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PubMed2006

Microdialysis for monitoring inflammation: efficient recovery of cytokines and anaphylotoxins provided optimal catheter pore size and fluid velocity conditions.

Microdialysis emerges as a useful tool to evaluate tissue inflammation in a number of clinical conditions, like sepsis and transplant rejection, but systematic methodological studies are missing. This study was undertaken to determine the recovery of relevant inflammatory mediators using the microdialysis system, comparing microdialysis membranes with two different molecular weight cut-offs at different flow rates. Twenty and 100 kDa pore sizes CMA microdialysis catheters were investigated using velocities of 0.3, 1.0 and 5.0 microl/min. Reference preparations for cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-10; m.w. 17-28 kDa] and chemokines (IL-8, MCP-1, IP-10 and MIG; m.w. 7-11 kDa) were prepared from plasma after incubating human whole blood with lipopolysaccharide. Reference preparation for complement anaphylatoxins (C3a, C4a, C5a; m.w. 9-11 kDa) was prepared by incubating human plasma with heat-aggregated immunoglobulin G. The reference preparations were quantified for the respective inflammatory molecules and used as medium for the microdialysis procedure. Through the 20 kDa filter only the four chemokines passed, but with low recovery (3-7%) and limited to the 1.0 microl/min velocity. The recovery with the 100 kDa filter was as follows: IL-1beta = 75%, MCP-1 = 55%, MIG = 50%, IL-8 = 38%, C4a = 28%, IP-10 = 22%, C5a = 20%, C3a = 16%, IL-6 = 11, IL-10 = 8% and TNF-alpha = 4%. The highest recovery for all chemokines and anaphylatoxins were consistently at velocity 1.0 microl/min, whereas IL-1beta and IL-10 recovered most efficiently at 0.3 microl/min. Thus, microdialysis using catheters with a cut-off of 100 kDa is a reliable method to detect inflammation as judged by a defined panel of inflammatory markers. These findings may have important implications for future clinical studies.

Anaphylatoxins↗

PubMed1991

Sarcoidosis and major histocompatibility complex genes with special emphasis on BF F subtypes.

Frequencies for HLA class I and II histoglobulins and C4A, C4B, BF complement proteins were performed for 59 sarcoidosis patients. The DR5 allele was present in 55.9% of patients as compared to 31.5% of controls. We noticed that its increase was more relevant in males and in those with a poor prognosis. BF F allele was significantly over-represented in patients (29.09% vs. 19.15% of control), especially in women. Special emphasis was given to BF F subtyping, to define an association between a particular BF F subtype and patient's sex or disease outcome.

Alleles↗

PubMed1994

Nafamostat mesilate reduces blood cell adhesion to cardiopulmonary bypass circuits: an in-vitro study.

Nafamostat mesilate (FUT-175) is a protease inhibitor, working as an inactivator of coagulation, fibrinolysis and platelet aggregation. Although FUT-175 directly blocks contact factors in coagulation, it also may decrease activation of humoral cascade systems when used in cardiopulmonary bypass circuits. We performed an in vitro study using fresh human blood in the following cardiopulmonary bypass circuits: standard circuit (C), biosurfaced circuit (B) and standard circuit containing FUT-175 (F). Each circuit was primed with 500 ml of electrolyte solution and 500 ml of fresh blood. Cardiopulmonary bypass was performed using a roller pump for four hours in two sets of each circuit configuration. Platelet factors (platelet count and beta-thromboglobulin), coagulation factors (thrombin-antithrombin III complex and fibrinopeptide A), fibrinolysis factors (alpha 2-plasmin inhibitor complex and alpha 2-plasmin inhibitor), complement factors (C3a, C4a), free hemoglobin, and granulocyte elastase were measured at the beginning and end of the study. Hemocytograms were measured concurrently. The FUT-175 group showed significantly lower levels of the measured indices than the biosurfaced group in thrombin-antithrombin III complex (7.4 +/- 2.1 vs. 54.9 +/- 38.1 ng/ml), fibrinopeptide A (7.2 +/- 2.0 vs. 20.2 +/- 14.6 ng/ml), beta-thromboglobulin (1940 +/- 250 vs. 2438 +/- 314 ng/ml) and free hemoglobin (25.2 +/- 14.3 vs. 73.8 +/- 18.4 mg/dl). There were no significant differences between Group F and Group B in platelet count, C3a, C4a and granulocyte elastase, although these indices were significantly lower in Groups F and B when compared to Group C.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzamidines↗

PubMed1991

Effect of a short maximal physical exercise on coagulation, fibrinolysis, and complement system.

