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PubMed2026

The complement system in inflammatory bowel disease: from early observations to emerging frontiers.

PURPOSE OF REVIEW: The complement system is one of the most evolutionarily conserved arms of innate immunity and has re-emerged as an important regulator of intestinal inflammation in inflammatory bowel disease (IBD). Early observations from the mid-1970 s such as complement deposition in diseased bowel tissue and elevated serum complement levels in patients with ulcerative colitis and Crohn's disease have evolved into a nuanced understanding of how individual complement components can exert both protective and pathogenic effects in IBD. This review highlights recent advances in complement biology and examines how complement shapes intestinal immune responses, particularly in the setting of ongoing inflammation. RECENT FINDINGS: The complement system consists of more than 60 proteins that act as rapid first responders to infection. Although traditionally considered primarily liver-derived circulating effectors, recent work has demonstrated local synthesis and activation of key complement components at mucosal sites, including the colon. In parallel, genome-wide association studies have identified variants in complement genes associated with severe IBD complications. Collectively, these findings reveal a dichotomous role for complement in IBD, whereby excessive activation promotes inflammation, while impaired function compromises host defense and worsens disease outcomes. SUMMARY: Complement-targeted therapies have been effective in other diseases but have not yet translated to IBD. A deeper understanding of context-dependent protective versus pathogenic complement functions will be essential for developing future therapeutic strategies.

Humans↗
PubMed1995

Complement biosynthesis in the central nervous system.

Complement is an important effector arm of the human immune response. Binding of proteolytic fragments derived from activation of complement by specific receptors leads to responses as diverse as inflammation, opsonization, and B-cell activation. The importance of characterizing the expression and regulation of complement in the CNS is highlighted by growing evidence that complement plays a significant role in the pathogenesis of a variety of neurological diseases, such as multiple sclerosis and Alzheimer's disease. In vitro studies have demonstrated that astrocytes, the predominant glial cell type in the brain, are capable of expressing or producing a majority of the components of the complement system. Expression of many complement proteins synthesized by astrocytes is regulated by both pro- and anti-inflammatory cytokines, many of which are also produced by several cell types in the CNS. In addition to astrocytes, ependymal cells, endothelial cells, microglia, and neurons have recently been shown to synthesize various complement proteins or express complement receptors on their cell surfaces. Together, these studies demonstrate that several cell types throughout the brain have the potential to express complement and, in many cases, increase expression in response to mediators of the acute phase response. These studies suggest that complement may play a greater role in CNS immune responses than previously thought, and pave the way for better understanding of the dynamics of complement expression and regulation in vivo. Such understanding may lead to therapeutic manipulation of complement host defense functions in a variety of inflammatory and degenerative diseases in the CNS.

Acute-Phase Reaction↗
PubMed1986

Elimination of terminal complement complexes in the plasma membrane of nucleated cells: influence of extracellular Ca2+ and association with cellular Ca2+.

Nucleated cells, unlike erythrocytes, are able to survive limited complement attack by eliminating potentially cytolytic complement channels from the plasma membrane (PM) by processes that involve, plasma membrane (PM) by processes that involve, but may not be limited to, endocytosis. The observation that C5b-9 channels, as well as C5b-8 and C5b-7 intermediates, are rapidly eliminated from the cell surface of nucleated cells has prompted us to examine whether terminal complement complexes stimulate membrane events that lead to accelerated elimination of these complexes. We have suggested previously that ion flux through terminal complement complexes might influence the rate of elimination on the basis of our finding that terminal complement complexes with larger functional channel sizes are more rapidly eliminated. In this study, we examined the role of Ca2+ on the elimination rate of terminal complement complexes in the PM of Ehrlich cells, because changes in Ca2+ flux across the PM are known to influence many metabolic activities including endocytosis. To determine the elimination rate for terminal complement complexes by functional analysis, cells bearing C5b-7 or C5b-8 complexes with or without a sublytic dose of C9 were incubated at 37 degrees C for various time intervals before converting the remaining complexes to lytic C5b-9 channels. The initial elimination rates for the terminal complement complexes were compared in the presence of 0.015, 0.15, and 1.5 mM CaCl2 in the medium. Sufficient lowering of the extracellular Ca2+ concentration, (Ca2+)o, resulted in prolonging the elimination of each of the terminal complement complexes to a different extent. The effect of (Ca2+)o on the elimination rate was most pronounced for C5b-8 in the presence of a sublytic number of C5b-9, with less of an effect on C5b-8 alone, and the least effect with C5b-7. The elimination rates for terminal complement complexes were also determined by measuring the persistence of C5b antigen on the cell surface at 37 degrees C in the presence of various (Ca2+)o by using fluorescence-activated cell sorter analysis and were comparable with that obtained by functional analysis. Examination of the effect of terminal complement complexes on the cellular Ca2+ concentration, (Ca2+)i, revealed that these complexes increased the (Ca2+)i in proportion with the known functional pore size of the terminal complement complex in the PM. In addition, Quin 2, which can buffer internal Ca2+ transients, was found to increase the susceptibility of Ehrlich cells to lysis by C5b-9, further suggesting a relationship between the (Ca2+)i and the elimination process.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoquinolines↗
PubMedDate not supplied

