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PubMed1989

Complete intron/exon organization of DNA encoding the alpha' chain of human C3.

The third component of human complement (C3), a central molecule in both the classical and alternative pathways of complement, is comprised of two polypeptides, termed the alpha and beta chains. Activation of C3 cleaves the alpha chain into two fragments, C3a, an inflammatory peptide, and the alpha' chain which remains covalently linked to the beta chain. Proteolytic fragments derived from the alpha' chain during activation and regulation of complement play a significant role in host defense and regulation of the immune response. Two cosmid clones covering the alpha' chain region were used to characterize the structure of this portion of the C3 gene. The alpha' chain is encoded by 24 exons, which range in size from 52 to 213 base pairs (bp) with an average size of 115 bp. The splice donor sequence at the beginning of intron 12 has a rare sequence variant of GC instead of the usual GT sequence. Ten introns have been completely sequenced and were surprisingly short, ranging in size from 85 to 242 bp with an average of 140 bp. Other introns range in size from 250 bp to over 4 kilobases in length. The gene size for this portion of C3 is estimated to be 23-24 kilobases. Comparison of exon structure with protein domains and with peptide mapping studies demonstrates that several binding sites on C3 are encoded by single exons. These data support the hypothesis that individual exons can code for functional protein domains.

Base Sequence↗

PubMed1987

Alterations in select immunologic parameters following total artificial heart implantation.

We examined select immunologic parameters in three recipients of a total artificial heart and correlated changes with the clinical course. Two patients remain alive and were studied for 320 and 240 days, respectively; the third died 10 days after implantation. All patients demonstrated transient complement activation immediately postoperatively, as indicated by an increase in plasma levels of C3a des Arg. In the two long-term survivors, C3a des Arg levels again increased, concomitant with intravascular hemolysis associated with high blood shear rates imposed by the drive system of the heart. All three patients had a marked lymphopenia immediately postoperatively, and the two long-term survivors demonstrated marked fluctuations in total lymphocyte count. There was a progressive decline in the number of peripheral blood helper/inducer T cells in the two long-term survivors. A large number of activated (HLA-DR positive) suppressor/cytotoxic T cells were also noted in these two patients. A progressive decrease in B cells was also observed; however, total IgG and IgM levels were not decreased. No changes in neutrophil phagocytic or respiratory burst capacities were identified. The cause of these changes in lymphocyte populations is not clear; however, they may have impact on the use of this device as a bridge to transplantation and may lead to decreased immunocompetence during long-term use.

Blood Transfusion↗

PubMed1987

Complement activation in extracorporeal circuits.

Clinical studies performed with various types of hemodialyzers provide a data base and conceptual framework for understanding blood-material interactions that result in complement activation. Current findings suggest that the complement-activating potential of biomaterials may be defined by quantitating either fluid-phase C3a antigen or measurement of surface-bound C3 fragments. Furthermore, systematic studies can reveal material properties that regulate both the production and distribution of the human anaphylatoxins. Assessing the fate of the C5a anaphylatoxin is particularly important because it is likely that generation of this bioactive molecule in extracorporeal circuits initially triggers granulocyte responses and may produce cardiopulmonary manifestations if the C5a is formed in sufficient quantities. It seems likely that detailed knowledge of these varied phenomena will permit rational design of newer "biocompatible" materials and membranes.

Biocompatible Materials↗

PubMed1982

A study of the cellular and humoral immune response in patients with myelofibrosis.

There was evidence of impaired cellular immunity in 10 patients with myelofibrosis. In-vitro lymphocyte transformation with phytohaemagglutin, concanavalin A, and dinitrochlorobenzene skin reaction were diminished. Signs of impaired humoral activity were also found, the primary response to alpha-Helix pomatia haemocyanin being impaired, particularly in the immunoglobulin-A class. Moreover three patients had a benign paraproteinaemia. Immunecomplexes (IC) could be demonstrated with various test systems. The indirect granulocyte phagocytosis test was positive in 50%, the C1q-binding in 70% and the polyethylene glycol precipitation test in 50%. In most patients complement levels were normal, although the patient with the most advanced disease had low C3A, C3 and C4 levels accompanied by high levels of IC. No correlation could be shown between impaired immune response or levels of IC when they were related to spleen diameter or degree of anaemia. Some relation however existed between disturbed immune response and IC when they were related to time elapsed since diagnosis. It is suggested that the impaired immune response is the result of primary bone marrow disease and that the presence of IC may reflect the extent of fibrosis.

