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PubMedDate not supplied

Circulating immune complexes, immunoglobulin classes (IgG, IgA and IgM) and complement components (C3c, C4 and Factor B) in diabetic Nigerians.

OBJECTIVE: To evaluate serum levels of circulating immune complexes (CICs), immunoglobulin classes (IgG, IgA and IgM) and Complement Components (C3c, C4 and Factor B) in Nigerians with Type 1 or Type 2 diabetes mellitus. DESIGN: Case control study. SETTING: University College Hospital, Ibadan, Oyo State, Nigeria. SUBJECTS: Forty-two subjects with diabetic mellitus (17 Type 1 D. M. and 25 Type 2 D. M.) and 21 apparently healthy control subjects. INTERVENTION: Serum level of CICs was measured by polyethylene glycol precipitation method while single radial immunodiffusion method was used to measure serum levels of immunoglobulins and complement components. RESULTS: Only CICs were significantly higher in Type 1 diabetic subjects compared with the controls whereas CICs C3c, C4 and IgM were significantly increased in Type 2 diabetic subjects compared with the controls. The levels of CICs, C3c and IgM were significantly elevated in Type 2 diabetics compared with Type 1 diabetics. CONCLUSION: CIC concentrations may serve as a useful index of depressed host defences usually associated with diabetics mellitus and that humoral immunity is deranged more in Type 2 diabetics compared with Type 1 diabetics. Probably as a result of hyperinsulinaemia associated with insulin resistance.

Adult↗
PubMed1974

Mechanisms of immune lysis of the red cells in hereditary erythroblastic multinuclearity with a positive acidified serum test and paroxysmal nocturnal hemoglobinuria.

The red cells of patients with hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), a form of congenital dyserythropoietic anemia, and the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are lysed more readily than normal cells by certain antibodies, notably cold agglutinins (anti-I) and complement. With some but not other examples of anti-I, HEMPAS and PNH cells adsorbed more antibody than normal cells. Equal quantities of adsorbed antibody bound equal quantities of the first component of complement (C1) to normal, PNH, and HEMPAS cells. However, for a given quantity of bound antibody and C1, much more of the fourth component of complement (C4) was bound to HEMPAS cells than to normal cells. This resulted in the binding of proportionately larger quantities of the third component of complement (C3) to these cells. The same amount of bound C3 was found on the membranes of normal and HEMPAS cells for a given degree of lysis. Hence, the marked increase in lysis of HEMPAS cells is due to the increased adsorption of antibody and/or increased binding of C4.PNH cells bound the same amount of C4 per bound C1 as normal cells but bound more C3 than normal cells. However, the mean concentration of C3 on the membrane of PNH cells was one-third to one-fifth that on normal cells for a given degree of lysis. Hence, the increased lysis of PNH cells is due to the increased binding of C3 and increased hemolytic effectiveness of the bound C3.

Adsorption↗
PubMed1994

[Effect of hemodialysis using cuprophan and polysulfone dialyzers on rosette tests, concentration of immunoglobulins and complement components in serum of patients with chronic renal failure].

In 15 patients with chronic renal failure, the effect was studied of haemodialysis using cuprophan and polysulfone dialyzers on rosette tests, and the concentrations of immunoglobulins and C3c and C4 complement components in peripheral blood. It was found that the per cent of E and EAC rosettes decreases within 30 minutes of the procedure, IgG, IgA and IgM levels increase after 120 minutes of the procedure, while the concentrations of C3c and C4 components are not changing significantly during haemodialysis using both types of the dialyzers. The authors found that the polysulfone membrane seemed not to be more biocompatible than the cuprophan one.

Adult↗
PubMed1984

The C4 and Slp genes of the complement region of the murine H-2 major histocompatibility complex.

Recent analyses, at the protein and DNA levels of structure, of the murine complement components C4 and the closely related sex-limited protein, Slp have led to new insights into the H-2/S region-linked C4 and Slp genes and their products. The primary products are 200 000 Da precursors which are cleaved, intracellularly and extracellularly, into the the mature alpha-beta-gamma-subunit molecules of plasma. Precursor order of subunits is beta-alpha-gamma; a complementary DNA clone spanning the alpha-gamma junction has been extensively analysed. The C-terminal of the alpha-chain is of particular interest because of post-secretion processing which differentiates 'secreted' and 'plasma' forms of C4, both apparently functional, and because allelic variants of C4 and the Slp protein, which differ substantially in molecular masses, owe their differences principally to different levels of glycosylation of the alpha-chain. Allelic variations in rate of C4 synthesis (C4-high compared with C4-low) have been analysed in cultures of hepatocytes and macrophages. Three distinct modes of genetic regulation of the expression of the Slp protein have been identified.

Alleles↗
PubMed1988

Allelic variants for complement factors C3, C4, and B in acute necrotizing ulcerative gingivitis.