Assessment of complement activation in vivo.

Hemolytic assays that measure the functional integrity of the complement system and the quantitation of individual components by immunochemical techniques have been widely used in the past for the assessment of in vivo complement activation. However, the complement system comprises a large number of interacting serum proteins which are subject to independent synthetic and catabolic processes. The fact that complement proteins are rapidly metabolized under in vivo conditions adds to the complexity of complement analysis. Assays that are based on monoclonal antibodies with specificities for activation-dependent neoepitopes now allow the direct determination of complement fragments in plasma. These methods are superior to the quantitation of native proteins. Several parameters that differentially affect the generation or the catabolism of individual complement activation products still have to be taken into account when elevated plasma levels of complement fragments suggest in vivo complement activation. These factors include the binding to complement fragment receptors, the degradation by serum proteases and renal or hepatic clearance. An accurate estimation of complement activation in vivo requires the simultaneous determination of both the native components and the activation products.

Animals↗
PubMed2002

Therapeutic inhibition of the early phase of complement activation.

The complement system is a key component of innate immunity against invading pathogens. However, undesired activation of complement is involved in inflammation and associated tissue damage in a number of pathological conditions, such as ischemia/reperfusion injury, autoimmune diseases, and rejection of allo- and xenografts. During recent years, various therapeutically active complement inhibitors have been developed. In vivo studies using these inhibitors underscored the value of complement inhibition in the prevention of tissue damage. The currently available complement inhibitors mainly target the effector phase of the complement system that is common to all three activation pathways. Such a complete block of complement activation breaks the innate anti-microbial barrier, thereby increasing the risk for infection. Therefore, the development of potent complement inhibitors that interfere in the recognition phase of a specific complement activation pathway will generate important novel possibilities for treatment. The present review is focused on molecules that are able to inhibit the function of C1q and MBL, the recognition units of the classical pathway and the lectin pathway of complement, respectively. The potential value of these molecules for the development of therapeutically active complement inhibitors is discussed.

Animals↗
PubMed1986

Arthropathic group A streptococcal cell walls require specific antibody for activation of human complement by both the classical and alternative pathways.

The induction of acute arthritis in rats by a single intraperitoneal injection of group A streptococcal cell wall is associated with the activation of complement. We have therefore investigated the interaction of arthropathic peptidoglycan-polysaccharide complex of streptococcal cell walls and human complement. The incubation of cell wall in normal human serum results in the formation of complexes of cell wall and the C3 and C4 components of complement. Using agammaglobulinemic serum, we have further shown that the activation of complement and formation of complement-cell wall complexes absolutely requires the presence of a small quantity of specific antibody. This antibody is present in normal human immunoglobulin G and is effective as the Fab fragment (alternative pathway). Although antibodies specific for three cell wall epitopes were capable of inducing complement-cell wall complex formation by the classical complement pathway, only anti-A polysaccharide antibody (N-acetyl-D-glucosamine epitope) was effective by the alternative complement pathway. A complement consumption assay showed that anti-cell wall antibody was required not only for complement-cell wall complex formation, but also for activation of complement by streptococcal cell wall in human serum. These studies suggest that a minimal level of anti-cell wall antibody may be required for the induction of arthritis in rats by streptococcal cell wall.

Adult↗
PubMed1992

The effects of aortic reconstruction and collagen impregnation of Dacron prostheses on the complement system.