Antibody Formation↗

PubMed1984

Biologically active products of complement and acute lung injury in patients with the sepsis syndrome.

To determine if biologically active products of complement appear during sepsis and to establish the relationship of these components to the respiratory and hemodynamic complications of sepsis, we measured C5a des Arg and C3a des Arg (radioimmunoassay), neutrophil chemotaxis, and neutrophil-aggregating activity in plasma obtained from 40 patients at the time sepsis was suspected clinically. Levels of C3a des Arg and C5a des Arg were elevated in 35 and 38 patients, respectively, and in all 25 with positive blood cultures. Highest C5a des Arg levels occurred in patients with hypotension (less than 90 mmHg) and/or acidemia. The C5a des Arg concentrations were significantly higher in patients with than in those without neutrophil-chemotactic activity. Neutrophil-aggregating activity was less sensitive an index of complement activation, as it was positive in only 8 patients and correlated poorly with C5a des Arg and C3a des Arg values. Using a composite scoring system to quantify sepsis-related pulmonary abnormalities, we found that neither biologic nor immunologic assays of complement activation products correlated with the initial severity nor predicted the development or worsening of associated acute lung injury.

Bacterial Infections↗

PubMed1990

Evolutionary implications of a new bypass activation pathway of the complement system.

The classical pathway of complement activation is a highly specific and amplifiable effector system responding to recognition of foreign antigens by antibody. It comprises a group of well characterized proteins in mammalian plasma. There are many similarities with the alternative pathway of complement activation, which suggests that they have a common evolutionary origin. Both pathways have homologous components, use related activation and regulatory mechanisms, result in the release of the anaphylatoxins C3a and C5a, and deposit C3b onto activating surfaces. This fixed C3b then becomes the focus of further immune reactions, involving either the lytic complement components or C3b receptors on effector cells. Phylogenetic data indicate that the alternative pathway is the older, and that the classical pathway evolved from it. Here Timothy Farries and colleagues review this evolutionary process and present a possible sequence of events that is suggested by recent functional data from their laboratory.

Animals↗

PubMed1979

Complement-dependent histaminase release from human granulocytes.

The role of particle-bound complement proteins in the induction of noncytotoxic enzyme release from human granulocytes was investigated with the use of sera genetically deficient in complement and highly purified complement components. Release of histaminase, one of two important histamine catabolizing enzymes, and beta-glucuronidase from polymorphonuclear leukocytes was solely dependent on particle-bound C3b (the larger cleavage product of the third component of complement) when fluid-phase complement was excluded. The extent of enzyme release was a function of particle-bound C3b input, was reduced by exposing the particles to C3b inactivator, and was blocked by fluid-phase C3b. Phagocytosis of the C3b-coated particles was not required for enzyme release from neutrophils. In contrast, phagocytosis of "opsonized" particles was required for noncytotoxic release of histaminase and arylsulfatase from eosinophils; other proteins, as well as C3b, were able to opsonize particles for induction of enzyme release from eosinophils. These studies suggest a dual role for complement (particularly C3) in modulating vascular permeability phenomena, i.e., release of vasoactive mediators by the action of C3a and C5a, and release of the corresponding enzymes that inactivate the mediators by C3b.

Amine Oxidase (Copper-Containing)↗

PubMed1996

[Complement regulatory proteins CR 1, MCP, DAF, and MACIF levels in patients with Behçet's disease].

