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PubMed1991

Ex vivo removal of IgE in atopic asthma by extracorporeal plasmoimmunoadsorption (EPIA): development of a clinical adsorbent.

We have developed an immunoadsorbent (IA) for ex vivo removal of IgE after in vitro screening of matrix (Sepharose and tresyl-activated Toyopearl) and ligand (monospecific rabbit polyclonal anti-IgE antiserum and monoclonal antibodies (Abs) or their Fab fragments). Specific adsorptive capacity (SAC) for IgE was maximal in Sepharose-based IA with both types of Abs. Fab-containing IA on Sepharose retained 70-90% of the SAC of native Ab-containing IA. Toyopearl-based IA showed comparable SAC under static conditions but worked unsatisfactorily under continuous flow conditions. To assess the complement-activating capacity (CAC) of IA in vitro anaphylatoxin (C3a, C4a, C5a) generation was applied. CAC was directly related with the amount of immobilized Ab ligand, without depending on Ab specific activity. Fab-containing IA showed more CAC than native Ab-containing IA, and polyclonal IA more than monoclonal IA. Therefore, IA for IgE apheresis were prepared from native monoclonal Abs and CNBr-activated Sepharose CL 4B under aseptic conditions and packed into a glass column. This IA was used in 17 clinical IgE apheresis treatments of five atopic asthma patients. No substantial side effects were observed; in vivo IA effectively removed IgE from plasma (83 to 98%).

Adult↗
PubMed1998

Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts.

BACKGROUND: Intravascular fibrin deposition and platelet sequestration occur with porcine xenograft rejection by baboons. Disseminated intravascular coagulopathy may arise either as a direct consequence of the failure to fully deplete xenoreactive natural antibodies and block complement, or because of putative cross-species molecular incompatibilities in this discordant species combination. METHODS: Three baboons were conditioned with retrovirally transduced autologous bone marrow to induce tolerance to swine antigens. Xenoreactive natural antibodies and complement were depleted by plasmapheresis and the use of Gal alpha1-3Gal column adsorptions; baboons were then splenectomized and underwent renal xenografting from inbred, miniature pigs. Soluble complement receptor type-1 with protocol immunosuppression (mycophenolate mofetil, 15-deoxyspergualin, steroids, and cyclosporine) was administered. RESULTS: A bleeding diathesis was clinically evident from days 5 to 12 after transplantation in two baboons. Low levels of circulating C3a, C3d, and iC3b were measured despite the absence of functional circulating complement components. Profound thrombocytopenia with abnormalities in keeping with disseminated intravascular coagulopathy were observed. Prolongation of prothrombin and partial thromboplastin times was accompanied by evidence for tissue factor-mediated coagulation pathways, high levels of thrombin generation (prothrombin fragment F(1+2) production and thrombin-antithrombin complex formation), fibrinogen depletion, and production of high levels of the fibrin degradation product D-dimer. Importantly, these disturbances resolved rapidly after the excision of the rejected xenografts in two surviving animals. Histopathological examination of the rejected xenografts confirmed vascular injury, fibrin deposition, platelet deposition, and localized complement activation. CONCLUSIONS: Systemic coagulation disturbances are associated with delayed xenograft rejection.

Animals↗
PubMed2000

Damage to porcine islets of Langerhans after exposure to human blood in vitro, or after intraportal transplantation to cynomologus monkeys: protective effects of sCR1 and heparin.