Complement activation has been associated with numerous clinical hazards such as platelet aggregation, adult respiratory distress syndrome, and renal dysfunction. The complement system is activated by exposure of different biomaterials to blood. Recently a watertight knitted Dacron aortic prosthesis impregnated with bovine collagen has been developed. One potential disadvantage is that this bovine collagen may activate the complement system and evoke the production of inflammatory mediators. We conducted a prospective randomized trial to study the systemic effects of collagen-impregnated prostheses and of aortic surgery with implantation of Dacron prosthesis on the complement system in the perioperative period and at 3 months after operation. Forty-one patients randomly received either a collagen-impregnated (n = 20) or a nonimpregnated prosthesis (n = 21). Twelve patients who had cholecystectomy served as controls. CH50 consumption and C3a generation were determined to study overall complement activation. Furthermore, C3a/C3 fractions were calculated. Finally, C4 and factor B consumption were determined to evaluate the complement stimulation via the classic and the alternative pathways, respectively. We found significant activation of the complement system during the operation in both the collagen group (CH50 consumption: 40%, p = 0.03; C4 consumption: 74%, p < 0.0001; factor B consumption: 73%, p < 0.0001; C3a/C3 fraction increase: 173%,p = 0.04), and the nonimpregnated group (CH50 consumption: 40%, p < 0.0001; C4 consumption: 71%, p < 0.0001; factor B consumption: 76%, p < 0.0001; C3a/C3 fraction increase: 165%, p = 0.025), with no statistically significant differences between the groups of prostheses. Activation was initiated via both the classic and the alternative pathway. This indicates aortic implantation significantly activates the complement system, but that collagen-impregnated prostheses do not stimulate the complement system any more than its nonsealed substrate. Comparing results in patients with vascular disease with controls, a significantly increased complement activation was observed in the vascular group (CH50 consumption: 40%, p < 0.0001; C4 consumption: 74%, p < 0.0001; factor B consumption: 75%, p < 0.0001; C3a/C3 fraction: 169%, p = 0.002), compared with the controls (CH50 consumption: 71%; C4 consumption: 104%; factor B consumption: 94%; C3a/C3 fraction: 119%, all p = NS), with statistical significant differences between the vascular group and cholecystectomies (CH50: p = 0.005; C4: p = 0.002; factor B: p < 0.0001, and C3a/C3 fraction: NS). This observation demonstrates that aortic surgery with the implantation of a Dacron prosthesis significantly activates the complement system.

Adult↗
PubMed1984

Inherited complement deficiencies.

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Blood Donors↗
PubMed1990

Complement activation by individual and combinations of monoclonal antibodies to Actinomyces viscosus T14V fimbriae: a probe for epitope distribution on these polymeric proteins.

The spatial requirements for IgG activation of the classical complement pathway has provided a basis for utilizing complement consumption by individual and pairs of monoclonal antibodies (mAbs) to compare the repeating epitope patterns of the type 1 and type 2 fimbriae of Actinomyces viscosus T14V and to examine the co-operative effects of mAbs against these polymeric proteins. Three of five mAbs specific for the type 1 fimbriae consumed complement when assayed individually. Four patterns of complement consumption were detected with pairs of these mAbs: inhibition, addition, enhancement or synergy. Inhibition occurred when both members of a pair reacted with the same epitope but only one consumed complement. A strictly additive effect was observed if both mAbs consumed complement and, in addition, recognized the same epitope. Complement consumption by mAbs against certain epitopes was enhanced by non-complement consuming mAbs that reacted with different epitopes. Synergy was observed with extremely low concentrations of two mAbs each of which reacted with a different epitope and consumed complement. In contrast to the anti-type 1 mAbs, only one of seven mAbs against the type 2 fimbriae consumed more than 20% of the available complement. Pairs of anti-type 2 mAbs exhibited only inhibition or synergy. The latter effect was particularly striking as pairs containing mAbs that reacted with different epitopes and failed to consume complement or were minimally active when assayed individually were extremely efficient. These data indicated that the spatial arrangements of individual mAbs bound to repeating epitopes in the type 1, but not the type 2, fimbriae were appropriate for activation of complement. Thus, the repeating epitope patterns of the two types of fimbriae apparently differ.

Actinomyces↗
PubMed1995

Human CD59 expressed in transgenic mouse hearts inhibits the activation of complement.

