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PubMedDate not supplied

[Nephelometry as optic immunochemical method in the laboratory practice].

The authors offer a modification of the nephelometric method for clinical immunology laboratory to be used for measuring proteins (albumin, C3-complement, IgG, IgA, IgM, and alpha 2-macroglobulin) in human biological fluids. The original method making use of only Russian-made reagents and equipment has been used on a full scale for measuring the proteins in the blood serum, cerebrospinal fluid, urine, and saliva of normal subjects. The sensitivity and specificity of the method depend predominantly on the physicochemical parameters of the study.

Albumins↗

PubMed1977

Reversible crescentic glomerulonephritis following an acute exacerbation of chronic relapsing pancreatitis.

A patient had recurrent episodes of acute glomerulonephritis following exacerbations of chronic relapsing pancreatitis. Light microscopy of the renal biopsy performed during the episode of acute glomerulonephritis showed fibroepithelial crescents involving 70% of the glomeruli. The patient recovered without specific therapy. The time interval involved and the presence of subendothelial deposits with mesangial deposition of C3 complement and IgM suggest immune complex injury.

Acute Disease↗

PubMedDate not supplied

[Electron microscopic and immunomorphologic study of the placenta in genital mycoplasmosis].

Peculiar ultrastructural features allowed the authors to reveal M. Homminis corpuscles in placental tissues of women with genital mycoplasmosis. Mycoplasma was found in the amniotic epithelium, chorionic plate, in the lumen of villous capillaries, this showing possible hematogenic way of the infection from mother to fetus. In the placenta of women with genital mycoplasmosis immunopathological processes develop in association with formation of pathogenic immune complexes (PIC) that are fixing the C3 complement fraction. Location of PIC on the syncytiotrophoblast membranes and vascular endothelium causes immunological inflammation with the involvement of immunocompetent cells resulting in the destruction of syncytial membranes and membranes of the placental barrier. Damage to the placental barrier membranes promotes the development of placental failure, a complicated course of pregnancy and delivery, deterioration of the state of the fetus and newborn infant.

Adult↗

PubMed1976

Studies of human pregnancy. I. Immunoglobulins attached to the trophoblast.

The human placenta was studied for the binding of immunoglobulins IgG, IgM, IgE, and C3 complement to the cell membrane of the trophoblast by use of fluorescein-conjugated and unlabelled antihuman immunoglobulins. Gestations of 8 to 40 weeks were evaluated for placental tissues taken from women undergoing therapeutic abortion, elective induction of labor, cesarean section, spontaneous labor, and toxemia of pregnancy. IgA was increased on the syncytial cytotrophoblast membranes at 8 to 10 weeks' gestation; IgE was present on the surface of the trophoblast only during spontaneous labor; and IgG was observed on the syncytial cytotrophoblastic cell membrane and basement membrane, and in the cytoplasm and the nucleus in all stages of gestation.

Cell Membrane↗

PubMed1998

[Early rheumatoid synovitis and its evolution].

The clinical and morphological evidence of rheumatoid synovitis of 3 months to 5 years duration was analyzed. Its early lesions were characterized by angiomatosis, vasculopathy, and proliferation of synoviocytes and fibroblasts. Protein infiltrates contained IgG and C3 complement. Herpes simplex was detected in the vessels and synoviocytes. Structural changes may be explained by immune mechanisms and by infectious agents as well. Chronic inflammation, vasculitis, and sclerosis were prevalent in late rheumatoid synovitis. Lymphoid follicles, macrophages, and endothelial proliferation can be markers for infectious persistence.

Adult↗

PubMed2000

Molecular cloning and protein analysis of divergent forms of the complement component C3 from a bony fish, the common carp (Cyprinus carpio): presence of variants lacking the catalytic histidine.