Impaired immune defense mechanisms and genetic factors appear to play a role in susceptibility to acute necrotizing ulcerative gingivitis (ANUG). Therefore, possible etiological mechanisms might involve genes at the Major Histocompatibility Complex, which include the complement factor loci. We have tested for a possible association between certain complement factor alleles and ANUG using a case-control study design. Specific alleles at complement factors C3 and C4, and properdin factor B (Bf) loci were determined indirectly by high voltage agarose gel electrophoresis in 58 subjects with a history of ANUG and in 58 age-sex-matched healthy controls. The highest relative risk of ANUG, as obtained by conditional logistic regression, for alleles at the C3 locus was 1.9 (90% confidence limits 0.8 to 4.8; p = 0.229) for C3*F-positive individuals. The highest relative risk for alleles at the C4 locus was 2.6 (0.5 to 14.9; p = 0.358) for C4A*3-positive individuals. There was no evidence for an association between Bf allotype and risk of ANUG, with a relative risk of 1.2 for Bf*F- and relative risk of 1.0 for B*S-positive individuals. None of our estimates was statistically significant. We conclude, therefore, that it is unlikely that there is any association between complement factor gene haplotype and susceptibility to ANUG.

Acute Disease↗
PubMedDate not supplied

[Immunologic peculiarities of uveitis concurrent with systemic pathologies].

Immunologic examinations were performed in 111 patients with uveitis concurrent with a variety of systemic pathologies, including 85 males and 26 females, mean age--32.4 +/- 5.8. A higher IL-6 content in blood serum (BS) and in lachrymal fluid (LF) was detected in all patients. The IL-4 content was lower in uveitis associated with ankylosing spondylitis and with Reuter's disease, whereas, it was higher in juvenile rheumatoid arthritis. The systemic immunity changes were related with the hemostasis impairments in the phagocytic, humoral and cellular chains: an enhanced functional activity of phagocyte cells, a lower absolute quantity of T-lymphocytes, a higher count of B-cells, a reduced concentration of IgM and of circulating immune complexes (CIC), and a diminished general hemolytic activity of the complement in BS. A reduced concentration of the secretory fraction of IgA, IgG and IgM concurrent with higher concentrations of IgA, C3- and C4 complement components, CIC and of lysozyme activity in LF was detected in the local immunity system.

Adult↗
PubMed1996

[Immune complexes and C3 and C4 of the complement in urine of patients with glomerulonephritis].

The circulating immune complexes (CIC), urinary immune complexes (UIC), C3 and C4 in urine (UC3 and UC4) in 99 patients with immunologic glomerular diseases: 13 with extracapillaris GN (ExGN), 38 with membranoproliferative GN (MPGN), 33 with mesangial proliferative GN (MesPGN), 5 with focal segmental glomerulosclerosis (FSGS), 5 with membranous nephropathy (MN), and 3 with minimal change nephropathy (MC) were investigated in the study. Depending on the (IS) immunosuppressive treatment all patients were classified into 3 groups. Group I: 61 recently biopsied patients with glomerular disease consisted of patients attending our renal department, group II: 24 patients with biopsy proven glomerular disease IS treated in the past but with GN with restrained disease activity, group III: 14 patients with active glomerulopathy who have been treated for some months. Nephelometry C1q binding test was used for CIC detection and 3.5% polyethylene glycol precipitate for its detection in urine by C1q binding test was applied. Radial immunodiffusion (NANORID) method was used for urine C3 and C4 detection. UC3 were detected in urine from 37% of all patients: in 39% patients of group I (GN at time of diagnosis), 38% of group II (GN with restrained disease activity) and 36% of group III (active GN received immunosuppressive therapy for several months). It suggest that nonimmunological-mechanism induce C3 detected in the rine of such patients. According to histological findings UC3 was detected in 3 patients with ExGN of group I, in patient with ExGN of group II and in about half patients with MPGN from group I and II, in about 25% patients with MesPGN from group I and II. About half patients with MesPGN of group III, one patient with MPGN of group III and a few patients with other histological findings of group I were UC3 positive. Simultaneous excretion of C4 in urine was detected in some UC3 positive patients (in about 5% patients). At the same time in about 50% UC3 positive patients was observed urinary excretion of IC. CIC and UIC were detected in 25% of all patients: in 29% of group I, in 17% of group II, and in 29% patients of group III. According to histological findings CIC was detected in 3 patients with ExGN, in 7 patients with MPGN from 26 of group I, and 3 from 7 with MPGN of group II, and 3 patients with MesPGN of group I and 1 patients with MesPGN of group II, and 33% patients with MesPGN of group III with high proteinuria. These findings suggested that urinary IC reflected the immunological activity of glomerulopathy and their presence in patients urine after IS treatment suggests incomplete response to this therapy while urinary C3 and C4 were connected with urinary protein excretion and may be of importance in tubulointerstitial injury and progression of renal insufficiency.