Porcine-to-human xenotransplantation offers a potential solution to the critical shortage of human organs. The major immunological barrier to xenotransplantation between these species is a rapid rejection process mediated by preformed natural antibodies and complement. Xenogeneic organ grafts are especially susceptible to complement mediated injury because complement regulatory proteins, which ordinarily protect cells from inadvertent injury during the activation of complement, function poorly in regulating activation of heterologous complement. Removal of xenoreactive antibodies or systemic inhibition of complement activity has been shown to prolong graft survival. As an alternative to the systemic inhibition of complement activity, we have established a model system using transgenic animals to test whether the expression of human membrane bound complement regulatory proteins on mouse endothelial cells can inhibit the activation of human complement. CD59, which acts at the terminal stage of complement activation by inhibiting the formation of the membrane attack complex, was used as a paradigm for this model. A CD59 construct containing the putative CD59 gene promoter linked to the CD59 coding region was used to demonstrate expression of the human CD59 protein in various tissues of transgenic mice, including endothelial cells in the heart. In addition, we show that the transgenic CD59 protein is biologically active as determined by the ability to inhibit the formation of membrane attack complex in transgenic mouse hearts perfused ex vivo with human plasma. These results demonstrate that expression of membrane bound complement regulatory proteins can achieve complement inhibition in a xenogeneic organ and suggest that this approach may be useful for successful xenotransplantation between discordant species.

Animals↗
PubMed1985

The hereditary and acquired deficiencies of complement.

The identification of hereditary and acquired complement deficiencies in humans has led to a better understanding of the biologic importance of the complement system in immunity and autoimmune disease. Although the understanding of the relevance of complement in the pathogenesis of disease is incomplete, several characteristic clinical syndromes associated with complement deficiencies have been recognized and should be known to the practicing clinician. In allergic diseases, one need recognize the C1 inhibitor deficiency syndromes which can present as severe, recurrent angioedema in childhood or in the adult as recurrent angioedema in association with a lymphoid malignancy or autoimmune disease. Complement analyses allow one to readily diagnose C1 inhibitor deficiency in angioedema. Correct diagnosis is critical because safe effective therapy is available. Chronic urticaria is also uncommonly associated with complement deficiencies, particularly acquired C1q deficiency. Again, effective therapy for hypocomplementemic urticarial vasculitis and C1q deficiency is available and differs significantly from the usual management of chronic urticaria. Homozygous and acquired deficiencies of C3 are associated with severe immune deficiency and recurrent infections with gram-positive and gram-negative bacteria. Recurrent meningococcemia and gonococcemia are being identified frequently in patients with a deficient membrane attack mechanism relating to deficiency of C5, C6, C7, or C8. Nearly one third of the patients developing meningococcemia may have an associated complement deficiency indicating the importance of complement determinations in understanding the treatment and prognosis for these patients. Deficiency of almost every complement component has been reported in association with one or more rheumatic diseases, particularly systemic lupus erythematosus. Extensive studies of C2 deficiency and limited studies of C4 deficiency indicate that these components of the classical pathway of complement are important in preventing the development of SLE or are linked to other genes predisposing to SLE. The clinical presentations of SLE in association with C2 or C4 deficiency are relatively uniform. The patients exhibit typical skin manifestations suggestive of SLE and DLE and often exhibit antibodies to SSA (Ro). The association of complement deficiencies with clinical syndromes is important for today's physician. The syndromes and deficiencies described here are the beginning of an expanding knowledge relating to the pathobiology of complement in human disorders.

Angioedema↗
PubMed1997

Leishmania, macrophages and complement: a tale of subversion and exploitation.

Leishmania are intracellular protozoan parasites which reside primarily, if not exclusively, in host mononuclear phagocytes. Several studies have demonstrated that infectious promastigotes rapidly and efficiently fix complement when they encounter serum components during their transmission to the mammalian host. Activation of the complement system by a microorganism can have 3 distinct biological effects. First, fixation of the terminal complement components can result in complement-mediated lysis. Second, fixation of the 3rd component of complement can lead to opsonization of the organism for uptake by phagocytic cells. Finally, the elaboration of the complement anaphylotoxins, C3a and C5a, can lead to inflammation. In the present chapter, we discuss the interaction of leishmania promastigotes with the complement system. We show that infectious promastigotes avoid the lytic effects of complement and resist fixation of the terminal complement components. At the same time, however, these organisms depend on fixation of opsonic complement to invade host mononuclear phagocytes efficiently. We discuss the mechanisms which allow metacyclic leishmania promastigotes to exploit the opsonic properties of complement and the receptors on macrophages involved in leishmania recognition. The role of complement mediated inflammatory processes in the host response to leishmania infection is an area which requires additional study.

