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
2. Cell lysis
Functions 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. Bacterial lipopolysaccharide

3. Fungal cell walls

COMPLEMENT 4. Yeast

5. Viruses

CASCADE 6. Virally infected cells

7. Tumor cell lines

8. Some parasites
Antibody-Independent
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
Thank you for listening!