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The complement system helps clear pathogens from an organism. It is derived from many small plasma proteins that form the biochemical cascade of the immune system. The actions of the complement system affect both innate immunity and acquired immunity. Activation of this system leads to cytolysis, chemotaxis?, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis?.


The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage. The complement proteins are synthesized mainly by hepatocytes; however, significant amounts are also produced by monocytes, macrophages, and epithelial cells in the gastrointestinal and genitourinary tracts. Three biochemical pathways activate the complement system: the classical complement pathway, the alternate complement pathway, and the [Mannan-binding lectin (MBL)]? pathway.[1] [2]

The complement system influence the activity of numerous cells, tissues and physiological mechanism of the body. These effects may involve either the whole complement, or only individual components or fragments. Activation of the complement cascade, with the formation of the effector MAC unit, results in cytotoxic and cytolytic reactions. Target cells for MAC action may be heterologous erythrocytes, nucleated cells (autologous or foreign), bacteria (Gram-negative, susceptible to serum), microscopic fungi, viruses with a surface envelope and virus-infected cells.

The result of cytotoxic complement reaction may be beneficial for the body (elimination of the infectious agent or damaged cells) or harmful (damage to autologous normal cells by immunopathological reactions).

Different fragments, released from individual components during complement activation, operate by a non-cytolytic mechanism through specific receptors present on various cell types. The direction and intensity of the biological response depend on the state of the receptors (affinity and density) and on the function of cells bearing receptors. From the functional standpoint, complement receptors can be divided into two types: the adherent type and the other receptors. Adherent receptors mediate adherence of cells and other particles with bound C3b or C4b fragments and are known as CR1 to CR5. Adherence reaction mediated through the CR receptors on phagocytes lead to stimulation of phagocytosis, activation of metabolism and secretory function and movement of phagocytes into the inflammatory site. These receptors, present on the other cells of the immune system, are involved in a variety of immunoregulatory reactions. CR1 on erythrocytes may bind circulating immune complexes (that had activated complement) and transport them to the liver where the immune complexes are partially degraded and thus become more soluble.

The second group of receptors reacts with small complement fragments (C4a, C3a, C5a) as well as with C1q, Ba, Bb and factor H. Stimulation of these receptors results in various biological effects (chemotaxis, secretion of vasoactive amines, mediators of the inflammatory and anaphylactic reaction etc.). The main functions of the complement cascade and its role in the acute inflammatory reaction are summarized in Table 1.

Increase of vascular permeability; Smooth muscle contraction; Degranulation of mast cells and eosinophils C5a, C3a, C5a-desArg, C4a
Neutrophil activation and chemotaxis; Stimulation of prostaglandin and leukotriene production C5a, C5a-desArg
Opsonization of bacteria and immune complexes leading to phagocytosis C3b, C4b
Stimulation of the respiratory burst of professional phagocytes C3a, C5a-desArg,C1q
Lysis of bacteria and foreign cells C5b678(9)n
Solubilization of circulating immune complexes C3b, CR1

Table 1: The biological functions of complement and its role in the acute inflammatory reactions

Complement and Inflammation

The complement system is a potent mechanism for initiating and amplifying inflammation. This is mediated through fragments of complement components. To the most well-defined fragments belong anaphylatoxins. Anaphylatoxins are proteolytic products of the serine proteases of the complement system: C3a, C4a and C5a. They are polypeptides containing approximately 75 amino acid residues and meet all the criteria which characterize local hormones. The C-terminal arginine in the molecule of C3a is of fundamental importance for its biological activity. As soon as arginine is removed, the biological activity disappears completely. In the case of C5a, the removal of C-terminal arginine (C5a ) only decreases its biological activity.

The production of anaphylatoxins follows not only from complement activation, but also from activation of other enzyme system which may directly cleave C3, C4 and C5. Such enzymes include plasmin, kallikrein, tissue and leukocyte lysosomal enzymes, and bacterial proteases.

