UNIT 1: NATURE OF

THE IMMUNE
SYSTEM

Part 7: The Complement System 

 INTRODUCTION

Complex series of >30 proteins that circulate in an inactive precursor
form until activated 


Must be activated in a specific sequence, known as a cascade

3 pathways based on activating mechanism: classical, alternative, and

lectin


Complements or enhances the role of antibody in clearing foreign

substances


Numbered in order of discovery, so sequence of activation is not in

numerical order

General Properties of Complement Proteins


• Heat labile: destroyed by heating serum for 30 minutes at 560C


• Synthesized mostly by hepatocytes 


• Designated by “C” followed by numbers and letters (ex: C2a)


• Cleavage of proteins usually generates 2 fragments:


• One is released 


• The other attaches to cell surface and continues in the reaction sequence


• Active enzymes are written with a bar over the complex (ex: C4b2a)

 1. Opsonization


Main Functions
2. Cell lysis

of Complement


3. Chemotaxis 

 • Complement proteins amplify
the inflammatory response


PROINFLAMMATORY 
 • Production of anaphylatoxins 


• Needs to be tightly controlled

by regulatory mechanisms 

CLASSICAL
COMPLEMENT
CASCADE

Antibody-Dependent

CLASSICAL PATHWAY
RECOGNITION UNIT: C1


• C1 consists of 3 subunits C1q, C1r, and

C1s
• When Ab binds to Ag, a binding site is
exposed on the Fc portion of Ab for the
C1q globular heads
• (1) C1q molecule must bind to at least (2)
Fc portions of bound Ab to initiate the
cascade
• Binding of C1q causes C1r to enzymatically
activate C1s
Classical Pathway Activation Unit: C4b2a3b


• Activated C1s has only two substrates: C4 and

C2
• C1s first cleaves C4 into C4a and C4b
• C4a goes away
• C4b binds to cell surface
• Next, C1s cleaves C2 into C2a and C2b
• C2b – “see ya, wouldn’t want 2-b ya!”
• C2a binds to C4b
• Complex written as C4b2a
• C4b2a also known as C3 convertase because it
will then cleave C3
Classical Pathway Activation Unit: C4b2a3b


• C4b2a cleaves C3


• Amplification step: up to 200 C3’s can be cleaved by one

C3 convertase 


• C3a goes away


• C3b can:


1. Bind to C4b2a


2. Go off by itself and be an opsonin


3. Initiate the alternative pathway


• If C3b binds to C4b2a, it makes C4b2a3b (C5 convertase)




Classical Pathway: Membrane Attack Complex


• C4b2a3b cleaves C5


• C5a goes away


• C5b binds near the C4b2a3b complex,

initiating formation of the MAC


• C6, C7, C8 bind next in sequential order

making C5b678


• Multiple C9’s form a channel in the cell

membrane 🡪 cell lysis


• MAC = C5b6789

THE LECTIN
PATHWAY

Antibody-Independent 

 The Lectin Pathway


• Activation begins when Mannose-Binding Lectin (MLB)

recognizes and binds to surface mannose on foreign cells
• MBL-associated serine proteases (MASP’s) are the
enzymatic equivalent of C1r and C1s in the classical pathway
• MASP-2 cleaves C4 and then C2; cascade of events is
identical to classical from here to the end
 Triggered by:

1. Bacterial cell walls

ALTERNATIVE 2.

3.
Bacterial lipopolysaccharide

Fungal cell walls

COMPLEMENT 4.

5.
Yeast

Viruses

CASCADE 
 6.

7.
Virally infected cells

Tumor cell lines

Antibody-Independent 
 8. Some parasites

The Alternative Pathway


• Molecules of C3 undergo cleavage at

continuous low levels in normal
plasma


• C3b binds to nearest target cell

surface


• Along comes Factor B


• Factor D cleaves Factor B 


• Ba goes away; Bb binds


• C3bBb is the C3 convertase of the

alterative cascade 

The Alternative Pathway

• C3bBb is stabilized by properdin


• More C3 gets cleaved


• Forms the complex C3bBb3bP = C5

convertase


• C5 gets cleaved


• Formation of MAC is the same as

classical and lectin pathways

SUMMARY

Regulation of the Complement Cascade


• Control mechanisms are necessary to regulate complement activation and control production of
biologically active split products


• First type of control is extreme lability of activated complement


• Second type of control involves specific control proteins, examples:


1. C1 inhibitor blocks activity of C1r and C1s, as well as MASP’s


2. Factor H


3. Factor I (capital letter I)


4. CD55 (decay accelerating factor)


Complement Deficiencies 


1. Major Pathway Components


• Hereditary deficiency of any component except C9 results in increased susceptibility to infection

and delayed clearance of complexes


• Infants deficient in MBL associated with pneumonia, sepsis, and meningococcal disease 


• C3 deficiency most serious, key mediator in all pathways; prone to serious life-threatening infection
and immune-complex disease


• Deficiency of terminal components causes increased susceptibility to Neisseria infections


Laboratory Detection of Complement Abnormalities 


• Automated and manual techniques can measure individual components

and regulators – quantitative analysis 


• Another type of test is to assess functional activity of the cascade; you

may have enough of all the components, but are they working properly?
These assays determine % hemolysis achieved