Animals↗
PubMed2006

On-chip complement activation adds an extra dimension to antigen microarrays.

Antibody profiling on antigen microarrays helps us in understanding the complexity of responses of the adaptive immune system. The technique, however, neglects another, evolutionarily more ancient apparatus, the complement system, which is capable of both recognizing and eliminating antigen and serves to provide innate defense for the organism while cooperating with antibodies on multiple levels. Complement components interact with both foreign substances and self molecules, including antibodies, and initiate a cascade of proteolytic cleavages that lead to the covalent attachment of complement components to molecules in nanometer proximity. By refining the conditions of antibody profiling on antigen arrays we made use of this molecular tagging to identify antigens that activate the complement system. Antigen arrays were incubated with serum under conditions that favor complement activation, and the deposited complement C3 fragments were detected by fluorescently labeled antibodies. We used genetically C3-deficient mice or inhibition of the complement cascade to prove that the technique requires complement activation for the binding of C3 to features of the array. We demonstrate that antigens on the array can initiate complement activation both by antibody-dependent or -independent ways. Using two-color detection, antibody and complement binding to the relevant spots was measured simultaneously. The effect of adjuvants on the quality of the immune response and binding of autoantibodies to DNA with concomitant complement activation in the serum of mice suffering from systemic autoimmune disease was readily measurable by this new method. We propose that measurement of complement deposition on antigen microarrays supplements information from antibody binding measurements and provides an extra, immune function-related fingerprint of the tested serum.

Animals↗
PubMed2003

Complement activation following optic nerve crush in the adult rat.

Activation of the complement cascade following peripheral nerve axotomy and following traumatic brain injury has been demonstrated in previous studies. This study investigates the temporal pattern of microglia/macrophages and complement activation following axotomy of sensory CNS neurons, using a standardized experimental crush injury of the optic nerve in adult rats. Numerous ED1-labeled macrophages were found at the lesion site and distal to the injury at 7 days post injury (dpi). Complement C3-mRNA was upregulated 2-28 days post lesion, indicating local synthesis of complement in the optic nerve. Furthermore, increased immunoreactivity (IR) for the end product of the complement cascade, the membrane attack complex (MAC), was detected along disintegrating axons co-labeled with anti-neurofilament distal to the injury. Double-labeling for microglia show MAC-immunoreactivity expressed in their immediate vicinity, indicating a key role of microglia/macrophages in complement activation. The complement regulator Clusterin was upregulated in astrocytes at the lesion site as well as in the distal portion of the injured optic nerve, suggesting activation of a defense response to endogenous complement attack. A crush injury of the optic nerve leads to complement activation at the site of lesion and along the distal portion of the nerve, as well as upregulation of the complement inhibitor Clusterin at least in astrocytes. Reactive microglial cells seem to have a key role in complement activation as a local source of C3. We suggest that the balance between complement activation and their regulators may have impact on axonal degeneration following optic nerve injury.

Animals↗
PubMed1983

Complement-activating immune deposits in systemic lupus erythematosus skin.

Immune deposits at the cutaneous basement membrane zone are a characteristic feature of systemic lupus erythematosus. Previous studies using immunofluorescent methods to detect complement components have provided evidence that some deposits contain immune complexes capable of activating complement. However, this important biologic property of complexes has not been detected or measured using functional assays, and it has not been determined whether immune deposits can activate complement at the basement membrane zone. In this study immune deposits in biopsies of lupus skin have been examined using direct immunofluorescence for the third component of complement (C3) to detect complement deposited in vivo. In addition, the deposits have been studied using the leukocyte attachment assay and indirect C3 binding immunofluorescence to detect and measure complement activation at the basement membrane zone in vitro. The results show that complement activation occurs at the basement membrane in some but not all lupus skin containing immunoglobulin deposits, that deposits differ quantitatively in their ability to activate complement, and that direct C3 immunofluorescence is a relatively insensitive method for detecting complement-activating complexes. The results provide functional evidence suggesting that immune deposits in some lupus skin are complement-activating complexes and potentially capable of activating complement at the basement membrane in vivo. Furthermore, the results suggest functional assays for evaluating complement-activating complexes may be valuable supplements to immunofluorescence in exploring the relationship between immune deposits and systemic and cutaneous disease.