In 11 healthy young subjects, the plasma concentrations of the thrombin-antithrombin III complex, fibrinopeptide A, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were measured before and after a graded maximal bicycle exercise test. The analyses were carried out 30 min before and immediately before exercise, immediately after exercise, and 30 and 60 min later. All post-exercise values were corrected for plasma volume changes, which were calculated from hematocrit and hemoglobin values. Immediately post-exercise, thrombin-antithrombin III, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were all significantly elevated (p less than 0.01), compared with the pre-exercise values; 30 and 60 min later the values normalized and significant differences from the pre-exercise values could no longer be measured. Fibrinopeptide A did not change significantly after exercise. The present results provide evidence for a simultaneous activation of coagulation, fibrinolysis, and complement system as well as for a release of histamine after a short maximal exercise.

Adult↗

PubMed1991

Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.

Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.

Alleles↗

PubMed1987

High resolution electrophoresis for the allotyping of human C4. Proposal of a relational nomenclature.

Among the major histocompatibility complex (MHC)-linked complement genes, the loci for C4A and C4B exhibit the most extensive structural polymorphisms. Therefore the differentiation of variant and complex C4 phenotypes often proves difficult in conventional immunofixation electrophoresis. To improve the available technique of C4 typing a closed horizontal electrophoresis system was combined with poly- and monoclonal alkaline phosphatase immunoprobing on contact diffusion blots. The high resolution and sensitivity of this method not only facilitated C4 allotyping but also revealed additional polymorphic variation. Relative electrophoretic mobilities specific for each C4 allotype were established by computerized remission densitometry and provided the basis for a quantitative denomination of C4 variants. Typing by high resolution electrophoresis and the proposed relational C4 nomenclature could be valuable for further immunogenetical studies of the C4 protein polymorphism.

Alkaline Phosphatase↗

PubMed2001

Improved method for the allelic definition of C4A and C4B polymorphism (HLA class III).

The polymorphism of the fourth component of human serum complement (C4) is well established at the proteinic level; at the DNA level in the analysis of C4A and C4B gene polymorphism, the PCR technique is not widely and routinely used because it is time consuming and still presents reproducibility problems. This is a serious problem because only PCR genotyping allows the establishment of Rodgers-Chido reverse antigenicity without the need for classical family segregation studies, whose samples are not always easy to obtain. The most commonly used protocol requires an initial PCR followed by nested amplification of all the products supposed positive or negative. The two reactions are set up using differing cycling conditions, primers, and magnesium chloride concentrations. We developed a simplified procedure to easily obtain reproducible results and used a single protocol for all reactions. Nested PCR is made using only the positive samples, so we decrease the number of samples to handle, the time spent for the work, and the reagents used for the reactions. Moreover, we increased the reproducibility of the experiments.

Alleles↗

PubMed1993

The interaction of soluble human complement receptor type 1 (sCR1, BRL55730) with human complement component C4.

Human CR1 is a membrane-bound protein which plays an important role in the control of the human complement system. In addition to its involvement in the processing and clearance of immune complexes with C3b or C4b on their surface, CR1 acts as a cofactor for the proteolysis of C3b and C4b by Factor I. sCR1 is a recombinant, soluble form of CR1 which retains the cofactor activities of CR1, and is of potential therapeutic value for the suppression of complement-mediated tissue damage in vivo. An assay has been established using microtitre plates to explore the binding of sCR1 to the two isotypes of C4, C4A and C4B, and to C4 fragments. Specific binding of 125I-sCR1 to C4b and ammonia-treated C4 has been demonstrated. The binding of 125I-sCR1 to ammonia-treated C4 is dependent on pH and ionic strength, decreasing with an increase in pH and with an increase in ionic strength. At physiological ionic strength, up to twice as much 125I-sCR1 bound to ammonia-treated C4A as bound to ammonia-treated C4B. This preference of sCR1 for binding to the C4A isotype has implications for the clinical association of immune complex disease with C4A null alleles.

Ammonia↗

PubMed1989

Inhibition of the covalent binding reaction of complement component C4 by penicillamine, an anti-rheumatic agent.

D(-)-Penicillamine [D(-)-beta beta-dimethylcysteine] is an anti-arthritic drug, but its use is limited by adverse side effects, which include problems in immune-complex clearance. Complement is important as a source of inflammatory mediators in rheumatoid arthritis and is also involved in immune-complex clearance. Thus inhibition of the complement cascade would be likely to contribute to both the therapeutic and the toxic effects of penicillamine. It is shown that penicillamine and cysteine are potent inhibitors of the covalent binding of activated complement component C4 to immune complexes. [35S]Cysteine itself becomes covalently bound to C4b through the thioester site. Penicillamine and cysteine are more reactive with the C4A isotype than with the C4B isotype of the HLA class III protein C4. The limited amino acid sequence differences between C4A and C4B include a cysteine/serine interchange, and it is suggested that the cysteine residue in C4A contributes to the increased rate of reaction of C4A with the alpha-amino-beta-thiol compounds.