Unlike mammals, some bony fish species have been reported to possess multiple forms of the complement component C3. To explore the structural and functional diversity of bony fish C3, we have isolated eight distinct cDNA clones encoding C3 from a single carp (Cyprinus carpio). The eight sequences were grouped into five C3 types, designated C3-H1, C3-H2, C3-S, C3-Q1 and C3-Q2, each sharing 80-86 % amino acid sequence identity with the others. A striking amino acid substitution was noted at the position corresponding to the catalytic histidine, which is conserved in C3 from all the animals analyzed to date and provides the thioester with the ability to bind covalently to hydroxy groups on the target cells or to be hydrolyzed quickly; C3-S, C3-Q1 and C3-Q2 have serine, glutamine and glutamine residues, respectively, in place of the histidine which is conserved in C3-H1 and C3-H2. On the other hand, five distinct C3 forms, named C3-1 to C3-5, were purified from the serum of a single carp. N-terminal sequencing and covalent binding to [3H]glycine identified C3-1 as the translated product of C3-S, while C3-2 was that of C3-H1, and C3-5 that of C3-H2. C3-1 showed a hemolytic activity threefold higher than that of C3-2, whereas C3-5 was inactive, suggesting that the thioester catalytic mechanism is not a necessary determinant for C3 activity and that C3 lacking the catalytic histidine plays a significant role in the complement system of carp and probably other bony fish.

Amino Acid Sequence↗

PubMed1987

Cooperative action of complement component C3 and phagocytic effector cells in innate murine resistance to Trypanosoma lewisi.

Mice display strong natural resistance to the rat-specific Trypanosoma lewisi. Intravenously injected intact T. lewisi parasites were eliminated by mice within 18 to 24 h. In comparison, "nude" T. lewisi organisms lacking the surface coat were rapidly and totally cleared from the bloodstream within 2 h postinoculation. Similarly, in vitro-cultivated trypanosomes were readily eliminated by mice with the conspicuous absence of a lag phase. Elimination of nude T. lewisi, like that of intact trypanosomes, required murine complement component C3. Splenectomy of mice did not affect their ability to eliminate T. lewisi. However, C3 depletion with cobra venom factor rendered splenectomized mice susceptible to this rat trypanosome; in these mice, T. lewisi established prolonged and frequently fatal infections. Beige mice were able to efficiently eliminate T. lewisi. But combined treatments of beige (bg/bg) and heterozygous (bg/+) mice with cobra venom factor and silica dust, or normal rat serum and silica dust, incapacitated the natural resistance of these mice to T. lewisi. Such combined treatments of beige and control mice resulted in fulminating parasitemias and death of the animals. Altogether, the results of the present studies indicate that T. lewisi elimination by mice requires the following: exposure of C3 acceptors on the surface of the parasites; activation of murine C3, probably via the alternative complement pathway; and destruction of the C3b-coated parasites by their interaction with C3b receptor-bearing, phagocytic effector cells that are abundant in the spleen and sensitive to silica dust.

Animals↗

PubMed2005

Structures of complement component C3 provide insights into the function and evolution of immunity.

The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the alpha2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the alpha-chain, including movement of a critical interaction site through a ring formed by the domains of the beta-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.

Complement Activation↗

PubMed2003

An amperometric immunosensor based on an electrochemically pretreated carbon-paraffin electrode for complement III (C3) assay.

An electrochemical immunosensor based on the adsorption of anti-complement III antibody onto an electrochemical pretreated carbon-paraffin electrode has been proposed for the detection of complement III (C(3)). The competitive immunoassay format was adopted with horseradish peroxide-C(3) (HRP-C(3)) as a tracer, 3,3'5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide as the enzyme substrates. In order to measure the amount of HRP-C(3) binding onto the electrode surface, the product of the enzyme catalytic reaction was detected at 100 mV (vs. Ag/AgCl reference electrode). The system was optimized to realize a reliable determination of C(3) in the range of 0.06-10 microg/ml. It exhibits some advantages, such as simplicity of fabrication, rapidity of measurement, and satisfactory sensitivity and reproducibility.

Antibodies↗

PubMed1995

Differentiation-induced production of ASP in human adipocytes.

Acylation Stimulating Protein (ASP) is a human plasma protein that stimulates both triacylglycerol synthesis and glucose transport. ASP is identical to C3adesArg and is generated by the interaction of factor B, complement C3 and adipsin. We have demonstrated that mature fat cells express messages for factors B, complement C3 and adipsin; that human pre-adipocytes, when cultured under differentiating conditions to produce adipocytes, generate ASP in the culture medium; and that human adipocytes also become more responsive to ASP as they differentiate. The aim of this study, therefore, was to examine the temporal production of ASP during adipocyte differentiation in relation to other adipose specific factors involved in lipogenesis. The results demonstrate that (i) there was little ASP production by differentiating adipocytes over the first 7 days, with a marked increase in ASP thereafter (up to sixfold); (ii) this increase was paralleled by large increases in the message level of factor B and complement C3 and moderate increases in adipsin message; (iii) increases in lipoprotein lipase (LPL) message and glycerol-3-phosphate dehydrogenase (GPDH) activity (both key enzymes for substrate supply for triacylglycerol synthesis) occurred earlier than the increase in ASP; and (iv) in spite of the increase in LPL and GPDH, triacylglycerol synthetic capacity only markedly increases following the increase in ASP production in adipocytes. Although the present study cannot be interpreted as showing causality with respect to triacylglycerol synthesis, it does point to an important role for ASP in human adipose tissue physiology.