We previously reported that serum complements in patients with Behçet's disease were extremely low just before the ocular attack. On the other hand, C3a and C5a levels, which have anaphylactic activity and chemotactic activity for polymorphonuclear leucocytes, were higher just before the ocular attack than at the time of the ocular attack, and there was negative correlation between C3a/C5a and CH50. In this report, we evaluated complement regulatory proteins. The results of low levels of C3b/C4b receptor (CR1) and membrane cofactor protein (MCP), and low tendency of decay accelerating factor (DAF) and membrane attack complex inhibition factor (MACIF) suggested that the function of complement regulatory proteins in patients with Behçet's disease decreases as a whole. But mean levels of both CH50 and ACH50 were significantly higher than in the controls. Although it is unclear which is the cause and which is the result, we suppose the function of complement production works excessively and these phenomena are caused by making up for the lack of complement regulatory proteins.

Adult↗

PubMed1973

Activation of the alternate complement pathway by autologous red cell stroma.

The present study demonstrates the ability of human autologous RBC stroma to activate the alternate complement pathway (C3-Activator system, properdin system), as evidenced by the generation of C3-Activator (C3A) from C3-Proactivator (C3PA) when RBC ghosts and sonicated ghosts are incubated with autologous serum. Intact RBC's, hemoglobin, and concentrated platelet stroma, on the other hand, are inactive in this regard. We postulate that this in vitro activity of RBC stroma may occur intravascularly when erythrocytes are damaged by immune or nonimmune mechanisms. The ensuing interaction of activated complement components with platelets leading to release of platelet factor three (PF-3) may constitute a mechanism for activation of the coagulation system during acute hemolytic episodes.

Blood Coagulation↗

PubMed1975

Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.

The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.

Adenosine Diphosphate↗

PubMed1991

[In vitro and clinical study of complement activation during cardiopulmonary bypass with reference to types of oxygenator, primed autologous blood and patient's factor].

Complement activation during cardiopulmonary bypass (CPB) was studied in vitro and in vivo with regard to types of oxygenator, primed autologous blood and patient's factor. In vitro study was performed using human blood in a simple circuit involving an oxygenator, roller pump and connector tubing. In vivo study was carried out in 118 patients and divided into bubble (BO) and membrane oxygenator (MO) groups. The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also examined. In vitro study, C3a and C4a increased steeply in the BO group. On the other hand, in the MO group, C3a and C4a increased up to minute of 60, and afterwards gradually decreased. In clinical study, complement was more activated in the BO group than in the MO group. These results supported that in the BO group, immunoglobulin denatured by blood-gas interface played an important role in complement activation. In membrane oxygenator, blood-material interface was a major cause of complement activation. In order to reduce these complement activation, we introduced fresh concentrated red cells, which was almost free of immunoglobulin, as a primed blood. Application of this method in clinical study, complement activation was reduced and postoperative lung function was improved significantly. These changes were more significant in the BO group. In the high H/A group, differences of anaphylatoxin level between BO and MO group had a tendency to increase. This method is useful to the CPB case of neonate and infant, which was subjected to be primed with a large amount of blood.

Adolescent↗

PubMed1987

Activation of the classical and alternative pathways of complement by Treponema pallidum subsp. pallidum and Treponema vincentii.

Both in vivo and in vitro studies have indicated that complement plays an important role in the syphilitic immune responses. Few quantitative data are available concerning activation of the classical pathway by Treponema pallidum subsp. pallidum, and no information is available on treponemal activation of the alternative pathway. Activation of both pathways was compared by using T. pallidum subsp. pallidum and the nonpathogen T. vincentii. With rabbit and human sources of complement, both organisms rapidly activated the classical pathway, as shown by hemolysis of sensitized sheep erythrocytes and by the generation of soluble C4a. With human sources of complement, both organisms also activated the alternative pathway, as shown by hemolysis of rabbit erythrocytes and by the generation of soluble C3a in the presence of magnesium ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). During incubation, organisms remained actively mobile and did not lyse, indicating that activation was a function of complement reactivity with the intact outer treponemal surface. In addition, freshly harvested T. pallidum subsp. pallidum immediately activated both pathways of complement; preincubation of organisms did not enhance complement reactivity. T. vincentii was a more potent activator of this pathway. T. pallidum subsp. pallidum contained almost four times as much surface sialic acid as T. vincentii did. When sialic acid was enzymatically removed from T. pallidum subsp. pallidum, enhanced activation of the alternative pathway was detected. It is proposed that T. pallidum subsp. pallidum retards complement-mediated damage by the alternative pathway through surface-associated sialic acid. This may be an important virulence determinant that enables these organisms to readily disseminate through the bloodstream to infect other tissues.

