Complement system
The Complement System (Complete Notes)
Definition
The complement system is a group of more than 30 plasma proteins
and cell-surface proteins that work together with antibodies and
immune cells to protect the body against infections. Most complement
proteins are produced by the liver and circulate in the blood in an
inactive form (zymogens).
When activated, they trigger a cascade of reactions that:
Destroy microorganisms.
Promote inflammation.
Enhance phagocytosis.
Remove immune complexes and dead cells.
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Functions of the Complement System
1. Opsonization
C3b coats microorganisms, making them easier for neutrophils and
macrophages to engulf.
2. 🔥 Inflammation
C3a and C5a increase vascular permeability and attract inflammatory
cells.
C5a is a powerful chemotactic factor for neutrophils.
3. 💥 Cell lysis
C5b–C9 form the Membrane Attack Complex (MAC), which creates
pores in microbial cell membranes, causing cell death.
4. 🧹 Clearance of immune complexes
Helps remove antigen-antibody complexes from the bloodstream.
5. 🦠 Defense against infections
Particularly important against Gram-negative bacteria.
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Pathways of Complement Activation
There are three pathways, but all converge at C3 activation.
1. Classical Pathway
Trigger:
Antigen-antibody complexes (mainly IgG or IgM).
Sequence:
1. Antigen binds antibody.
2. C1 is activated.
3. Activation of C4 and C2.
4. Formation of C3 convertase (C4b2a).
5. C3 is split into C3a and C3b.
6. Formation of C5 convertase.
7. Formation of the MAC (C5b–C9).
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2. Lectin Pathway
Trigger:
Mannose-binding lectin (MBL) binds mannose on microbial surfaces.
Sequence:
MBL activates MASP proteins.
Cleavage of C4 and C2.
Forms the same C3 convertase (C4b2a) as the classical pathway.
Continues to MAC formation.
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3. Alternative Pathway
Trigger:
Direct activation by microbial surfaces (e.g., bacteria, fungi, viruses),
without antibodies.
Sequence:
1. Spontaneous activation of C3.
2. Factor B binds C3b.
3. Factor D cleaves Factor B.
4. Forms C3 convertase (C3bBb).
5. Amplifies C3 activation.
6. Forms C5 convertase.
7. Ends with MAC formation.
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Final Common Pathway
All three pathways produce:
C3 convertase → splits C3 into C3a and C3b.
C5 convertase → splits C5 into C5a and C5b.
C5b combines with C6, C7, C8, and C9 to form the Membrane Attack
Complex (MAC).
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Major Complement Components and Their Functions
Component Function
C1 Starts the classical pathway
C2, C4 Form C3 convertase (classical/lectin pathways)
C3 Central component of all pathways
C3a Promotes inflammation (anaphylatoxin)
C3b Opsonization and formation of C5 convertase
C5a Powerful chemotaxis and inflammation (anaphylatoxin)
C5b Initiates MAC formation
C6–C9 Complete the Membrane Attack Complex
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Membrane Attack Complex (MAC)
Components: C5b + C6 + C7 + C8 + multiple C9 molecules.
Function:
Forms pores in the cell membrane.
Causes osmotic lysis of microbes.
Especially effective against Gram-negative bacteria, such as Neisseria
meningitidis.
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Regulation of the Complement System
To prevent damage to the body's own cells, complement activity is
tightly regulated by proteins such as:
C1 inhibitor (C1-INH).
Factor H.
Factor I.
CD55 (Decay-Accelerating Factor, DAF).
CD59 (Protectin) – prevents MAC formation on host cells.
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Clinical Importance
Complement Deficiencies
C3 deficiency: Recurrent severe bacterial infections.
C5–C9 deficiency: Increased susceptibility to Neisseria infections.
C1 inhibitor deficiency: Causes hereditary angioedema.
DAF/CD59 deficiency: Associated with Paroxysmal nocturnal
hemoglobinuria.
Excessive Complement Activation
Can contribute to:
Autoimmune diseases (e.g., Systemic lupus erythematosus).
Glomerulonephritis.
Tissue injury during inflammation.
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Summary Flow
Classical pathway (Ag–Ab complex)
⬇️
Lectin pathway (MBL binds mannose)
⬇️
Alternative pathway (microbial surface)
⬇️
C3 convertase
⬇️
C3 → C3a + C3b
⬇️
C5 convertase
⬇️
C5 → C5a + C5b
⬇️
MAC (C5b–C9)
⬇️
Microbial cell lysis
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Key Exam Points (20 Marks)
The complement system consists of over 30 proteins that enhance
innate and adaptive immunity.
Three pathways activate complement: classical, lectin, and alternative.
C3 is the central component of all pathways.
C3b is the main opsonin.
C3a and C5a are anaphylatoxins that promote inflammation.
C5a is the most potent chemotactic factor for neutrophils.
MAC (C5b–C9) causes direct lysis of target cells.
Mnemonic 🧠
"3 C's of Complement"
C3b = Coats microbes (opsonization)
C5a = Calls neutrophils (chemotaxis)
C5b–9 = Creates pores (MAC)