BACKGROUND: Porcine islets offer an attractive alternative to human islets in clinical islet transplantation. The preferred method of islet transplantation is intra-portal injection into the liver. We have recently shown, both in vitro with human islets and in vivo with porcine islets, that islets exposed to allogeneic blood trigger an injurious inflammatory reaction characterized by activation of both coagulation and the complement systems. We have now tested whether a similar reaction is triggered when xenogeneic porcine islets are exposed to human blood in vitro and after intraportal transplantation into primates. Furthermore, we investigated the effect of inhibiting the complement and coagulation systems. METHOD: Islets isolated from adult and fetal porcine pancreas were perfused with fresh human blood in surface heparinized PVC tubings for 5-60 min. Blood cell counts and parameters related to coagulation and the complement system were analyzed, and islets were retrieved after the perifusion was examined by immunohistochemical method. Heparin and soluble complement receptor 1 (sCR1; TP10, 100 microg/ml) were added to the system in some experiments. Furthermore, adult porcine islets were transplanted intraportally into untreated and sCR1- (40 mg/kg BW i.v.) treated cynomolgus monkeys, and plasma insulin concentration was monitored during 60 min after transplantation. RESULTS: Porcine islets perifused with human blood triggered an immediate inflammatory reaction, characterized by a rapid consumption and activation of platelets, consumption of neutrophils and monocytes, activation of the coagulation and complement systems, and release of large amounts of insulin. Islet morphologic analysis revealed damaged islets embedded in clots and infiltrated with CD11+ leukocytes. C3a and C5b-9 was deposited on the islet surface, but human immunoglobulin was not. Complement inhibition with sCR1 reduced insulin release significantly. Intraportal islet transplantation into untreated cynomolgus monkeys resulted in a marked and rapid increase in plasma insulin concentration indicative of islet damage. Pretreatment of the monkeys with sCR1 resulted in significantly less insulin release than in untreated control monkeys. CONCLUSION: Exposure of isolated xenogeneic islets of Langerhans to blood, both in vitro and in vivo, resulted in acute islet damage. Complement and platelets seem to have a central role in the reactions described. Strategies to efficiently inhibit these reactions will be crucial for clinical intraportal islet xenotransplantation to be successful.

Animals↗
PubMed2001

In situ complement activation by polyethylene wear debris.

A frequent long-term complication of total joint arthroplasty is aseptic loosening, the end result of wear debris accumulation, synovitis, and osteolysis about the implant-bone or cement-bone interface. Complement, an effector system in plasma, synovial fluid, and tissue, has powerful chemotactic, inflammatory, and osteoclast-activating potentials. This study explored the complement-activating ability of polyethylene, a material used in joint implants. In vitro hemolytic assays using sheep red blood cells (E(sh)), human serum, and particulate polyethylene suggested alternative pathway complement activation, as well as polyethylene adsorption of activated complement components. These results were confirmed by enzyme-linked immunosorbent assay (ELISA) quantification of activated complement factors Bb and C3b. In situ double antibody immunoperoxidase staining for factors Bb, C3a, iC3b, and SC5-9 in synovial tissue from revision hip specimens showed localized alternative pathway activation and component adsorption. These results introduce a likely role for complement activation in particle-mediated recruitment, proliferation, and activation of macrophages during early events in osteolysis and implant loosening.

Biocompatible Materials↗
PubMedDate not supplied

Activation of plasma components by leukocyte removal filters.

The technique of leukocyte filtration has been introduced into cardiac surgery to reduce leukocyte mediated reperfusion injury. When autologous whole blood (WB) is used as filtrate, it is more likely to be activated by the filter material than are banked red blood cell concentrates (RCC), because of its richness in plasma components. This study was designed to compare the activation of plasma components during leukocyte filtration from WB (n = 10) taken from the heart-lung machine, with RCC (n = 10) obtained from the blood bank. Leukocyte filters made from either cellulose acetate or polyester were used. Blood samples were taken simultaneously from the inlet and outlet of the filter after filtration of either 700 ml of WB or 350 ml of RCC. Results indicated that the complement cascade was activated, as reflected by the increase of C3a and C5a during filtration of WB by filters made from cellulose acetate. In contrast, there was no significant increase of C3a and C5a during filtration of RCC. The clotting system, indicated by fibrinopeptide A, and the fibrinolytic system, indicated by fibrinogen degradation products, were not activated during leukocyte filtration. These data suggest that it is the WB taken from the heart-lung machine rather than the RCC from the blood bank that is being activated during leukocyte filtration. Thus, careful selection of filter material is important for leukocyte filtration of autologous whole blood during cardiac surgery.

