement components C1q, C1r, C3c, C4 and C5 showed weak or negative results. Although these organised glomerular deposits contain complement components, their pathogenesis remains uncertain.

Adult↗
PubMed1984

An enzyme-linked immunosorbent assay for the detection of complement components on red blood cells.

A new technic using the principle of enzyme-linked immunoassay (ELISA) has been developed for the detection of complement components on red blood cells sensitized in vivo or in vitro. Using a double-antibody technic, anticomplement antisera (anti-C3c or anti-C3c/C3d) produced in rabbits was incubated with the red blood cells, followed by incubation with antirabbit alkaline phosphatase conjugated antiglobulin. The amount of the enzyme fixed was measured spectrophotometrically by the enzymatic hydrolysis of the substrate PNPP. A calibration curve was made from red blood cells on which complement was deposited by the method of Fruitstone . The technic showed a greater sensitivity than the standard antiglobulin tests and allowed simultaneous qualitative and semiquantitative estimates. The technic can be performed in any laboratory equipped with the standard equipment found in a blood bank, including a spectrophotometer. The authors made a modification of Alsever 's solution, which allowed the safe and stable preservation of complement coated red blood cells for 15 days. Significant positive results were obtained clinically using this technic, while negative or weakly positive reactions were obtained by the conventional antiglobulin tests.

Animals↗
PubMed1984

Activated complement in inflamed aqueous humor.

Activated complement is an important mediator of inflammation. Radioimmunoassay was used to measure levels of C3a, an activated fragment of C3, in aqueous humor. Additionally, immunoelectrophoresis was performed on aqueous humor to detect Factor B and its conversion product, Bb, as well as C3c, a breakdown product of C3. All six samples of normal aqueous humor had no detectable C3a, C3c, or Factor B. All eight samples of aqueous humor from patients with anterior uveitis had measurable levels of C3a. Factor B and C3c were detected in 3/7 samples of inflamed aqueous humor. Factor B was converted fully to Bb in two of these three samples, suggesting alternative pathway activation of complement. Activated complement fragments are present in the aqueous humor of eyes with anterior uveitis and may help mediate the inflammatory process.

Adult↗
PubMed1988

Secretor state and complement levels (C3 and C4) in insulin dependent diabetes mellitus.

Lower levels of C3 and C4 components of the complement system have been reported for patients with insulin dependent diabetes mellitus (IDDM) but not among those with non-insulin dependent diabetes (NIDDM). We have found a significantly higher proportion of patients who are non-secretors of the ABO blood group antigens among patients with IDDM but not among those with NIDDM. As the gene that controls secretion of these antigens is in the same linkage group as that for the C3 complement component, we compared the levels of C3 and C4 of patients with IDDM by secretor state. The mean level of C3c for 45 non-secretors (75.2 IU/ml) was significantly lower than that found for 59 secretors (86.4 IU/ml) (p less than 0.025). The level of C4 among non-secretors (77.1 IU/ml) was also significantly lower than that of secretors (96.3 IU/ml) (p less than 0.025). The significance of these observations is discussed.

ABO Blood-Group System↗
PubMed1986

Detection of disulphide bonds and localization of interchain linkages in the third (C3) and the fourth (C4) components of human complement.

Disulphide bonds contribute significantly to the maintenance of structural/functional integrity of many proteins. Therefore it was of interest to study the distribution and the effect of disulphides on conformation of complement components C3 and C4. These proteins are precursors of several fragments with various binding sites and distinct physiological functions. The constituents of C3c (beta, alpha 27, alpha 43) and those of C4c (beta, alpha 27, alpha 16, gamma) were investigated, since other fragments of C3 or C4 do not participate in interchain linkages. Inter-and intra-chain disulphide bonds in C3c and C4c were localized by using a modification of conventional SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis such that the change in mobility of disulphide-bond-containing proteins can be detected throughout the transition from a non-reduced to a fully reduced state. Several forms of the alpha 43 fragment from C3, and of the gamma-chain of C4, with different mobilities can exist, depending on the number of intra-chain disulphide bonds reduced. The intermediates (heterodimers) generated by a partial reduction of C3c or C4c were characterized by two-dimensional SDS/polyacrylamide-gel electrophoresis performed in the absence, then in the presence, of beta-mercaptoethanol. The inter-chain linkages in C3c were determined to be beta-alpha 27 and alpha 27- alpha 43, thus indicating the presence of only one interchain bond in C3. The two interchain bonds in C4c are beta-alpha 27 and alpha 16-gamma. The third interchain bond in C4 (alpha 27-gamma, tentative) remains to be determined.

