There are three pathways of complement activation:

1. Classical pathway: This is an antibody dependent pathway. Pathway is triggered by the antigen–antibody complex formation

 2. Alternative pathway: This is an antibody independent pathway, triggered by the antigen directly

3. Lectin pathway: This is a recently described pathway. It resembles classical pathway, but it is antibody independent.

Stages of complement activation

There are four main stages in the activation of any of the complement pathways.

1. Initiation of the pathway

 2. Formation of C3 convertase

3. Formation of C5 convertase

4. Formation of membrane attack complex (MAC).

All the three pathways (Fig. 1) differ from each other in their initiation till formation of C3 convertase. Then, the remaining stages are identical in all the pathways.

Fig1. Activation of C1 (initiation step of classical complement pathway).

Classical Pathway

 Classical pathway is antibody dependent. However, not all antibodies can bind to complements of classical pathway. Decreasing order of ability of antibodies to fix complement is—IgM (most potent) > IgG3 > IgG1 > IgG2. The other classes of antibodies do not fix complements. CH 2 domain on IgG, CH 4 on IgM participate in complement binding. The classical pathway begins with activation of C1 and binding to antigen–antibody complex.

Initiation

The first step is the binding of C1 to the antigen–antibody complex (Fig.1).

* The first binding portion of C1 is C1q, which reacts with the Fc portion of IgM or IgG bound to antigen

* C1q is a hexamer having six globular heads each acting as a combining site

* Effective activation of classical pathway begins only when C1q is attached to the Fc portion of antibody by at least two of its globular binding sites

- IgM being pentameric, has five Fc regions, hence one molecule of IgM can initiate the pathway

- Whereas IgG is monomeric, therefore two IgG molecules are needed to initiate the process. Hence, IgM is much efficient stimulator of classical pathway.

* C1q binds in presence of calcium ions, which in turn activates sequentially C1r followed by C1s.

Formation of C3 Convertase

Activated C1s acts as an esterase (C1s esterase), which can cleave C4 to produce C4a (an anaphylatoxin), and C4b which binds to C1 and participates further in complement cascade.

* C14b in the presence of magnesium ions cleaves C2 into C2a, which remains linked to complement complex, and C2b (has kinin like activity), which is released outside

* C14b2a is referred to as C3 convertase of the classical pathway.

Formation of C5 Convertase

 C3 convertase hydrolyses many C3 molecules into two fragments: C3a (an anaphylatoxin) and C3b which remains attached to C14b2a to form C14b2a3b complex, which acts as C5 convertase of classical pathway.

Formation of Membrane Attack Complex

This phase begins with C5 convertase cleaving C5 into C5a (an anaphylatoxin, released into the medium) and C5b, which continues with the cascade.

* C5b is extremely labile, gets stabilized by binding soon with C6 and C7 to form C5b67 followed by addition of C8

* The hydrophobic regions on C7 and C8 help in penetration into the target cell membrane

* This inserted membrane complex (C5b678) has a catalytic property to bind to C9 molecule and then it polymerizes the C9 into a tubular channel of 10 nm diameter

* Penetration of C9 causes formation of channels or pores on the target cell membrane

* Each tubular channel behaves hydrophobic outside, but hydrophilic inside; thus allowing free passage of ions and water into the cell leading to cellular swelling and lysis

* Because C5b6789 destroys the target cell by attacking the cell membrane; it is called membrane attack complex (MAC) and the process of cytolysis is referred to as complement-mediated cytotoxicity (Figs 2 and 3).

Fig2. Formation of membrane attack complex.

Fig3. The complement pathways.

Alternative Pathway

 Alternative pathway (Fig. 3) is independent of antibody; hence is considered as a part of innate immunity. It also goes through the four stages; but differs from the classical pathway in first two stages. Unlike the classical pathway which involves all complement components from C1 to C9; in alternative pathway three complement components C1, C4 and C2 are not involved. Instead, it requires three other complement proteins present in serum named factor B, factor D and properdin.

Initiation

 The alternative complement cascade is initiated by various cell surface constituents that are foreign to the host, e.g. bacterial endotoxin (Table 1).

Table1. initiators of alternative pathway.

The first complement component to be involved in alternative pathway is free C3 in the serum. C3 hydrolyzes spontaneously, to generate:

* C3a which diffuses out and

* C3b fragment which attaches to foreign cell surface antigen.

Formation of C3 Convertase

* In the next step, Factor B binds to C3b coated foreign cells

* Factor D, another alternative pathway complement factor, acts on factor B, and cleaves it into Ba (diffuses out) and Bb (remains attached)

* C3bBb is also called C3 convertase of alternative pathway

- C3bBb has a very short half-life of 5 minutes. If it is stabilized by another complement protein called properdin its half-life is increased to 30 minutes.

The remaining two stages, i.e. formation of C5 convertase and formation of membrane attack complex are identical to that of classical pathway.

Lectin Pathway

Lectin pathway is another complement pathway of innate immunity described recently, that works independent of antibody.

* It is mediated through lectin proteins of the host that interact with mannose residues present on microbial surface; hence the name lectin pathway

* Among the four stages, the first stage differs from classical pathway

* Lectin pathway involves all complement components used for classical pathways except C1 (i.e. from C2 to C9); Instead of C1, host lectin protein called mannose binding lectins mediate the first ‘initiation’ stage (see Fig. 3).

Initiation

Antigens that activate lectin pathway are the mannose carbohydrate residues of glycoproteins present on microbial surfaces.

* A specific host lectin protein called mannose binding lectins (MBL) bind to mannose residues on microbial surface

* MBL is an acute phase reactant protein, similar to C1q in structure

* After binding of MBL to microbial surface, another host protein called MBL-associated serine protease (MASP) gets complexed with MBL

* MASP is similar or C1r and C1s and mimics their functions

* The remaining three stages are similar to the classical pathway

* The MBL–MASP complex cleaves C4 which in turn splits C2 and the MBL/MASP-C4b2a acts as C3 convertase.

Important differences between the three complement pathways are summarized in Table 2.

Table2. Differences between the three complement pathways.

اخر الاخبار

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المزيد

مواضيع ذات صلة

Mechanisms of innate immunity

Immunologic Manifestations of Viral, Rickettsial, and Mycoplasmal Diseases

Immunologic Manifestations of Fungal Diseases

The Structure of Antibodies

Myelomas and Monoclonal Antibodies

Telling the Difference Between Foreign and Self

The Basic Adaptive Immune Response

The Immunoglobulin Domain and Variations

Deficiencies of the Immune Response

Hypersensitivity

Cytokines

Complement Deficiencies and Pathogen Evasion