Cellulose↗
PubMed1990

Aqueous humor protein and complement in pseudophakic eyes.

Intraocular lens (IOL) insertion is now the standard method of aphakic correction in this country. Previous studies have shown that an IOL can activate the alternative complement system of normal human serum in vitro, thereby generating peptides capable of stimulating inflammation that can result in visual morbidity in pseudophakic eyes. The objective of the present study was to determine if human aqueous humor (AH) levels of total protein, total C3, and C3a cleavage products (activated C3) are influenced by an IOL in pseudophakic eyes as compared with phakic and aphakic eyes. AH from five diagnostic categories was examined: cataract, posterior capsulotomy-IOL, Fuchs' endothelial dystrophy with corneal edema, aphakic bullous keratopathy, and pseudophakic bullous keratopathy. The results of this study do not support the hypothesis that IOLs affect AH protein and complement levels. Statistically, there was no significant difference in AH protein levels when pseudophakic eyes were compared with phakic and aphakic eyes. No significant difference in C3a levels was demonstrated between pseudophakic and phakic eyes, whereas aphakic eyes had significant higher levels than those with pseudophakia. There were significantly greater levels of protein, C3, and C3a in eyes with edematous corneas versus those with clear corneas. Although these studies are difficult to interpret, AH levels of these substances appear to be more related to dysfunctional corneal endothelium and corneal edema than to the presence of an IOL.

Aphakia↗
PubMed2005

Characteristics of complement activation in mice bearing Lewis lung carcinomas treated by photodynamic therapy.

Following treatment of Lewis lung carcinomas (LLC) by Photofrin-mediated photodynamic therapy (PDT), tumor tissues and sera of host mice were collected for the analysis of complement activity. Elevated tumor C3 levels were detected between 1 and 24 h after PDT, while serum C3 levels increased significantly at 24 h post therapy. Increased alternative complement pathway activity in the serum was evident between 1 and 3 days post PDT. Blocking C3a- or C5a-receptors in the host mice decreased the efficacy of PDT in producing LLC tumor cures, supporting the importance of complement action in PDT-mediated tumor destruction.

Animals↗
PubMed1988

A predictive test for adverse reactions to contrast media. Preliminary results.

In a prospective study, whole blood samples drawn from patients prior to their being injected with contrast media were incubated with zymosan to activate the complement cascade. The samples were tested for various analytes, including C3a, thromboxane B2 (TxB2), beta thromboglobulin and platelet factor 4 (PF4). Of 207 patients receiving contrast media, only eight experienced reactions, which were mild. Levels of the platelet constituents were generally elevated in these patients. Specificity and sensitivity were 89% and 83%, respectively, for the combined TxB2 and PF4 radioimmunoassay data. Using the Wilcoxon-Mann-Whitney rank sum test, both PF4 and TxB2 were collected with RCM reactions at the R less than .05 level. Although preliminary, the results suggest that RCM reactions are predictable by the in vitro test procedures described.

Complement Activation↗
PubMed1978

Primary structural analysis of the polypeptide portion of human C5a anaphylatoxin. Polypeptide sequence determination and assignment of the oligosaccharide attachment site in C5a.

