Complement System Overview

Complement System Overview

• Part of the innate immune system
• Found in blood plasma
• Produced in the liver

Roles of Complement

• Killing (lysis) of foreign cells
• Tagging foreign material (opsonization)
• Pro-inflammatory signalling and chemoattraction

Complement Pathways

• All pathways converge to form C3 convertase and the membrane attack complex (MAC)

Classical Pathway

• Initiated by antibody binding
• C1 Complex: Composed of C1q, C1r, and C1s. C1q binds to the Fc region of antibodies.
• Activation: Binding of two or more antibodies to antigen activates C1r and C1s. C1r cleaves C1s, which in turn cleaves C4 and C2.
• C4b binds to the bacterial surface; C2a and C2b are formed.
• C4b and C2a combine to form the classical C3 convertase (C4b2a).

Lectin Pathway

• Initiated by a lectin (e.g., mannose-binding lectin (MBL))
• MBL binds to carbohydrates, specifically mannose, on the surface of bacteria and yeast.
• MBL-associated serine protease (MASP) cleaves C4 and C2, forming the C3 convertase (C4b2a).

Alternative Pathway

• Does not require antibody or microbe to initiate
• C3 is hydrolyzed to C3(H2O)
• C3(H2O) binds to Factor B, then Factor D cleaves Factor B into Bb and Ba fragments.
• C3bBb (initial convertase) binds to C3, forming C3bBbC3b (C3 convertase)
• C3b covalently attaches to the microbial surface activating an amplification loop.

Terminal Complement Pathway

• Formation of C5 convertase:
  • From the alternative pathway: C3bBb and another C3b form C3bBbC3b (C5 convertase).
  • From the lectin/classical pathway: C4b2a and another C3b form C4b2aC3b (C5 convertase).
• C5 cleavage: C5 convertase cleaves C5 into C5a and C5b.
• C5a: A powerful anaphylatoxin that recruits and activates immune cells.
• C5b: Initiates the membrane attack complex (MAC) formation.
• MAC Assembly: C5b recruits C6, C7, C8, and multiple C9 molecules to form a transmembrane pore in the microbial membrane.
• Bacterial Death: MAC forms pores in the microbial membrane, leading to leakage of cytoplasmic contents, bacterial lysis, and cell wall instability.

Complement Function

• Opsonization: C3b and C4b tag microbes, serving as opsonins for recognition by phagocytes.
• Inflammation: Cleaved 'a' products (e.g., C3a, C4a, C5a) are anaphylatoxins that bind to receptors on immune cells, triggering inflammation (chemotaxis, vasodilation, increased vascular permeability).
• Lysis: MAC formation leads to direct lysis of invading microbes.

Complement Regulation

• Preventing self-damage: Inhibitors prevent complement activation on host cells. Immune cells present complement regulatory proteins, preventing unintended damage to healthy tissue.
• Example: CD59 on mammalian cells inhibits C5b-C8 complex formation, preventing C9 recruitment.
• Consequences of deficiency: Individuals with terminal complement deficiencies are at increased risk of recurrent infections.