Basement Membrane↗
PubMed1985

Immune immobilization of Treponema pallidum: antibody and complement interactions revisited.

The Treponema pallidum immobilization test was designed for serodiagnosis of syphilis and is dependent upon specific antibody and a heat labile component of normal serum. Investigators have shown the component to be dependent upon divalent cations and it is presumed to be complement. Experiments were performed to reevaluate the interactions of antibody and complement and the mechanism of immobilization. The loss of treponemal motility was correlated to the loss of complement activity in the reaction mixture. When motility of treponemes incubated with immune serum IgG and complement had dropped to 50% (3.4 h), 72% of the available complement had been consumed. At the same time, treponemes incubated with normal serum IgG and complement were 82% motile and only 51% of the complement had been consumed. C6 deficient rabbit serum and C4 deficient guinea pig serum were used in conjunction with immune serum IgG to determine which components of the complement cascade were necessary for immobilization. Treponemes were not immobilized by either sera. Results suggest that the heat labile factor in normal sera is complement, that both early and late components of the complement cascade are necessary, and that the reaction proceeds via the classical complement pathway. Although T. pallidum is susceptible to the actions of antibody and complement, the organisms must interact with these components for at least 2 h before immobilization will result.

Animals↗
PubMed2005

The complement system at the fetomaternal interface.

The placenta has a unique structural organization that allows fetal cells expressing paternal alloantigens to establish a peaceful cohabitation with the maternal immune system. The fetal cells are continuously exposed to the humoral and cellular components of the maternal immune system present in the maternal blood that circulates in the intervillous space and in the decidual vessels. This review deals with the role played by the complement system at the placental level both in physiological and pathological conditions of pregnancies. Complement components found in the placental tissue derive to a large extent from blood circulating in placental vessels. However, some complement components may also be produced locally by macrophages and other cell types. Deposition of complement components at tissue level is usually found in association with inflammatory diseases. This is not the case in placentae in which deposits of complement components can also be documented in physiological conditions not resulting in fetal damage. Protection of the semiallogenic human conceptus against maternal complement activation products is achieved by surface expression of complement regulators that act at different steps of the complement sequence. These complement regulators are localized in a strategic position on the surface of villous trophoblast protecting the fetus from the damage that may derive from uncontrolled complement activation. However, pathological conditions of pregnancies may lead to deposition of a higher amount of complement activation products that may exceed the protection of local complement regulators.

Animals↗
PubMed1995

Participation of the blood platelet in immune reactions due to platelet-complement interaction.

OBJECTIVE: Review of different aspects of the primary interaction of complement with blood platelets in immunological reactions and the effect on platelet activation in healthy people and patients. DATA SOURCES AND SELECTION CRITERIA: Relevant original papers and review articles mainly of the English-written literature. RESULTS: Besides their major role in hemostasis and wound healing, blood platelets are involved in immunological reactions. They are not only able to interact with IgG through Fc receptors (FcR), they also react with complement components. This review summarizes interactions of complement with mainly human platelets. Such interactions may occur through complement receptors of the plasma membrane (e.g. C1q receptor, complement receptors 2 and 4), but also in a receptor-independent way including activation of the platelet by the membrane attack complex of complement C5b-9. In addition, activation of complement at the surface of the platelets may be induced after binding of anti-platelet antibodies to membrane glycoproteins (e.g. GpIIb/IIIa, GpIb/IX) or after binding of platelet-nonspecific immune complexes via FcR. Complement activation in turn may be regulated by various means including specific plasma or membrane proteins [e.g. decay-accelerating factor (DAF), membrane cofactor protein (MCP), membrane inhibitor of reactive lysis (MIRL), C8-binding protein (C8bp, homologous restriction factor hrf)]. As a further way of self-protection against complement attack, platelets may actively release C5b-9, deposited at the surface as C5b-9-enriched membrane vesicles. CONCLUSIONS: Two lines of interaction of platelet with complement can be distinguished. On the one hand, platelets are equipped with membrane proteins which protect them from complement attack against themselves. On the other hand, membrane receptors for activated complement components as well as for IgG are expressed on the surface, which enable the platelet to intervene in immunological reactions. This property varies between platelets of different species and needs further investigation also in view of the platelet as an intersection between immunology and hemostasis.

Antigen-Antibody Complex↗