Adipocytes↗

PubMed1999

Metabolism of activated complement component C3 is mediated by the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor.

Complement component 3 (C3) and alpha(2)-macroglobulin evolved from a common, evolutionarily old, ancestor gene. Low density lipoprotein-receptor-related protein/alpha(2)-macroglobulin receptor (LRP/alpha(2)MR), a member of the low density lipoprotein receptor family, is responsible for the clearance of alpha(2)-macroglobulin-protease complexes. In this study, we examined whether C3 has conserved affinity for LRP/alpha(2)MR. Ligand blot experiments with human (125)I-C3 on endosomal proteins show binding to a 600-kDa protein, indistinguishable from LRP/alpha(2)MR by the following criteria: it is competed by receptor-associated protein (the 39-kDa receptor-associated protein that impairs binding of all ligands to LRP/alpha(2)MR) and by lactoferrin and Pseudomonas exotoxin, other well known ligands of the multifunctional receptor. Binding of C3 is sensitive to reduction of the receptor and is Ca(2+)-dependent. All these features are typical for cysteine-rich binding repeats of the low density lipoprotein receptor family. In LRP/alpha(2)MR, they are found in four cassettes (2, 8, 10, and 11 repeats). Ligand blotting to chicken LR8 demonstrates that a single 8-fold repeat is sufficient for binding. Confocal microscopy visualizes initial surface labeling of human fibroblasts incubated with fluorescent labeled C3, which changes after 5 min to an intracellular vesicular staining pattern that is abolished in the presence of receptor-associated protein. Cell uptake is abolished in mouse fibroblasts deficient in LRP/alpha(2)MR. Native plasma C3 is not internalized. We demonstrate that the capacity to internalize C3 is saturable and exhibits a K(D) value of 17 nM. After intravenous injection, rat hepatocytes accumulate C3 in sedimentable vesicles with a density typical for endosomes. In conclusion, our ligand blot and uptake studies demonstrate the competence of the LRP/alpha(2)MR to bind and endocytose C3 and provide evidence for an LRP/alpha(2)MR-mediated system participating in C3 metabolism.

Animals↗

PubMed1975

Clearances of complement components, C3 proactivator and other serum proteins in chronic membranoproliferative glomerulonephritis (CMPGN).

In chronic membranoproliferative glomerulonephritis (CMPGN) the activation of the complement system through the properdin pathway plays an important role. The clearance of complement components and of the C3-proactivator (C3-PA) have been determined in 18 patients. Hemolytically active C5, C6, C7 and C3-PA were detected in the urine for the first time. The clearances of the complement components did not correlate with the clearances of other serum proteins with similar molecular weights. The specificities of the single complement components in the urine were tested by specific complement inhibitors such as hydrazine, KSCN, and the C4-inactivating factor.

Adolescent↗

PubMed2005

Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus.

AIMS: To determine the influence of metformin treatment on plasma C-reactive protein (CRP) and complement factor C3. METHODS: A double-blind, placebo-controlled trial of metformin in patients with poorly controlled Type 2 diabetes mellitus and body mass index > 25 kg/m2. CRP and C3 were analysed in stored plasma samples by in-house ELISAs. Patients attended two baseline visits before randomization and subsequently attended at 3, 6, 12 and 24 weeks post randomization. All patients gave informed consent according to a protocol approved by the Leeds Teaching Hospitals Research Ethics Committee. RESULTS: Baseline CRP in the patients randomized to placebo [1.33 (0.79, 2.25) mg/l] and metformin [1.24 (0.89, 1.71) mg/l] were similar (P = 0.8). Baseline CRP correlated with baseline C3 (r = 0.366) and HbA1c (r = 0.327). The difference in ratios of CRP levels at each visit to baseline between placebo- (n = 16) and metformin-treated (n = 26) subjects was significantly different at the 12-week (P = 0.002) and 24-week (P = 0.03) visits. The difference in CRP ratios between the two treatment groups remained significant after accounting for glycaemic control at both visits (P = 0.001 and P = 0.003, respectively). Baseline C3 was correlated with CRP. Baseline C3 was lower in the placebo-treated group [0.97 (0.88, 1.05) mg/ml] compared with the metformin-treated group [1.09 (1.02, 1.17) mg/ml, P = 0.03]. There was no difference in the mean change in C3 at any visit from baseline between placebo- and metformin-treated groups. CONCLUSION: Metformin may have a specific interaction with mechanisms involved in CRP synthesis or secretion, not directly related to improved insulin sensitivity and dampening of chronic inflammation.

