The complement system is a crucial component of the immune system that serves as a bridge between innate and adaptive immunity. It consists of a group of plasma proteins that circulate in an inactive form and become activated in response to infection. Once activated, the complement system works in close coordination with antibodies, phagocytic cells, and inflammatory mediators to eliminate pathogens efficiently.
The relevance of the complement system lies in its ability to recognize and destroy microbes, enhance phagocytosis through opsonization, promote inflammation, and directly kill pathogens via the Membrane Attack Complex (MAC).
While some complement pathways function independently of antibodies and provide immediate innate defense, others require antigen–antibody complexes, thereby strengthening adaptive immune responses.
1. What is the Complement System?
Definition
The complement system is a group of more than 30 plasma and membrane-bound proteins, synthesized mainly by the liver, that circulate in an inactive form (zymogens). Upon activation, these proteins complement the action of antibodies and phagocytes by enhancing pathogen clearance.
✨ One-line exam version :
The complement system is an essential part of immunity that links innate and adaptive immune responses by enhancing pathogen clearance, inflammation, and antibody-mediated defense.
Why is it called a “Cascade”?
It is described as a cascade because activation of one complement protein enzymatically activates the next, leading to rapid amplification of the immune response from a small initial trigger.
Central Component
C3 is the central molecule of the complement system.
👉 All three pathways converge at C3 cleavage, making it the most important component from an exam point of view.
2. The Three Pathways of Complement Activation (Overview)
Before the complement system can exert its effects, it must be activated. Activation occurs through three distinct pathways, classified based on how they begin.
1. Classical Pathway (Antibody-Dependent)
- Triggered by antigen–antibody complexes
- Requires IgM or IgG
- Links adaptive immunity with the complement system
2. Lectin Pathway (Antibody-Independent)
- Triggered by Mannose-Binding Lectin (MBL)
- MBL recognizes specific sugars on microbial surfaces
- Functionally similar to the classical pathway but does not require antibodies
3. Alternative Pathway (Innate Immunity)
- Activated spontaneously by the tick-over mechanism
- Does not require antibodies or lectins
- Plays a key role in early innate defense
Exam Note
👉 All three pathways converge at the cleavage of C3 into C3a and C3b.
3. Biological Functions of the Complement System (High-Yield)
When asked to “Explain the functions of the complement system,” answers should be structured around three core mechanisms.
1. Cell Lysis – The Membrane Attack Complex (MAC)
- Complement proteins C5b to C9 assemble to form the Membrane Attack Complex (MAC).
- MAC inserts into the microbial membrane and forms a transmembrane pore.
- This pore causes osmotic imbalance, leading to cell lysis.
Exam Tip:
MAC is particularly effective against Gram-negative bacteria, especially Neisseria species.
2. Opsonization – Enhanced Phagocytosis
- C3b is the major opsonin of the complement system.
- C3b coats the surface of pathogens.
- Phagocytes possess complement receptors (CR1) that bind C3b, making phagocytosis faster and more efficient.
Common Exam Question:
Which complement component acts as the major opsonin? → C3b
3. Inflammation – Role of Anaphylatoxins
- C3a and C5a are called anaphylatoxins.
- They bind to mast cells, causing histamine release.
- This leads to vasodilation, increased vascular permeability, and recruitment of immune cells.
Important Differentiation:
👉 C5a is more potent than C3a and is also a powerful chemotactic factor for neutrophils.
4. Regulation of the Complement System (Self-Protection Mechanisms)
Because the complement system is highly destructive, it must be tightly regulated to prevent damage to host tissues.
Key Regulatory Proteins
1. C1 Inhibitor (C1-INH)
- Prevents spontaneous activation of the classical pathway
- Deficiency leads to Hereditary Angioedema
2. CD59 (Protectin)
- Prevents MAC formation on host cells
- Blocks polymerization of C9
3. Decay Accelerating Factor (DAF / CD55)
- Disrupts C3 convertase on host cell surfaces
- Protects self-cells from complement attack
Quick Exam Summary
- Central molecule: C3
- Major opsonin: C3b
- Anaphylatoxins: C3a, C5a
- Most potent inflammatory mediator: C5a
- MAC components: C5b–C9
- Only positive regulator: Properdin
Thus, the complement system plays a central role in host defense, immune regulation, and immune surveillance, ensuring rapid elimination of pathogens while maintaining immune balance. Its dysfunction can lead to recurrent infections, excessive inflammation, or autoimmune disorders, highlighting its critical importance in the immune system.