The C5a molecule is one of two spasmogenic fragments (i.e. C3a and C5a) released from serum components C3 and C5 during complement activation. These fragments are called anaphylatoxins because their ability to stimulate mast cell histamine release, smooth muscle contraction, and increased vascular permeability may lead to a fatal reaction resembling anaphylactic shock in experimental animals. In addition, the C5a molecule, which is a glycoprotein, is perhaps the most potent of all humoral chemoattractants for polymorphonuclear leukocytes. Most of the structural analyses in this study were performed on the desArg 74 form of human C5a (C5adesArg). C5adesArg represents a natural form of C5a that is recovered from activated serum when no inhibitors are added to block the action of serum carboxypeptidase. The complete primary structure of the human C5a polypeptide portion is reported here. A partial characterization of intact human C5a has been previously reported (Fernandez, H. N., and Hugli, T. E. (1976) J. Immunol. 117, 1688--1694). The polypeptide portion of C5a contains 74 amino acids, accounting for a molecular weight of 8,200 while the carbohydrate portion accounts for approximately 3,000. The carbohydrate portion of C5a exists as a single complex oligosaccharide unit attached to an asparagine at position 64. An unusual feature of the C5a molecule is its large content of half-cystine, which accounts for more than 9% of its total residues. Two repeating Cys sequences occur in the linear structure and 6 of the 7 half-cystines in C5a are located at nearly identical positions to those in the human C3a molecule. In fact, sequence similarities between C3a and C5a indicate their common genetic ancestry. The role of C5a and C5adesArg as chemotactic factors prompted comparisons of their structural features with those of the chemotactically active formyl-Met peptides (Schiffman E., Corcoran, B. A., and Wahl, S. M. (1975) Proc. Natl. Acad. Sci. U.S.A. 72, 1059--1062). Removal of the COOH-terminal arginyl residue from C5a reduces chemotactic activity; therefore, the terminal portion of this molecule appears to play an active role in stimulating leukocyte migration. Hence the COOH-terminal sequence of C5a was examined for structural similarities to that of the formyl-Met peptides. Since methionine assumes a special functional importance in the formyl-Met peptides, attention is focused on the single methionyl residue in C5a. This methionyl residue, located near the COOH terminus of the molecule, may play an active role in the functional expression of C5a as a chemotactic factor. Although human and pig C3a show a close structural and functional relationship to C5a they lack the ability to excite leukotaxis, and this difference may correlate with the absence of a methionyl residue near the COOH terminus of C3a.

Amino Acid Sequence↗
PubMed1986

Complement activation in haemodialysis: a comparison of new and re-used dialysers.

The magnitude of leucopenia and complement activation when reusing cellulose based (Cuprophan) and synthetic (polyacrylonitrile AN-69S) haemodialysis membranes as well as their modifications by the priming of the dialysers with fresh frozen plasma and by the introduction of a period of stagnation during haemodialysis were studied using radioimmunoassay (C3a), centrifugal analysis (C3d), immunochemical (C3, Factor B) and functional (CH50 and alternate pathway) assays. Our findings demonstrate that complement activation and leucopenia induced by Cuprophan are linked and are modified when the membrane is reused, or primed with plasma protein. However, chemical exposure during reuse to sodium hypochlorite modifies these observations. Reuse of the AN-69S membrane resulted in no modification of either leucopenia or complement activity, but this membrane consistently demonstrated lower levels of C3a than observed with either first use or reused Cuprophan membranes.

Acrylic Resins↗
PubMed1993

Beta2 integrins are required for neutrophil degranulation induced by hemodialysis membranes.

An untoward consequence of hemodialysis is degranulation of peripheral blood neutrophils. The mechanisms that mediate this process, however, have not been conclusively identified. In the present study, the participation of complement activation and beta 2 integrins (CD11/CD18) in hemodialysis-induced neutrophil degranulation was investigated. Incubation of neutrophils with cuprophan membrane stimulated the release of very small amounts of the cytoplasmic granular protein, elastase. This release was markedly enhanced by the addition of plasma. Inactivation of complement reduced degranulation by approximately 60%, but the contribution of anaphylatoxins C3a and C5a to the degranulation process was modest. Treatment of plasma with EDTA completely abolished neutrophil degranulation in the presence of cuprophan membrane. Further, when incubated with plasma and cuprophan membrane, neutrophils that are deficient in beta 2 integrins released only 10% as much elastase as normal cells. Together, these observations strongly suggest that one or more members of the beta 2 integrin family of receptors is essential for cuprophan membrane-induced neutrophil degranulation and that both complement-related and noncomplement-related factors serve as receptor ligands.