C-Reactive Protein↗

PubMed2001

Mycobacterial protein HbhA binds human complement component C3.

Mycobacterium tuberculosis and Mycobacterium avium are facultative intracellular pathogens that are able to survive and replicate in mononuclear phagocytes. Human complement component C3 has previously been shown to mediate attachment and phagocytosis of these bacteria by mononuclear phagocytes. In this study, a C3 ligand affinity blot protocol was used to identify a 30-kDa C3-binding protein in M. tuberculosis and Mycobacterium smegmatis and a 31-kDa C3-binding protein in M. avium. The C3-binding proteins in M. tuberculosis and M. avium localized to the cell membrane fraction and partitioned to the detergent fraction during Triton X-114 phase partitioning. The C3-binding protein from M. tuberculosis was partially purified using a cation exchange column and was shown to bind concanavalin A. The N terminus and an internal fragment of the partially purified C3-binding protein were subjected to amino acid sequence analysis. The resulting amino acid sequences matched the M. tuberculosis heparin-binding hemagglutinin (HbhA) protein. Recombinant full-length HbhA and the C terminus of HbhA fused to maltose-binding protein, but not recombinant HbhA lacking the C-terminal region, bound human C3. Recombinant full-length HbhA coated on polystyrene beads, was found to enhance the adherence and/or phagocytosis of the coated beads to J774.A1 cells in both the presence and absence of human serum. The presence of complement-sufficient serum increased the adherence of the HbhA-coated beads to the J774.A1 cells in a C3-dependent manner. If HbhA within the bacterial cell membrane functions similarly to isolated HbhA, this protein may enhance the adherence and phagocytosis of M. tuberculosis and M. avium to mononuclear phagocytes through the binding of C3 and interaction with C3 receptors on mononuclear phagocytes.

Amino Acid Sequence↗

PubMed2004

Complement protein C3 binding to Mycobacterium tuberculosis is initiated by the classical pathway in human bronchoalveolar lavage fluid.

In high concentrations of fresh nonimmune human serum, Mycobacterium tuberculosis activates the alternative pathway of complement and binds C3 protein, resulting in enhanced phagocytosis by complement receptors on human alveolar macrophages. Yet in the lung, the alternative pathway of complement is relatively inactive compared to the classical pathway. To begin to determine whether C3 opsonophagocytosis of M. tuberculosis by alveolar macrophages can occur in the lung of the immunologically naive host, we characterized the binding of C3 to M. tuberculosis in different concentrations of fresh nonimmune human serum and concentrated human bronchoalveolar lavage fluid. Here we show that in human serum, C3 binding to M. tuberculosis is rapid, initiated by either the alternative pathway or the classical pathway, depending on the concentration of serum, and occurs by covalent linkages between the bacterial surface and the C3 cleavage products, C3b or C3bi. Human bronchoalveolar lavage fluid contains C3 protein and functional classical pathway activity that mediates the binding of C3 to the surface of M. tuberculosis. These studies provide evidence that when M. tuberculosis is first inhaled into the lungs of the human host, the bacterium is opsonized by C3 cleavage via classical pathway activation within the alveolus, providing a C3-dependent entry pathway into resident alveolar macrophages.

Bronchoalveolar Lavage Fluid↗

PubMed1985

Common evolutionary origin of alpha 2-macroglobulin and complement components C3 and C4.

