Definition

The complement cascade is an essential component of the innate immune system, a series of biochemical reactions involving a group of proteins called complement proteins.
These proteins play a critical role in defending the body against pathogens, enhancing the ability of antibodies and phagocytic cells to clear microbes and damaged cells, and promoting inflammation.

Functions of the Complement Cascade:

Opsonization
- C3b coats pathogens, enhancing their recognition and uptake by phagocytes.
Chemotaxis and Inflammation
- C3a and C5a recruit immune cells to the site of infection and increase vascular permeability.
Direct Killing
- The MAC lyses target cells, especially Gram-negative bacteria.

There are three main pathways for complement activation, each initiated by distinct mechanisms but converging at the activation of C3

Triggered by antigen-antibody complexes (immune complexes).
Involves complement protein C1, which binds to the Fc region of antibodies (IgG or IgM) attached to a pathogen.
Leads to activation of C2 and C4, eventually forming C3 convertase, which cleaves C3 into C3a and C3b.

Initiated by mannose-binding lectin (MBL) or ficolins binding to carbohydrates on the pathogen’s surface.
Similar to the classical pathway, it activates C2 and C4 to form C3 convertase.

Activated directly on microbial surfaces in the absence of antibodies.
Involves spontaneous hydrolysis of C3, stabilizing C3 convertase on pathogen surfaces via factors B, D, and properdin.

C3 Convertase: Central to all pathways; cleaves C3 into C3a (an anaphylatoxin that promotes inflammation) and C3b (an opsonin that marks pathogens for phagocytosis).
C5 Convertase: Converts C5 into C5a (a potent inflammatory mediator) and C5b, which initiates the membrane attack complex (MAC).
Membrane Attack Complex (MAC): Composed of C5b, C6, C7, C8, and multiple C9 proteins, forming a pore in the pathogen’s membrane, leading to cell lysis.

To prevent damage to host tissues, the complement cascade is tightly regulated by proteins such as:
- Factor H and Factor I: Regulate the alternative pathway.
- CD55 (DAF) and CD59: Protect host cells by inhibiting C3 convertase and MAC formation, respectively.
- Dysregulation of the complement cascade can lead to autoimmune diseases, chronic inflammation, or increased susceptibility to infections.

The classical pathway begins when an antibody (IgG or IgM) binds to an antigen on the surface of a pathogen, forming an antigen-antibody complex.
The C1 complex (composed of C1q, C1r, and C1s) binds to the antigen-antibody complex.
C1q recognizes and binds to the Fc region of the antibodies, activating C1r and C1s.
C1s cleaves C4 into C4a and C4b and C2 into C2a and C2b.
C4b binds to the pathogen surface, while C2a associates with C4b to form the C3 convertase enzyme complex (C4b2a).
The C3 convertase (C4b2a) cleaves C3 into C3a and C3b.
C3a acts as a chemoattractant, recruiting neutrophils and macrophages.
C3b binds to the pathogen’s surface, facilitating opsonization and enhancing phagocytosis
The C5 convertase is formed by the association of C3b with C4b2a.
C5 convertase cleaves C5 into C5a and C5b.
C5a acts as a potent inflammatory mediator, recruiting and activating neutrophils and other immune cells.
C5b initiates the assembly of the membrane attack complex (MAC).
C5b sequentially interacts with C6, C7, C8, and C9, forming the MAC complex.
The MAC inserts into the pathogen’s cell membrane, forming pores that cause osmotic imbalance and cell lysis.
Components C3a and C5a act as anaphylatoxins, promoting inflammatory responses by increasing vascular permeability and recruiting immune cells.
C3b also functions as an opsonin, binding to the pathogen’s surface and enhancing phagocytosis by macrophages and neutrophils.