Anaphylatoxins↗

PubMed1990

Generation of complement-derived anaphylatoxins in normal human donor corneas.

Complement-derived anaphylatoxins (C3a, C4a, and C5a) are potent, stable mediators of acute inflammation. Because human corneas contain functional complement, the authors subjected normal human donor corneas to various forms of immunologic or chemical injury to determine if the complement system could be activated and anaphylatoxins generated. The experimental cornea of each donor pair was injected with lipopolysaccharide (LPS) or immune complexes or injured by application of acid or alkali. The remaining cornea of each donor pair served as a control. After incubation of corneas in tissue culture media for 6 hours and elution in phosphate-buffered saline for 24 hours, C3a, C4a, and C5a were measured in corneal eluates by radioimmunoassay. Compared with control corneas, C3a levels were significantly increased in corneas injected with LPS or immune complexes and in corneas injured with acid or alkali. C4a levels were significantly elevated in corneas injected with immune complexes and in corneas injured with acid or alkali but not in corneas injected with LPS. C5a levels were detectable only in corneas injured with acid or alkali. These results suggest that immunologic reactions in the human cornea may activate the classic or alternative complement pathways and generate anaphylatoxins. Additionally, chemical injuries with acid or alkali generate anaphylatoxins in the cornea. Anaphylatoxins may participate in the acute inflammatory response of the human cornea to chemical or immunologic injury.

Acids↗

PubMed1990

Homozygous C4A deficiency in systemic lupus erythematosus: analysis of patients from a defined population.

Homozygous C4A deficiency was found at a prevalence of 16% (13/80 patients) in systemic lupus erythematosus (SLE). The patients represented all diagnosed cases retrieved from a defined population in Southern Sweden, which minimizes the influence of patient selection. Photosensitivity was more common among C4A-deficient patients than among other SLE patients (p less than 0.05). Otherwise, clinical features were similar in the two groups. In addition, no differences were found with regard to presence of various autoantibodies (anti-dsDNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB, rheumatoid factors and anti-cardiolipin). In patients expressing both C4A and C4B isotypes, C4B/C4A quotients were fairly stable in plasma irrespective of disease activity. This argues against preferential break-down of either isotype during complement activation in the disease. The increased photosensitivity of C4A-deficient patients partly resembles the findings in patients with complete deficiencies of classical pathway components.

Antibodies, Antinuclear↗

PubMed1988

Synthetic peptide inhibitors of complement serine proteases--II. Effects on hemolytic activity and production of C3a and C4a.

Synthetic peptides based on the amino acid sequence at the site of cleavage of C3 by classical and alternative pathway convertases were found to be poor inhibitors of hemolysis except at concns of 1 mM and higher. Synthetic peptides of a second type, based on the C-terminal sequence of antithrombin III, were more effective; the best among them caused significant inhibition of hemolysis at a concn of 5 microM. A hybrid peptide composed of the sequence at the site of cleavage of C4 by C1s attached to an antithrombin III sequence was selective, inhibiting the classical pathway with no effect on the alternative pathway at a concentration of 25 microM. Several of the antithrombin III peptides that inhibited hemolysis did not inhibit C4 activation by the classical pathway or activation of C3 by the classical and alternative pathways suggesting that these peptides affect hemolysis by inhibiting enzymes other than C1s and C4b2a of the classical pathway and C3bBb of the alternative pathway.

Amino Acid Sequence↗

PubMed1992

The Seventh K Prathap Memorial Lecture. The pathogenesis of autoimmune immune complex disease.

It has been proposed that autoimmune immune complex disease, of which SLE is the type example, is caused essentially by a failure to properly metabolise immune complexes and that this allows the establishment of feedback cycles which cause more immune complexes to be formed. The essential genetic predisposition to this disease is complement deficiency of the components of the early classical pathway and some degree of genetic complement deficiency, particularly of C4a, is found in more than half the patients. It seems likely that acquired complement deficiencies, possibly present at the time of initiation of the disease, may be important in many of the other cases.

Autoimmune Diseases↗

PubMed1996

Alkylation of cellulosic membranes results in reduced complement activation.

4-Vinyl pyridine was grafted to the surface of the cellulosic membrane Cuprophan, and subsequently alkylated with both C10 and C16 aliphatic chains. Complement activation of heparinized human blood, corrected for anaphylatoxin adhesion, was measured by radioimmunoassay. The surface treatments both yielded substantial reductions in C5a activity, with a lessor reduction in C3a and C4a activity. Alkylation with 10 and 16 carbon chains resulted both in enhancements of albumin adsorption and stability. These enhancements as well as the reductions in complement activation were statistically indistinguishable between the two treatments. The reduction in complement activation was influenced more by adsorption of endogenous albumin and possibly by the vinyl pyridine graft, than the removal of surface active hydroxyl groups from Cuprophan.