A comparison of the sequence of the subunit of human alpha 2-macroglobulin (alpha 2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639 amino acid residues) reveals eight extended regions of sequence similarity. These regions contain between 19% and 31% identically placed residues and account for 75% and 67%, respectively, of the polypeptide chains of alpha 2M and pro-C3. Published sequence data for complement component C4 show that segments of this protein match well with corresponding stretches in alpha 2M and pro-C3. It is proposed that alpha 2M, C3 and C4, which all contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary origin and are homologous proteins. Several larger regions of low sequence similarity indicate the presence of structural domains in each of these proteins that specifically modify an underlying common gross structure. The quartets of basic residues in pro-C3 and pro-C4, at which cleavage takes place to produce the mature subunits of these proteins, and most of the residues forming the anaphylatoxin peptides of C3 and C4 (C3a and C4a) are absent in alpha 2M. In addition, C3 and C4 contain large portions, which extend beyond the COOH terminus of alpha 2M.

Amino Acid Sequence↗

PubMed2004

Reference distributions for complement proteins C3 and C4: a practical, simple and clinically relevant approach in a large cohort.

The two serum proteins of the complement cascade in the highest concentrations, C3 and C4, respond to various conditions in much the same manner as do other positive acute-phase proteins. A major difference is that they are relatively sluggish in response to cytokine drive, requiring several days rather than hours to be detectably elevated by serial measurements. As with other acute-phase proteins, there are many processes that up- or down-regulate synthesis, including infection or inflammation, hepatic failure, and immune-complex formation. Clinicians may find it difficult to distinguish among these processes, because they often occur simultaneously. The situation is further complicated by genetic polymorphism, with rare instances of markedly reduced synthesis and circulating levels, and consequent vulnerability to infection. C3 and C4 are measured for clinical purposes to help define certain rheumatic and immunologically mediated renal diseases. Interpreting the measured blood levels of these two components requires one to consider the intensity of the inflammatory drive, the timing of the suspected clinical process, the production of complement-consuming immune complexes, and the possible existence of benign circumstances. In this fifth article in a series, reference ranges for serum levels of two complement proteins (C3 and C4) are examined. The study is based on a cohort of over 55,000 Caucasian individuals from northern New England, who were tested in our laboratory in 1994-1999. Measurements were standardized against certified reference material (CRM) 470/reference preparation for proteins in human serum (RPPHS), and analyzed using a previously described statistical approach. Individuals with unequivocal laboratory evidence of inflammation (C-reactive protein of 10 mg/L or higher) were excluded. Our results show that the levels of C3 and C4 change little during life and between the sexes, except that they increase slightly and then fall after age 20 in males and at about age 45 in females. When values were expressed as multiples of the age- and gender-specific median levels, the resulting distributions fitted a log-Gaussian distribution well over a broad range. When patient data are normalized in this manner, the distribution parameters can be used to assign a centile corresponding to an individual's measurement, thus simplifying interpretation.

Acute-Phase Proteins↗

PubMed2004

Direct immunofluorescence on uninvolved, lesional and perilesional skin in patients with endemic pemphigus foliaceus (fogo selvagem).

BACKGROUND: Research on direct immunofluorescence in pemphigus foliaceus ("fogo selvagem") has been focused mainly on the study of perilesional and lesional skin, while little attention has been given to uninvolved skin. We analyzed the frequency of IgA, IgM, IgG and its subclasses (IgG1, IgG2, IgG3 and IgG4) and C3 complement fraction deposition in intercellular spaces (ICS) and basal membrane zone (BMZ) in uninvolved, lesional and perilesional skin from 47 fogo selvagem patients. MATERIAL/METHODS: For each patient biopsies were collected from lesional, perilesional and uninvolved skin, and then analyzed by direct immunofluorescence. The panel of antibodies consisted of IgA, IgM, IgG and its subclasses (IgG1, IgG2, IgG3 and IgG4) and C3 complement fraction. RESULTS: The results showed a predominance of IgG and IgG4 deposit in all skin samples, followed by C3 complement fraction and IgG1 deposits. The positive response for IgG on uninvolved (91.48%), lesional (93.61%) and perilesional (97.87%) skin was similar to that found for IgG4 in the same samples: 95.74%, 95.74% and 97.87%, respectively. Regarding IgG1, the uninvolved skin showed lower results (14.89%) than the lesional (29.78%) and perilesional skin (29.78%). Concerning C3 complement fraction, the perilesional skin showed higher results (40.42%) than the uninvolved and lesional skin (34.04% for both). CONCLUSIONS: The results suggest the importance of uninvolved skin for direct immunofluorescence in the diagnostics of pemphigus foliaceus. Our results suggest that any cutaneous region can demonstrate pemphigus antibodies by direct immunofluorescence.

Complement C3↗