Adolescent↗
PubMedDate not supplied

[A factor from the venom of the Central Asiatic cobra Naja naja oxiana, which inactivates component C4 of human complement].

An acid glycoprotein (mol. m. 60 kDa) containing 6 sialic acid residues and N-terminal Thr was isolated from the venom of the central asian cobra Naja naja oxiana. The protein has an anticomplementary activity selectively inactivating of the C4 component of the human complement. This factor (CFA-Ib) binds C4 with Ki = 0.27 +/- 0.13 microM and then irreversible inactivates it with a rate constant k = 0.75 +/- 0.25 min-1. Membrane bound C4b restores its ability of CFA-Ib binding. This binding hinders component C2 sorption on C4b and C3 convertase formation.

Complement C3-C5 Convertases↗
PubMed1990

Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.

The C4B isotype of the fourth component of human complement (C4) displays 3- to 4-fold greater hemolytic activity than does its other isotype C4A. This correlates with differences in their covalent binding efficiencies to erythrocytes coated with antibody and complement C1. C4A binds to a greater extent when C1 is on IgG immune aggregates. The differences in covalent binding properties correlate only with amino acid changes between residues 1101 and 1106 (pro-C4 numbering)--namely, Pro-1101, Cys-1102, Leu-1105, and Asp-1106 in C4A and Leu-1101, Ser-1102, Ile-1105, and His-1106 in C4B, which are located in the C4d region of the alpha chain. To more precisely identify the residues that are important for the functional differences, C4A-C4B hybrid proteins were constructed by using recombinant DNA techniques. Comparison of these by hemolytic assay and binding to IgG aggregates showed that the single substitution of aspartic acid for histidine at position 1106 largely accounted for the change in functional activity and nature of the chemical bond formed (ester vs. amide). Surprisingly, substitution of a neutral residue, alanine, for histidine at position 1106 resulted in an increase in binding to immune aggregates without subsequent reduction in the hemolytic activity. This result strongly suggests that position 1106 is not "catalytic" as previously proposed but interacts sterically/electrostatically with potential acceptor sites and serves to "select" binding sites on potential acceptor molecules.

Animals↗
PubMed1976

Genetic polymorphism of C3 and serum levels of immunoglobulins, C3, C4 components of complement and C3-proactivator in four different populations of Afghanistan.

The C3 phenotype distribution was studied in 4 different populations from Afghanistan. The gene frequencies of C3S allele were: Tajiks (0,8547), Pushtoons (0.8812), Hazaras (0.9036) and Osbeks (0.8530). These values were significantly higher than in European populations studied previously. No significant differences were found between the mean serum levels of C3, C4 and C3-proactivator among 4 population groups. A higher concentration of IgG, IgA and IgM was observed in Afghanistan sera than reported for Europeans.

Afghanistan↗
PubMed1974

Fourth component of human complement: description of a three polypeptide chain structure.

The fourth component of human complement (C4) was shown to be composed of three distinct polypeptide chains linked by disulfide bonds and noncovalent forces. The sum of the molecular weights of the chains equalled that of the intact molecule. The mol wt of the alpha-, beta-, and gamma-chains were respectively, 93,000, 78,000, and 33,000 daltons. Action of C1s on C4 affected only the alpha-chain, reducing its mol wt to 87,000 daltons. The size of the activation peptide. C4a, is therefore estimated to be 6,000 and that of the major fragment C4b, 198,000 daltons. Periodic acid-Schiff-stained SDS polyacrylamide gels of reduced C4 revealed carbohydrate to be associated with all three chains. A modification of the original method of isolation of C4 is presented.

Chemical Phenomena↗
PubMed2006

Real-time PCR quantification of human complement C4A and C4B genes.

BACKGROUND: The fourth component of human complement (C4), an essential factor of the innate immunity, is represented as two isoforms (C4A and C4B) in the genome. Although these genes differ only in 5 nucleotides, the encoded C4A and C4B proteins are functionally different. Based on phenotypic determination, unbalanced production of C4A and C4B is associated with several diseases, such as systemic lupus erythematosus, type 1 diabetes, several autoimmune diseases, moreover with higher morbidity and mortality of myocardial infarction and increased susceptibility for bacterial infections. Despite of this major clinical relevance, only low throughput, time and labor intensive methods have been used so far for the quantification of C4A and C4B genes. RESULTS: A novel quantitative real-time PCR (qPCR) technique was developed for rapid and accurate quantification of the C4A and C4B genes applying a duplex, TaqMan based methodology. The reliable, single-step analysis provides the determination of the copy number of the C4A and C4B genes applying a wide range of DNA template concentration (0.3-300 ng genomic DNA). The developed qPCR was applied to determine C4A and C4B gene dosages in a healthy Hungarian population (N = 118). The obtained data were compared to the results of an earlier study of the same population. Moreover a set of 33 samples were analyzed by two independent methods. No significant difference was observed between the gene dosages determined by the employed techniques demonstrating the reliability of the novel qPCR methodology. A Microsoft Excel worksheet and a DOS executable are also provided for simple and automated evaluation of the measured data. CONCLUSION: This report describes a novel real-time PCR method for single-step quantification of C4A and C4B genes. The developed technique could facilitate studies investigating disease association of different C4 isotypes.