The anaphylatoxins have powerful effects on blood vessel walls, causing contraction of smooth muscle and an increase in vascular permeability. These effects show specific tachyphylaxis (i.e. repeated stimulation induces diminishing responses) and can be blocked by antihistamines; they are probably mediated indirectly via release of histamine from mast cells and basophils. C5a is the most powerful, approximately 100 times more effective than C3a, and 1000 times more effective than C4a. The smooth muscle contraction in the lungs is primarily mediated by LTC and LTD. This activity decrease in the following order:


C5a is extremely potent at stimulating neutrophil chemotaxis, adherence, respiratory burst generation and degranulation. C5a also stimulates neutrophils and endothelial cells to express more adhesion molecules. Ligation of the neutrophil C5a receptor is followed by mobilization of membrane arachidonic acid which is metabolized to prostaglandins and leukotrienes including LTB, another potent chemoattractant for neutrophils and monocytes. Following ligation of monocyte C5a receptors, IL-1 is released. Thus the local syntesis of C5a at sites of inflammation has powerful pro-inflammatory properties.

At the same time, C3b and C4b fragments act as opsonins enhancing phagocytosis. In addition to inducing phagocytosis, ligation of complement receptors on neutrophils, monocytes and macrophages may also stimulate exocytosis of granules containing powerful proteolytic enzymes, and free radical production through the respiratory burst.

Classical pathway

The classical pathway is triggered by activation of the C1-complex (which consists of one molecule C1q and two molecules C1r and C1s), either by C1q's binding to antibodies from classes M and G, complexed with antigens, or by its binding C1q to the surface of the pathogen. This binding leads to conformational changes in C1q molecule, which leads to the activation of two C1r (serine protease) molecules. Then they cleave C1s (another serine protease). The C1-complex now binds to and splits C2 and C4, producing C2b and C4b. The inhibition of C1r and C1s is controlled by C1-inhibitor. C4b and C2a bind to form C3-convertase (C4b2a complex). Production of C3-convertase signals the end of the Classical Pathway, but cleavage of C3 by this enzyme brings us to the start of the Alternative Pathway.

Alternative pathway

The alternative pathway is triggered by C3 hydrolysis directly on the surface of a pathogen. It does not rely on a pathogen-binding protein like the other pathways. In the alternative pathway, C3 is split into C3a and C3b. Some of the C3b is bound to the pathogen where it will bind to factor B, this complex will then be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb. In other words, after hydrolysis of C3, C3b complexes to become C3b2a3b, which cleaves C5 into C5a and C5b. C5a and C3a are known to trigger mast cell degranulation. C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane ("punches a hole") to initiate cell lysis. Furthermore, products of C3 and C5 enhance neutrophil phagocytosis, that is, they are chemokines.

Lectin pathway

The lectin pathway is homologous to the classical pathway, but with the opsonin, [mannan-binding lectin (MBL)]? and ficolins, instead of C1q. This pathway is activated by binding mannan-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which can then split C4 and C2 into C4b and C2b. C4b and C2b then bind together to form C3-convertase, as in the classical pathway.

Recently it has been shown that [mannan-binding protein (MBP)]? is the main opsonin in the human blood serum. This was confirmed by observations on infants with recurrent infections due to opsonin deficiency. All such children were found either to lack MBP, or to have very low concentrations of the lectin. MBP has been found to initiate complement-mediated lysis of mannan-coated erythrocytes and this lysis requires the presence of the classical pathway complement component C4, but not C1q. This new lectin pathway of complement activation is important not only for the killing of microorganisms through the interaction of carbohydrates on their surfaces and MBP or other collectins (humoral lectins found in humans and other mammals) but also for the opsonizing activity.

Shock and Tissue Injury

The complement cascade also interacts with other triggered-enzyme cascade: coagulation, kinin generation and fibrinolysis. There is another connection between these systems: the regulatory protein, C1 inhibitor, inhibits not only C1r and C1s but also Factor XIIa of the coagulation system, kallikrein of the kinin system and plasmin of the fibrinolytic cascade.