Cations, Divalent↗
PubMed1976

Role of purine N-3 in the biologic activities of poly(A) and poly(I).

Poly(c3A) (poly 3-deazaadenylic acid) and poly(c3I) (poly 3-deazainosinic acid) differ in biological reactivity from their parent compounds poly(A) and poly(I) and from their 7-deaza counterparts poly(c7A) and poly(c7I). Three parameters of biological reactivity were evaluated : (1 degree) interferon induction, (2 degrees) anti-complement activity, (3 degrees) reverse transcriptase inhibition. Unlike poly(A)-poly(U), poly(I)-poly(C) and poly(I)-poly(br5C), the mixtures of poly(c3A) + POLY(U), poly(c3I) + poly(C), and poly(c3I) + poly(br5C) failed to elicit an interferon response in "super-induced" primary rabbit kidney cells; Poly(I) and its analogs poly(c3I) and poly(c7I) inhibited hemolytic complement activity, whereas poly(A) and its analogs poly(c3A) and poly(c7A) failed to do so. Both poly(I) and poly(c7I), but not poly(c3I), lost their anti-complement potency when annealed to either poly(C) or poly(A)-poly(U). Similarly, poly(I) and poly(c7I), but not poly(c3I), suppressed the interferon inducing ability of poly(A)-poly(U), suggesting that both poly(I) and poly(c7I), but not poly(c3I), added to poly(A)-poly(U) to form a triple-helical structure. Poly(I), poly(C7I) and poly(c7A)exerted a distinct inhibitory effect on turine leukemia virus, while under the same conditions poly(c3I) and poly(c3A) showed little, if any, inhibitory effect.

Animals↗
PubMed1991

Complement activation in diabetes mellitus.

To see whether or not there is complement activation in patients with diabetes mellitus, we investigated the plasma concentrations of C4, C3, C4a, C3a and SC5b-9 in either juvenile or adult onset insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients at least 2 years after diagnosis. C4, C3, SC5b-9 plasma levels were not significantly different in IDDM and NIDDM patients than in age-matched controls. Anaphylatoxin peptide conversion product C4a, but not C3a, was found significantly higher in adult-onset IDDM patients than in patients with juvenile onset IDDM, NIDDM patients and age-matched controls. Complement activation did not appear to be correlated with the metabolic control, nor the duration of disease nor the presence of circulating antibodies (including islet cells (ICA), insulin (IA), thyroid microsomal (TMA), and thyroglobulin (TGA)). Although there are many factors that may trigger complement activation, we found the highest levels of C4a in elderly subjects (both diabetics and control subjects) and particularly in those who had clinically detectable vascular complications.

Adolescent↗
PubMed2002

The structural basis of compstatin activity examined by structure-function-based design of peptide analogs and NMR.