Complement C3↗
PubMed1991

Complement activation in cancer patients undergoing immunotherapy with interleukin-2 (IL-2): binding of complement and C-reactive protein by IL-2-activated lymphocytes.

Plasma samples from cancer patients undergoing immunotherapy with high-dose recombinant interleukin-2 (IL-2) were obtained over a 5-day course of treatment and assayed by radioimmunoassay or enzyme-linked immunosorbent assay for the complement degradation products, C3a, iC3b, Ba, Bb, C4d, and SC5b-9. In the majority of patients, pretreatment C3a, Ba, Bb, and SC5b-9 plasma levels were comparable with those measured in normal donor plasma. However, by the end of the 5-day treatment course, C3a levels had increased 15.6-fold. In several patients, peak concentrations of C3a were as high as those reported in patients with sepsis or burn injury. Plasma levels of alternative pathway components Ba and Bb also increased, 8.0- and 5.0-fold, respectively, during IL-2 treatment. Likewise, levels of one of the terminal complexes, SC5b-9, increased 5.0-fold and the plasma C4d and iC3b concentrations increased 4.8- and 2.9-fold, respectively, by the fifth day of treatment. To determine whether activated lymphocytes participate in IL-2-induced complement activation, peripheral blood mononuclear cells (PBMC) obtained from IL-2 recipients before and 5 days after beginning therapy were reacted with monoclonal antibodies (MoAbs) against C3c and the terminal complement complex SC5b-9. Dual-color cytofluorographic analysis showed that within the CD3(+) population, the percentage of cells binding the anti-C3c and anti-SC5b-9 MoAbs increased 6.2-fold and 5.1-fold, respectively, by day 5. The anti-C3c MoAb also bound to CD3(+) cells stimulated in vitro with IL-2 and then exposed to serum. Moreover, fluid-phase iC3b was generated from purified C3 by PBMC activated in vitro with IL-2, but not by unstimulated cells. Serum levels of C-reactive protein (CRP) are markedly elevated in patients undergoing IL-2 immunotherapy. This hepatic acute phase reactant has been shown to activate the classical pathway when bound to cell surfaces. Because levels of the classical component C4d increase markedly during IL-2 treatment, we sought to determine if CRP became bound to PBMC during IL-2 treatment and found that during therapy, the percentage of CD3(+) cells reactive with an anti-CRP MoAb increased from less than 2% to greater than 18%. When PBMC were activated with IL-2 in vitro and then exposed to exogenous CRP, greater than 20% of the CD3(+) cells reacted with the anti-CRP MoAb.(ABSTRACT TRUNCATED AT 400 WORDS)

C-Reactive Protein↗
PubMed1983

Catabolites of the third component of complement in urines of hereditary nephritis patients.

Hereditary nephritis protein (HNP), an unusual urine protein from patients with hereditary nephritis (Alport Syndrome), was purified 120-fold to homogeneity. A slightly larger protein, pro-HNP, was similarly purified and was found to be a precursor of HNP. Both pro-HNP and HNP showed immunological identity to the third component of human complement, C3, and to its catabolite C3c. Pro-HNP had a molecular weight of 143,000 and, in equimolar ratio, polypeptide chains or fragments of molecular weights 75,000, 40,000, and 28,000. The largest and smallest chains contained carbohydrate. HNP had a molecular weight of 141,000 and fragments of molecular weights 60,000, 38,000, 26,000, and 17,000 in equimolar ratio; the two smallest fragments contained carbohydrate. Plasmin digestion of pro-HNP showed that the 75,000-Da chain, identical with the intact beta-chain of C3, broke down to the 60,000- and 17,000-Da fragments of HNP. In both pro-HNP and HNP, the polypeptide chains were linked by disulfide bonds, with the exception of the 17,000-Da fragment of HNP. This fragment was readily dissociated from the rest of the HNP molecule in the presence of sodium dodecyl sulfate. Amino acid analyses showed that both pro-HNP and HNP contained approximately 22 half-cystine residues per molecule. Extinction coefficients, epsilon 1% 1cm, at 280 nm were calculated to be 8.5 and 8.8 for pro-HNP and HNP, respectively.

Amino Acids↗