The Complement system

What is the complement system?

The complement system consists of serum and cell surface proteins that interact with one another and with other molecules of the immune system in a highly regulated manner to generate products that function to eliminate microbes.

What are key features of the complement system?

• The complement system is activated by microbes and by antibodies and lectins that are bound to microbes and other antigens.

• Activation of the complement involves the sequential proteolysis of proteins to generate enzyme complexes with proteolytic activity. Proteins that acquire proteolytic enzymatic activity by the action of other proteases are called zymogens.

• Several of the biologically active cleavage products of complement activation become covalently attached to microbial cell surfaces, to antibodies bound to microbes and other antigens and to apoptotic bodies.

What is the classical pathway?

The classical pathway is primarily activated by antigen-antibody complexes, linking the complement system to adaptive immunity.

Explain the classical pathway.

1. Initiation:

• The classical pathway is triggered when C1q, a component of the C1 complex (C1q, C1r, and C1s), binds to the Fc region of antibodies (typically IgG or IgM) that are attached to antigens.

• C1q binding activates C1r, which in turn activates C1s.

2. Formation of C3 Convertase:

• Activated C1s cleaves C4 into C4a and C4b.

• C4b binds to the pathogen or immune complex surface and interacts with C2, which is then cleaved by C1s into C2a and C2b.

• C4b and C2a combine to form the C3 convertase of the classical pathway (C4b2a).

3. C3 Activation:

• The C3 convertase cleaves C3 into C3a and C3b.

• C3b binds to the pathogen surface, acting as an opsonin, and also contributes to the formation of the C5 convertase.

4. Terminal Pathway:

• The C5 convertase cleaves C5 into C5a and C5b.

• C5b initiates the assembly of the membrane attack complex (MAC), involving C6, C7, C8, and multiple copies of C9, leading to lysis of the pathogen.

What is the lectin pathway?

The lectin pathway is activated by pattern recognition receptors (PRRs) that bind to microbial carbohydrates, making it part of the innate immune response.

Explain lectin pathway.

• The lectin pathway begins when mannose-binding lectin (MBL) or ficolins bind to specific carbohydrate patterns (e.g., mannose or N-acetylglucosamine) on the surface of pathogens.

• MBL or ficolins are associated with MASPs (MBL-associated serine proteases, MASP-1 and MASP-2), which are activated upon binding.

2. Formation of C3 Convertase:

• Activated MASP-2 cleaves C4 into C4a and C4b, and C2 into C2a and C2b.

• C4b2a forms the C3 convertase of the lectin pathway.

3. C3 Activation:

• The C3 convertase cleaves C3 into C3a and C3b, amplifying the response and opsonizing the pathogen.

4. Terminal Pathway:

• Similar to the classical pathway, the lectin pathway leads to the formation of the C5 convertase, cleavage of C5, and assembly of the MAC.

What is the alternative pathway?

The alternative pathway is spontaneously activated and relies on the presence of pathogens to amplify the complement response. It is a critical part of innate immunity and does not require antibodies.

Explain the alternative pathway

Spontaneous Activation:

• In the fluid phase, C3 undergoes low-level spontaneous hydrolysis to form C3(H2O).

• Factor B binds to C3(H2O) and is cleaved by Factor D into Ba and Bb.

• C3(H2O)Bb acts as a fluid-phase C3 convertase, cleaving additional C3 into C3a and C3b.

2. Formation of Surface-Bound C3 Convertase:

• C3b binds to pathogen surfaces and interacts with Factor B, which is cleaved by Factor D to form C3bBb, the C3 convertase of the alternative pathway.

• Properdin (Factor P) stabilizes the C3bBb complex on the pathogen surface, enhancing its activity.

3. Amplification Loop:

• The alternative pathway amplifies the production of C3b, regardless of which pathway (classical, lectin, or alternative) initiated complement activation.

4. Terminal Pathway:

• The alternative pathway also forms the C5 convertase (C3bBbC3b), leading to the cleavage of C5 and the formation of the MAC.