We have previously identified compstatin, a 13-residue cyclic peptide, that inhibits complement activation by binding to C3 and preventing C3 cleavage to C3a and C3b. The structure of compstatin consists of a disulfide bridge and a type I beta-turn located at opposite sides to each other. The disulfide bridge is part of a hydrophobic cluster, and the beta-turn is part of a polar surface. We present the design of compstatin analogs in which we have introduced a series of perturbations in key structural elements of their parent peptide, compstatin. We have examined the consistency of the structures of the designed analogs compared with compstatin using NMR, and we have used the resulting structural information to make structure-complement inhibitory activity correlations. We propose the following. 1) Even in the absence of the disulfide bridge, a linear analog has a propensity for structure formation consistent with a turn of a 3(10)-helix or a beta-turn. 2) The type I beta-turn is a necessary but not a sufficient condition for activity. 3) Our substitutions outside the type I beta-turn of compstatin have altered the turn population but not the turn structure. 4) Flexibility of the beta-turn is essential for activity. 5) The type I beta-turn introduces reversibility and sufficiently separates the two sides of the peptide, whereas the disulfide bridge prevents the termini from drifting apart, thus aiding in the formation of the hydrophobic cluster. 6) The hydrophobic cluster at the linked termini is involved in binding to C3 and activity but alone is not sufficient for activity. 7) beta-Turn residues Gln(5) (Asn(5))-Asp(6)-Trp(7)(Phe(7))-Gly(8) are specific for the turn formation, but only Gln(5)(Asn(5))-Asp(6)-Trp(7)-Gly(8) residues are specific for activity. 8) Trp(7) is likely to be involved in direct interaction with C3, possibly through the formation of a hydrogen bond. Finally we propose a binding model for the C3-compstatin complex.

Amino Acid Sequence↗
PubMed1975

Circular dichroism of C3a anaphylatoxin. Effects of pH, heat, guanidinium chloride, and mercaptoethanol on conformation and function.

Circular dichroism spectra for C3a anaphylatoxins (protein fragments generated enzymatically in serum during activation of the third component of complement (C3)) from human and porcine sources were compared in the region of 190 to 250 nm. The spectra were indistinguishable in this region, although an estimated difference of approximately 20% exists between the primary structures of human and porcine C3a. Calculations indicated a total of 40 to 45% alpha helical content based on either the 208 or 222 nm extremum of the CD spectra. Addition of either mercaptoethanol or 6 M guanidinium chloride to human C3a produced a marked decrease in the mean residue ellipticity centered at 222 nm without irreversibly affecting the biological activity. Simultaneous addition of mercaptoethanol and guanidinium chloride virtually eliminated the CD contribution at 222 nm and resulted in more than 90% inactivation of the anaphylatoxin. Removal of the denaturant and reducing agent restored both the biological activity and the CD spectrum of C3a. Heat treatment or reduction and alkylation of human C3a produced biologically inactive and conformationally modified anaphylatoxin. In contrast, C3a inactivated by enzymatic removal of the COOH-terminal arginyl residue was structurally unchanged as judged by CD measurements. Consequently, it is proposed that in addition to the essential COOH-terminal arginyl residue, a highly ordered conformation is required for biological functionality of the C3a molecule.

Animals↗
PubMed1990

[The histologic study of the inner ear in guinea pigs on anaphylatoxin].

Complement is known to relate to many inflammatory reactions. C4a, C3a and C5a, known as anaphylatoxins, are known to cause strong inflammatory reactions. In this study, the role of anaphylatoxins on the pathogenesis in the cochlea was examined. On hundred forty six male Harley guinea pigs, weighing about 350 grs, all susceptible to preyer's reflex, were used in this study. Anaphylatoxins were made from guinea pig serum treated with zymosan, and inoculated into the carotid artery of the guinea pigs. Parts of these animals were sacrificed and examined at ten minutes, one day, two days, three days, seven days, ten days and fifteen days after injection of anaphylatoxins. Pathological changes in inner ears were observed by light microscopy. After 10 minutes, inner ears were found morphologically normal. After one day, inner ears were found to be almost morphologically normal but the stria vascularis was observed with cystic formation. After two days, cystic formations in the stria vascularis were enlarged and Reissner's membranes were collapsed in some other animals. After three days, the stria vascularis in the various cochlear turns except in the basal turn, were extremely atrophied, some cochlear nerves showed degeneration and some cochlea showed endolymphatic hydrops. After seven days, ten days and fifteen days, the morphological changes showed atrophy in the stria vascularis similar to the results observed on the third days. Atrophy in the stria vascularis was improved gradually with time, but the degeneration of the cochlear nerve was not improved. Opinions have been divided on the cause of inner ear disease including Meniere's disease. Many authors have reported that infectious diseases, for example mumps, measles and cytomegalovirus infection, have caused human sensorineural hearing loss. These diseases have been reported to result in atrophy in the stria vascularis, degeneration of the cochlear nerve and some other pathological changes. In this study, it was clearly observed that the atrophy of the stria vascularis, the endolymphatic hydrops and other morphological changes were caused by introduction of anaphylatoxins. These results were similar to the pathological changes observed in inner ear diseases in human beings. Therefore, inflammatory substances, including anaphylatoxins, were closely related to the cause of inner ear diseases. The animal model used in this report is considered to be important for elucidating the pathogenesis of inner ear diseases.

