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The Complement
System
Jason Ryan, MD, MPH
Complement System
• Proteins circulating in blood stream
• Can bind to pathogens, especially bacteria
• Binding results in bacterial cell death
• Various names of proteins
[Link]
• C3, C5, C6
• C3a, C3b
 [Link]

C3
• Most abundant complement protein
• Synthesized by liver
• Can be converted to C3b
• C3b binds to bacteria → bacterial death
• All complement activation involves C3→C3b
Complement System
Membrane
Attack
Complex

[Link]

C3 → C3b → Bacteria

3 Pathways
Alternative
Classical
Lectin
 [Link]

Alternative Pathway
• C3 spontaneously converts to C3b
• C3b rapidly destroyed unless stabilized by binding
• C3b binds amino and hydroxyl groups
• Commonly found on surface of pathogens
• Surfaces that bind C3b:
• Bacterial lipopolysaccharides (LPS)
• Fungal cell walls
• Viral envelopes
C3b
• Stable C3b can bind complement protein B
• Complement protein D clips B bound to C3b
• Forms C3bBb = C3 convertase
• Result: Stable C3b can cleave more C3 → C3b
[Link]
• Rapid accumulation of C3b on surfaces

C3b

C3b C3bBb
(stable)
C3
B, D
 [Link]

Factor H
• Plasma glycoprotein synthesized in liver
• Blocks alternative pathway on host cells
• Accelerates decay of C3 convertase (C3bBb)
• Cleaves and inactivates of C3b
• Used by cancer cells and bacteria
• Allows evasion of alternative pathway
• Key pathogens:
• H. Influenza
• N. Meningitidis
• Many streptococci
• Pseudomonas
Ferreira V et al. Complement control protein factor H: the good, the bad, and the inadequate
Mol Immunol. 2010 Aug; 47(13): 2187–2197.
Lectin Pathway
• Mannose-binding lectin (MBL)
• Produced by liver → blood and tissues
• Circulates with MASPs
• Mannose associated serine proteases
• Binds surfaces with mannose (many microbes)
[Link]

• Cleaves C2 → C2b
• Cleaves C4 → C4b
• C2b4b is a “C3 convertase”
• Converts C3 → C3b
 [Link]

Classical Pathway
• Antibody-antigen complexes
• Bind C1
• Cleaves C2 → C2b
• Cleaves C4 → C4b
• C2b4b is a “C3 convertase”
• Converts C3 → C3b
C1
• Large complex
• C1q, C1r, C1s, C1-inhibitor
• Must bind to two Fc portions close together
• C1inhibitor falls off
[Link]
• C1r and C1s become active
• Create C3 convertase (C2b4b)

Cr Cs
C1i
 [Link]

C Reactive Protein (CRP)

• “Acute phase reactant”
• Liver synthesis in response to IL-6 (Macrophages)
• Can bind to bacterial polysaccharides
• Activates early classical pathway via C1 binding
• Consumes C3, C4
• Generates C3b
• Does not active late pathway
• Little consumption of C5-C9

Biro et al. Studies on the interactions between C-reactive protein and complement proteins.
Immunology. 2007 May; 121(1): 40–50.
C3a and C3b

Anaphylatoxin
Histamine Release Mast Cells
C3a Increased Vascular Permeability
[Link]

C3
C3b MAC

MΦ (opsonin)
 [Link]

Complement System
Membrane
Attack
Complex

C3 → C3b → Bacteria

Alternative
C2 → C2b C4b  C4
Spontaneous
Lectin Classic
MBL C1
Membrane Attack Complex
• Stable C3b leads to formation of the MAC
• MAC formed from C5, C6, C7, C8, C9

[Link]

Wikipedia/Public Domain
 [Link]

C5a

Anaphylatoxin
C5a Neutrophil Chemotaxis

C5
C5b MAC
Complement System
C3a, C5a
Membrane
Attack
Complex

[Link]

C3 → C3b → Bacteria

Alternative
C2 → C2b C4b  C4
Spontaneous
Lectin Classic
MBL C1
 [Link]

Inhibition of Complement
• Membrane proteins protect human cells
• Decay Accelerating Factor (DAF/CD55)
• MAC inhibitory protein (CD59)
• DAF disrupts C3b attachment
• CD59 disrupts MAC
• Especially important for protecting RBCs
• Deficiency of DAF or CD59 leads to hemolysis
PNH
Paroxysmal Nocturnal Hemoglobinuria
Binds
Nitric Oxide
Anemia RBC Lysis

Hemoglobinuria
Free plasma Hgb NO depletion
[Link]

Renal Failure
↑ Smooth Muscle
Thrombosis Tone

Erectile Dysphagia Abdominal

Dysfunction Pain
 [Link]

PNH
Paroxysmal Nocturnal Hemoglobinuria

• Classically causes sudden hemolysis at night

• Fatigue, dyspnea (anemia)
• Abdominal pain (smooth muscle tension)
• Thrombosis
• Leading cause of death
• Usually venous clots
• Unusual locations: portal, mesenteric, cerebral veins
Inherited C3 Deficiency
• Recurrent infections encapsulated bacteria
• Pneumococcal and H. flu pneumonia
• Begins in infancy
• Immune complex (IC) deposition
• IC cleared when they bind complement
[Link]
• Macrophages have complement receptors
• C3 deficiency: glomerulonephritis from IC deposition
• Other type III hypersensitivity syndromes can occur
 [Link]

C5-C9 Deficiency
Terminal complement pathway deficiency

• Like C3, impaired defense against encapsulated bugs

• Still have C3a (anaphylatoxin)
• Also have C3b (opsonin for macrophages)
• Recurrent Neisseria infections
• Most often meningitis
Hereditary Angioedema
• Deficiency of C1 inhibitor protein
• Many functions beyond complement system
• Breaks down bradykinin (vasodilator)
• Deficiency leads to high bradykinin levels
[Link]
• Episodes of swelling/edema
 [Link]

Hereditary Angioedema
• Recurrent episodes swelling without urticaria
• Begins in childhood
• Swelling of skin, GI tract, upper airway
• Airway swelling can be fatal
• Diagnosis: Low C4 level
• Lack of C1 inhibitor
• Consumption of C4
• Can treat with C1 inhibitor concentrate
ACE Inhibitors
Cough
Bradykinin Angioedema
AI

X X
ACE Inhibitors
[Link]
A2

Inactive
Metabolite

NEVER give ACE-inhibitors to patients

with Hereditary Angioedema
 [Link]

C3 Nephritic Factor
• Autoantibody
• Stabilizes C3 convertase
• Overactivity of classical pathway
• Found in >80% patients with MPGN II
• Leads to inflammation, hypocomplementemia
Hypocomplementemia
• CH50
• Patient serum added to sheep RBCs with antibodies
• Tests classical pathway
• Need all complement factors (C1-C9) for normal result
• Normal range: 150 to 250 units/mL
[Link]
• C3 or C4 level
• Low in many complement mediated diseases (consumption)
• Lupus and lupus nephritis
• MPGN
• Post-streptococcal glomerulonephritis