Under some circumstances the consequences of complement activation in vivo may be deleterious rather than beneficial. The state of shock that may follow bacteraemia with Gram-negative organisms may, in part, be mediated by complement, which is extensively activated by endotoxin. The large quantities of C3a and C5a which result from this cause activation and degranulation of neutrophils, basophils and mast cells. These anaphylatoxins may stimulate intravascular neutrophil aggregation leading to clothing and deposition of emboli in the pulmonary microvasculature. At this site neutrophil products, including elastase and free radicals, may cause the condition of shock lung. This condition is characterized by interstitial pulmonary oedema due to damage to small blood vessels, exudation of neutrophils into alveoli, and arterial hypoxaemia. Extracorporeal blood circulation, for example through heart-lung bypass machines, or over cuprophane dialysis membranes, may similarly cause activation of complement, accompanied by transient leukopenia, thought to be caused by aggregation of neutrophils in the lungs.

Tissue injury following ischaemic infarction may also cause complement activation. Abundant deposition of membrane attack complex may be readily seen in tissue following ischaemic injury. A possible pathophysiological role for complement activation following tissue ischaemia was demostrated in experimental models of myocardial infarction: complement depletion reduced the size of tissue injury and infusion of soluble CR1 has recently been shown to have a similar effect.

Role in disease

It is thought that the complement system might play a role in many diseases with an immune component, such as Alzheimer's disease, asthma, lupus erythematosus, various forms of arthritis, autoimmune heart disease and multiple sclerosis.

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly meningitis).

Complement mediates inflammation by two major pathways:

  • by activated leukocytes, which are attracted to sites of immune complex deposition by locally-produced anaphylatoxins C5a and C5a and which bind to C3b and C4b fixed to the immune complexes;
  • by the [membrane attack complex (MAC)]?, which cause cell lysis and thus stimulates prostaglandin synthesis from arachidonic acid, mobilized from perturbed cell membranes.

These two mechanisms of damage are well exemplified by considering two types of glomerular disease. Autoantibodies to glomerular basement membrane cause inflammation which can be inhibited by either complement depletion or by neutrophil depletion. In contrast, membranous nephritis, (which may be induced experimentally by antibodies to subepithelial antigens), is unaffected by neutrophil depletion, but almost totally abrogated in animals deficient in C5. In this disease the basement membrane is presumed to act as a physical barrier to neutrophil exudation, so that the heavy proteinuria is caused by deposition of membrane attack complex.

The activation of complement by [immune complex]? is normally beneficial. Immune complexes bearing C3b are efficiently removed from tissues and from the circulation by monocytes and other phagocytes. However there are circumstances in which immune complex production continues at a high level; complement activation by immune complexes may then prove deleterious. Such complexes may form in tissues, for example in glomeruli of patients with autoantibodies to glomerular basement membrane (Goodpasture's syndrome) or at motor end-plates in patients with autoantibodies to acetylcholine receptors (myasthenia gravis). Alternatively, immune complexes may become trapped in blood vessel walls having travelled trough the circulation. This occurs, for example in systemic lupus erythematosus, and in bacterial endocarditis in which an infected heart valve provides the source of immune complexes which deposit in the kidney and other microvascular beds.

Secretor state and complement levels (C3 and C4) in insulin dependent diabetes mellitus

Blackwell CC, Weir DM, Patrick AW, Collier A, Clarke BF Diabetes Res 1988 Nov;9(3):117-119 Department of Bacteriology, University of Edinburgh, Medical School, UK.

Lower levels of C3 and C4 components of the complement system have been reported for patients with insulin dependent diabetes mellitus (IDDM) but not among those with non-insulin dependent diabetes (NIDDM). We have found a significantly higher proportion of patients who are non-secretors of the ABO blood group antigens among patients with IDDM but not among those with NIDDM. As the gene that controls secretion of these antigens is in the same linkage group as that for the C3 complement component, we compared the levels of C3 and C4 of patients with IDDM by secretor state. The mean level of C3c for 45 non-secretors (75.2 IU/ml) was significantly lower than that found for 59 secretors (86.4 IU/ml) (p less than 0.025). The level of C4 among non-secretors (77.1 IU/ml) was also significantly lower than that of secretors (96.3 IU/ml) (p less than 0.025). The significance of these observations is discussed.




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