Anaphylatoxins↗
PubMed1989

The role of the complement system in the pathogenesis of multiple organ failure in shock.

The results of our experiments suggest that the development of MOF is the result of a concerted autodestructive inflammatory process affecting the endothelium which is probably triggered off by the complement system. The combination of two noxious events (application of a low dose of endotoxin during hemorrhagic shock) leads to an enormous intravasal activation of complement including formation of C5a and the deposition of active split products of C3 (C3a, C3b) in the tissue of lung, liver, small intestine and kidney. Histological examination revealed ARDS-like pulmonary changes with inflammatory microvascular lesions and granulocytic infiltration primarily in the liver and to a lesser degree in the intestines and the kidney. The severity of organic lesion closely correlated with the extent of complement deposited. This corroborates the clinical observation that pulmonary and hepatic lesions are always the first signs of MOF, no matter what kind of noxious influence (trauma or peritonitis) gave rise to its development (Mc Menamy, 1980). Which mechanisms are involved in the processes by which active split products of C3 cause damage to tissue? C3a possesses strong chemotactic forces which can bring about aggregation of granulocytes in the tissue. Deposition of C3b on the contrary may lead to the formation of the cytolytically active membrane-attack-complex with the result of direct cell damage. We did not find any severe organic lesion or deposition of complement in our controls (endotoxin only, hemorrhage only). Our results suggest that MOF is a sequel of a generalized, autodestructive, inflammatory process which results from a hyperintensive and uncontrolled humoral immunoresponse to noxious events.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylatoxins↗
PubMed2004

Proteases of the complement system.

The complement system is a group of about 35 soluble and cell-surface proteins which interact to recognize, opsonize and clear or kill invading micro-organisms or altered host cells (e.g. apoptotic or necrotic cells). Complement is a major part of the innate immune system. Recognition proteins such as C1q, MBL (mannan-binding lectin) and ficolins bind to targets via charge or sugar arrays. Binding causes activation of a series of serine protease proenzymes, such as C1r, C1s and MASP2 (MBL-associated serine protease 2), which in turn activate the atypical serine proteases factor B and C2, which then activate the major opsonin of the system, C3. Activated C3 binds covalently to targets, and is recognized by receptors on phagocytic cells. Two of the complement proteases, factors D and I, circulate not as proenzymes, but in activated form, and they have no natural inhibitors; their substrates are transient protein complexes (e.g. C3bB and C3bH) which form during complement activation. Factor B and C2 also have no natural inhibitor; they are active only when proteolytically cleaved and bound in an unstable, short-lived complex with C3b or C4b. C1r, C1s and the MASPs, in contrast, are regulated more conventionally by the natural serpin, C1-inhibitor. Complement proteases in general have very narrow specificity, and low substrate turnover with both natural and synthetic substrates. Excessive activation of complement is inflammatory, and causes tissue damage (e.g. in rheumatoid arthritis, or in ischaemia/reperfusion injury). Substances that regulate complement activation are likely to be useful in the regulation of inflammation. Complement activation might potentially be controlled at many different steps. Much attention has been focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a (containing activated factor B and C2 respectively), as these generate the inflammatory peptides C3a and C5a.

Complement Activation↗