Adult↗
PubMed2003

On the site of C4 deposition upon complement activation via the mannan-binding lectin pathway or the classical pathway.

The mannan-binding lectin (MBL) pathway and the classical pathway of complement activation are initiated by the binding of the recognition structure of the initiator complexes, MBL and C1q, respectively, to their ligands, i.e. carbohydrate structures or immune complexes. Proenzymes associated with MBL or C1q are then activated and generate C3 convertase through the activation of C4 and C2. The cleavage product of C4, C4b, attaches covalently to nearby hydroxyl or amino groups. The current picture is that C2 must then attach to C4b before being cleaved by the same associated proteases into the enzymatically active fragment, C2b. This suggests a stringent requirement for the deposition of C4b very close to the initiator complex, or indeed onto the initiator complex. We examined the possibility of C4b being bound to the initiator complex by a solid-phase assay, allowing for the selective elution of the initiator complexes, followed by quantification of the C4b being eluted and the C4b remaining on the solid phase. Also, we estimated the generation of complexes between the released initiator complex and C4b. More than 99% of deposited C4b was bound directly to the solid phase rather than to the initiator complex. Our approach cannot answer the question of the whereabouts of the C2 when it is cleaved.

Binding Sites↗
PubMed1982

Bacterial and fungal infection in children with fulminant hepatic failure: possible role of opsonisation and complement deficiency.

Serious bacterial infection, including eight episodes of bacteraemia, developed in seven of 15 (47%) children with fulminant hepatic failure. Those with infections had a slightly higher leucocyte response than those who did not. Serum immunoglobulin concentrations were normal or raised in all patients. Opsonisation of heat-killed baker's yeast, functionally measured total haemolytic complement, C4, C5, total alternative pathway activity, factor B and D activity, and C3 concentrations were all significantly (p less than 0.005) reduced at presentation but returned to normal in those who survived. The severity of defects in yeast opsonisation, C4, and factor B activity at presentation were significantly correlated with the subsequent development of infection. In five patients bacteraemia occurred at a time when opsonisation and complement components were defective. Plasma infusions in vivo improved opsonisation in vitro and only one bacterial isolate was obtained within four days of such an infusion. Those patients who developed infection had received significantly (p less than 0.05) fewer plasma infusions than those who did not. Our findings suggest that both alternative and classical pathways of complement are defective in children with severe liver disease and may contribute to the susceptibility of such patients to infections. Plasma infusions might be useful in reducing the incidence of bacterial infection in such conditions.

Acute Disease↗
PubMed1981

A prospective study of serum complement (C3 and C4) levels in normal human pregnancy: effect of the development of pregnancy-associated hypertension.

Serum levels of complement components (C3 and C4) were measured serially in 173 initially normotensive pregnant women and the results compared with those obtained in 32 nonpregnant women of similar ages. There was significant elevation of serum levels of both C3 and C4 during gestation. Pregnancy-associated hypertension developed in the third trimester in 26 pregnant women but they had the-same degree of elevation of serum C3 and C4 levels as did the 147 pregnant women who remained normotensive throughout their pregnancy. Measurements of serum C3 and C4 levels and therefore of no value in predicting the development of pregnancy-associated hypertension.

Adolescent↗
PubMed1997

The internal thioester and the covalent binding properties of the complement proteins C3 and C4.

The covalent binding of complement components C3 and C4 is critical for their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which involves a conformational change initiated by the cleavage of a single peptide bond, the thioester becomes available to react with molecules with nucleophilic groups. This description is probably sufficient to account for the binding of the C4A isotype of human C4 to amino nucleophiles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxyl nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbohydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioester provides a means to contain this very damaging reaction to the immediate proximity of the site of activation.

Complement C3↗
PubMed2003

An age-associated decrease in the frequency of C4B*Q0 indicates that null alleles of complement may affect health or survival.

We studied the distribution of complement C4, C3, and factor B allotypes in 423 healthy Icelandic subjects from 17 to 89 years of age. A marked decrease was observed in the carrier frequency of variant alleles of complement C4B (C4B(*)Q0) and C3 (C3(*)F). These results confirm our previous observations on Hungarian subjects and suggest a negative effect of C4B(*)Q0 on health or survival.

Adolescent↗