Complement is a heat-labile series of 18 plasma proteins, many of which are enzymes or proteinases. Collectively, these proteins are a major fraction of the beta-1 and beta-2 globulins.

The complement system proteins are named with a capital C followed by a number. A small letter after the number indicates that the protein is a smaller protein resulting from the cleavage of a larger precursor by a protease. Several complement proteins are cleaved during activation of the complement system; the fragments are designated with lower case suffixes, such as C3a and C3b. Usually, the larger fragment is designated as “b” and the smaller fragment as “a.” The exception is the designation of the C2 fragments; the larger fragment is designated C2a and the smaller fragment is C2b.

Proteins of the alternative activation pathway are called fac tors and are symbolized by letters such as B. Control proteins include the inhibitor of C1 (C1 INH), factor I, and factor H.

The complement system displays three overarching physio logic activities (Table 1). These are initiated in various ways through the following three pathways (Table 2):

Table1. Three Main Physiologic Activities of the Complement System

Table2. Initiators of Three Complement Activation Pathways

1. Classic pathway

2. Alternative pathway

3. Mannose-binding lectin pathway

The three pathways (Fig. 1) converge at the point of cleavage of C3 to C3b, the central event of the common final path way, which in turn leads to the activation of the lytic complement sequence, C5 through C9, and cell destruction (Fig. 2).

Fig1. Early steps of complement activation. The steps in the activation of the alternative, classical, and lectin pathways are shown. Note  the sequence of events is similar in all three pathways, although they differ in their requirement for antibody and in the proteins used. (From Abbas AK, Lichtman AH: Basic immunology: functions and disorders of the immune system, updated edition, ed 3, Philadelphia, 2011, Saunders.)

Fig2. Late steps of complement activation. A, The late steps of complement  activation start after the formation of the C5  convertase and are identical in the alternative and classical pathways. Products generated in the late steps induce inflammation  (C5a) and cell lysis (the membrane attack  complex [MAC]). B, The properties of the  proteins of the late steps of complement  activation are listed. (From Abbas AK, Licht man AH: Basic immunology: functions and dis orders of the immune system, updated edition, ed 3, Philadelphia, 2011, Saunders.)

Activation of Complement

Normally, complement components are present in the circulation in an inactive form. In addition, the control proteins C1 INH, factor I, factor H, and C4-binding protein (C4-bp) are normally present to inhibit uncontrolled complement activation. Under normal physiologic conditions, activation of one pathway probably also leads to the activation of another path way, as follows:

• The classic pathway is initiated by the bonding of the C1 complex, consisting of C1q, C1r, and C1s, to antibodies bound to an antigen on the surface of a bacterial cell.

• The alternative pathway is initiated by contact with a foreign surface such as the polysaccharide coating of a microorganism and the covalent binding of a small amount of C3b to hydroxyl groups on cell surface carbohydrates and proteins. The pathway is activated by low-grade cleavage of C3 in plasma.

• The mannose-binding lectin pathway is initiated by binding of the complex of mannose-binding lectin and associated serine proteases (MASP1 and MASP2) to arrays of mannose groups on the surface of a bacterial cell.

Enzyme Activation

After complement is initially activated, each enzyme precursor is activated by the previous complement component or complex, which is a highly specialized proteinase. This converts the enzyme precursor to its catalytically active form by limited proteolysis.

The pathways leading to the cleavage of C3 are triggered enzyme cascades. During this activation process, a small pep tide fragment is cleaved, a membrane-binding site is exposed, and the major fragment binds. As a consequence, the next active enzyme of the sequence is formed. Because each enzyme can activate many enzyme precursors, each step is amplified until the C3 stage; therefore, the whole system forms an amplifying cascade.

Complement Receptors

 Various cell types express surface membrane glycoproteins that react with one or more of the fragments of C3 produced during complement activation and degradation. The functions of these receptors depend on the type of cell and often are incompletely understood. Complement receptor 1 (CR1) is important in enhancing phagocytosis and CR3 is also important in these host defense mechanisms.

Plasmodium falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) on human erythrocytes. CR1 is a complement regulator and immune adherence receptor on erythrocytes required for shuttling C3bC4b-opsonized particles to the liver and spleen for phagocytosis.

Effects of Complement Activation

The activation of complement and the products formed during the complement cascade have a variety of physiologic and cellular consequences. Physiologic consequences include blood vessel dilation and increased vascular permeability. The cellular consequences include the following:

• Cell activation, such as production of inflammatory mediators.

 • Cytolysis or hemolysis, if the cells are erythrocytes. The most important biologic role of complement in blood group serology is the production of cell membrane lysis of antibody-coated targets.

• Opsonization, which renders cells vulnerable to phagocytosis.

In addition to the function of complement as a major effector of antigen-antibody interaction, physiologic concentrations of complement have been found to induce profound alterations in the molecular weight, composition, and solubility of immune complexes. The activation of complement may also play a role in mediating hypersensitivity reactions. This process may occur from direct alternative pathway activation by immunoglobulin E (IgE)–antigen complexes or through a sequence initiated by the activated Hageman coagulation factor that causes the generation of plasmin, which subsequently activates the classic pathway. In either case, activation of complement components from C3 onward leads to the generation of anaphylatoxins in an immediate-hypersensitivity reaction.

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مواضيع ذات صلة

The Complement System: Classic Pathway

Immune-Mediated Disease

Evaluation of Immunodeficiency Syndromes

Plasma Cell Biology

B Lymphocyte Subsets

Natural Killer and K-Type Lymphocytes

Antigen Recognition by T Cells

Antigen Processing and Antigen Presentation to T Cells

Cytotoxic T Lymphocytes

T Regulatory Lymphocytes

Helper T Lymphocytes

Sites of Lymphocyte Development