Adsorption↗

PubMed1992

The relative roles of C4A and C4B in prevention of immune precipitation, solubilisation and immune adherence.

C4A and C4B levels were measured in serum from 246 normal individuals. Complement-mediated solubilisation, assayed using alkaline phosphatase anti-alkaline phosphatase immune complexes (IC), correlated with both C4A and C4B levels. However, C4A and C4B levels showed no correlation with solubilisation of bovine serum albumin (BSA) ICs, or with the prevention of immune precipitation of BSA or alkaline phosphatase ICs, nor with immune adherence assayed using thyroglobulin and BSA ICs.

Antigen-Antibody Complex↗

PubMed1998

Cardiopulmonary bypass circuit treated with surface-modifying additives: a clinical evaluation of blood compatibility.

BACKGROUND: The cardiopulmonary bypass (CPB) circuit induces blood activation and a systemic inflammatory response in cardiac surgical patients. The CPB circuit treated with surface-modifying additive (SMA) has been found to reduce blood activation by in vitro and ex vivo experiments. This study evaluates the surface thrombogenicity and complement activation of SMA circuits during clinical CPB. METHODS: Twenty patients undergoing coronary artery bypass grafting were randomly divided into two groups. In the SMA group (n = 10), all blood-contacting surfaces in the CPB circuit were treated or coated with SMA, whereas in the control group (n = 10) patients were perfused with an identical circuit without treatment. RESULTS: During CPB, platelet count and beta-thromboglobulin were found similar in both the SMA and the control groups. Prothrombin activation indicated by fragment F1 + 2 was found less in the SMA group (p < 0.05). After CPB, platelet deposition on the CPB circuit was significantly less (p < 0.05) in the SMA group than in the control group as assessed by the labeled monoclonal antibody against platelet glycoprotein IIIa. Complement activation identified by C3a and terminal complex C5b-9 did not differ between the two groups, but C4a generation was less in the SMA group (p < 0.05). Leukocyte activation identified by elastase and cytokine release indicated by interleukin-8 were found uniformly in both groups. Postoperatively, chest tube drainage, blood transfusion, duration of ventilatory support, as well as the intensive care unit and hospital stay were not significantly different between the two groups. CONCLUSIONS: These preliminary clinical results suggest that SMA inhibits platelet interaction with the biomaterial surface of the CPB circuit. Complement activation assessed by the terminal complement complex is not influenced by SMA. The clinical benefit of this surface-modifying technique has yet to be assessed in a larger population of patients undergoing cardiac operations.

Blood Platelets↗

PubMed1993

Complement polymorphism in herpes gestationis: association with C4 null allele.

BACKGROUND: Herpes gestationis (HG) is a rare, pregnancy-related skin disease characterized by the production of an autoantibody to a component of the hemidesmosome. It is associated with the class II antigens HLA-DR3 and HLA-DR4, but its potential association with the "class III antigens" C2, C4, and factor B has not previously been studied. OBJECTIVE: Our purpose was to study complement polymorphism in HG. METHODS: Using electrophoresis and immunofixation techniques, we determined the allele frequencies of C4A, C4B, C3, and factor B in 42 patients with a history of HG. RESULTS: Ninety percent of patients carried a C4 null allele (C4*QO). No statistically significant association with C3 or factor B alleles was seen. CONCLUSION: HG is associated with the presence of a C4*QO. Whether the C4*QO is the primary genetic association, or whether the C4*QO is related to its linkage disequilibrium with DR3 and DR4 has yet to be determined.

Adult↗

PubMed1985

Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region.

Molecular maps have been prepared of the HLA region on human chromosome 6 that includes the complement C4 and steroid 21-hydroxylase genes (21-OH), using DNA of individuals deficient (QO) in either of the two forms C4A or C4B. In all, 18 haplotypes with C4A QO were examined by Southern analysis and two had deletions of 28-30 kb that included both the C4A and 21-OHA genes. Of six C4B QO haplotypes, one had a deletion that included both the C4B and 21-OHA genes. Thus, some of the C4 null alleles are due to deletion of the gene but the majority in this sample are not. Deletion occurred in two common haplotypes suggesting that in the population as a whole, C4A deficiency is due to deletion in about one-half the C4A QO haplotypes. As duplication of C4A or C4B genes does occur, the possibility that unequal cross-over could explain the C4 deletion was examined by preparing cosmid clones from the DNA of an individual typed C4A QO. A cloned genomic fragment containing the single C4B gene was isolated and found to be similar to the homologous region of a cosmid from a normal individual carrying a C4A gene. This suggests that if a cross-over has occurred it is in a region where the two genes are identical. The biological significance of the rather frequent occurrence in the population of haplotypes with C4A or C4B deletion together with the accompanying deletion of the 21-OHA gene is discussed.

Alleles↗