Animals↗

PubMed1991

Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis.

To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane attack complex SC5b-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (DJD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d. Therefore, novel assays for complement activation indicate that both classical and alternative pathways are involved in complement turnover and that the alternative pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis.

Arthritis, Rheumatoid↗

PubMed1989

[A study on complement activation in cardiopulmonary bypass--experimental and clinical evaluations].

Complement activation in patients undergoing cardiopulmonary bypass (CPB) was studied, with particular reference to anaphylatoxins. Complement levels were compared between a bubble oxygenator group (BOG) and a membrane oxygenator group (MOG). The influence of primed homologous blood on complement activation was also evaluated. C4a levels gradually increased during CPB in the BOG, whereas in the MOG they changed little. There was a marked initial rise of C4a levels in the BOG of high H/A (primed homologous vs. circulating autologous blood volume ratio). C3a levels increased more steeply in the BOG than in the MOG. In general C5a levels remained low in both groups, but were slightly higher in the BOG than in the MOG. Complement levels were determined in monkeys (Macaca fascicularis) undergoing continuous intraaortic infusion of 1) autologous blood extracorporeally bubbled with O2, 2) blood contacted with nylon, or 3) O2 microbubbles. The results indicated 1) elevation of C4a and C3a in the bubbled blood group, 2) elevation of C3a alone in the nylon group, and 3) no elevation of either anaphylatoxin. It was thus inferred that 1) during CPB, the complement might be rather dominantly activated via the classical pathway in the BOG, and via the alternative pathway in the MOG, 2) higher anaphylatoxin levels in the BOG than in the MOG might be related to mode and grade of blood trauma including plasma denaturation, and 3) the H/A ratio might be a factor able to modify complement activation.

Adolescent↗

PubMed1984

Allergic reactions to antimicrobial agents: a review of reactions to drugs not in the beta lactam antibiotic class.

Allergic reactions to antimicrobial drugs are common causes of morbidity but rarely of death. Despite the lack of proven immunodiagnostic tests for reactions to the non-beta-lactam drugs, the agents that cause reactions usually can be identified by analysis of their propensity to cause reactions, temporal relationships of exposure to reactions, and remission of reactions when the drugs are discontinued. Measurements of plasma histamine levels, high-molecular-weight neutrophil chemotactic factor, and heparin-like activity and of urinary histamine and prostaglandin D2 metabolites should help clarify the role of mast cell mediator release in the various forms of these reactions. Measurements of C3a, C4a, and C5a, in biologic fluids should facilitate analysis of the contributions of complement activation to the reactions observed. Assessment of these pathophysiologic parameters should provide a more rational basis for the selection of specific pharmacologic interventions to suppress allergic reactions. If no alternative drugs are available, infected patients who are allergic often can be gradually desensitized with the agents to which they are allergic. While much important work remains to be completed, current approaches can minimize the morbidity and mortality rates associated with allergic reactions to antimicrobial agents.

Anti-Bacterial Agents↗

PubMed2004

Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches.

Compstatin is a 13-residue cyclic peptide that has the ability to inhibit the cleavage of C3 to C3a and C3b. The effects of targeting C3 cleavage are threefold, and result in hindrance of: (i) the generation of the pro-inflammatory peptide C3a, (ii) the generation of opsonin C3b (or its fragment C3d), and (iii) further complement activation of the common pathway (beyond C3) with the end result of the generation of the membrane attack complex. We will report on our progress on: (i) rational design of more active compstatin analogues based on the three-dimensional structure of compstatin, (ii) experimental combinatorial design based on the generation of a phage-displayed peptide library partially randomized with the implementation of structure-induced restraints, and (iii) theoretical combinatorial design based on a novel computational optimization method, structure-induced restraints and flexible structural templates. All three approaches have resulted in analogues with improved activities. Currently, the lead analogue has the sequence acetyl-I[CVYQDWGAHRC]T-NH(2) (where the brackets denote cyclization), and is 16-fold more active than the parent peptide. We will also report on our progress towards understanding the dynamic character of compstatin using molecular dynamics simulations. The identification of an ensemble of interconverting conformers of compstatin with variable populations is a first step towards the incorporation of dynamic elements in the design of new analogues using dynamics-activity relationships in addition to structure-activity relationships.

Animals↗

PubMed1996

[The evaluation of the bio-compatibility and the clinical usefulness of heparin-coated cardiopulmonary bypass circuits].

We studied the biocompatibility and the clinical usefulness of heparin-coated cardiopulmonary bypass circuits (Duraflow-II) compared with non-coated circuits. First study was done to clarify the biocompatibility of heparin coated circuit. 33 cases of elective coronary artery bypass grafting were randomized into two grops. Both group had full dose heparin in this study and laboratory tests were done such as blood cell count, free hemoglobin, AT-III, fibrinogen, FDP, and complement system. The use of heparin-coated circuits resulted in a reduction of C3a generation, and a reduction of fibrinogen consumption. The decline of AT-III may be due to bonding of coated heparin to AT-III, leading to effective anticoagulation. Next study was carried out in 26 cases. In heparin coated group, the amount of heparin was reduced to 200 IU/kg compared to 350 IU/kg in control group. ACT was maintained above 300 sec. and 400 sec. respectively. The amount of post operative bleeding was identical in both groups. There was no case which required autologous blood transfusion, re-operation for bleeding in both groups. Myocardial infarction and hospital mortality were not seen in this study. Concerning the fear of graft occlusion in low dose heparin surgery, there was no statistical difference of graft patency in both groups. In conclusion, heparin coated CPB circuits (Duraflo-II) are favorable in the meaning of biocompatibility and sefely used with low dose heparin.

Biocompatible Materials↗

PubMed1989

Factor C3f is a spasmogenic fragment released from C3b by factors I and H: the heptadeca-peptide C3f was synthesized and characterized.

C3f, a heptadeca-peptide having the amino acid sequence of NH2-Ser-Ser-Lys-Ile-Thr-His-Arg-Ile-His-Trp-Glu-Ser-Ala-Ser-Leu-Leu-Arg- COOH, is liberated during the catabolic degradation of C3b in serum. The amino acid sequence of C3f is known both from the cDNA-derived structure of C3 and from protein analysis after isolation of the natural factor. C3f was synthesized by solid phase peptide synthesis. Both natural and synthetic C3f had identical retention times by RP-18 high performance liquid chromatography (HPLC) analysis and the respective amino acid compositions agreed with the expected theoretical values. C3f, but not des-Arg-C3f, was weakly spasmogenic inducing contraction of guinea pig ileum at a level of 5-10 x 10(-6) M. Since C3f and C3a were cross-tachyphylactic, it was concluded that these two spasmogens compete for the same receptors. Both C3f and des-Arg-C3f at concns of 1-4 x 10(-4) M enhanced vascular permeability in guinea pig skin. These observations further suggest that C3f functionally resembles C3a anaphylatoxin. Formation of C3f in human serum following CVF activation of C3 could be demonstrated by radioimmunoassay (RIA). Digestion of C3f with purified human serum carboxypeptidase N produced C3f-desArg. These observations suggest that when serum complement protein C3 undergoes conversion to C3b, further degradation by Factors H and I readily generates C3f. C3f is a weak spasmogen that functions like C3a anaphylatoxin and C3f-desArg is a major metabolite in serum.

Amino Acid Sequence↗