Download Kuby Immunology 6/e - Dr. Jennifer Capers, PhD

Chapter 6
The Complement System
Dr. Capers
Kindt • Goldsby • Osborne
Kuby IMMUNOLOGY
Sixth Edition
Chapter 7
The Complement System
Copyright © 2007 by W. H. Freeman and Company
Complement System

Major effector branch of humoral immune
system in vertebrates
○ However, invertebrates possess proteins related to
complement system
○ Even sea urchins have complement
Functions of Complement

7 Functional Categories:
○ Initiate complement components
○ Enzymatic mediators
○ Membrane binding (opsonins)
○ Inflammatory mediators
○ Membrane attack proteins
○ Complement receptor proteins
○ Regulatory proteins
Components of Complement

Soluble proteins and glycoproteins
 Synthesized mainly by liver hepatocytes and
other cell types
 5% of serum globulins
○ Circulate as inactive proenzymes – proteolytic
cleavage removes inhibitory fragment and
exposes active site
Components of Complement

Designated by numerals, letter symbols,
or trivial names
○ Examples: C1-C9, factor D, homologous
restriction factor

Peptide fragments made by activation
 “a” for smaller fragment – C3a
 “b” for larger fragment – C3b

Complexes with enzymatic activity have
bar on top – C4b2a
Complement Activation

Early steps – resulting in C5
○ Can occur by 3 pathways:
 Classical
 Alternative
 Lectin

Final steps leading to membrane-attack
complex (MAC) are identical in all 3
pathways
Classical Pathway

Antibody Dependent
○ Activated by Ag-Ab complex (most commonly
IgM and IgG)
○ Early stages involve C1, C2, C3, and C4
Classical Pathway

What C1 looks like
Classical Pathway
Classical Pathway
Classical Pathway
Classical Pathway
Classical Pathway
Alternative Pathway

Antibody-Independent
 Component of innate immune system
 Early stages involve C3, factor B, factor D,
and properdin

Initiated by cell surface constituents
foreign to host
○ For example – Gram- and Gram+ bacteria
Alternative Pathway
Lectin Pathway

Antibody-Independent
○ However, proceeds more like classical
pathway
- Uses C4 and C2

Activated by binding of mannose-binding
lectin (MBL) to mannose residues on
glycoproteins or carbs on surface of
microorganisms
Membrane Attack Complex (MAC)
Forms pores in cell membrane
 Ions and small molecules can freely
pass through pores
 Cell cannot maintain osmotic stability

Regulation
Components are capable of attacking
host cells
 Components undergo spontaneous
inactivation if they are not stabilized with
other components
 C3 convertase is major amplification
step in all 3 pathways

○ Regulatory proteins are present that control
C3 convertase
Biological Consequences of
Complement Activation

Amplifies humoral response and causes
it to be an effector response
○ Lyse cells
○ Participate in inflammatory response
○ Opsonization of antigen
○ Clearance of immune complexes
Cell Lysis
MAC and lyse broad spectrum of cells
 Gram+ bacteria generally more resistant
because of thick peptidoglycan
 Some have developed ways to evade
MAC

Mediating Inflammation

Cleavage products of complement
components mediate inflammation
○ Smaller fragments bind to basophils and mast
cells
○ C3a and C5a (anaphylatoxins) induce smooth
muscle contraction and increase vascular
permeability
Opsonization

C3b and C4b have opsonizing activity –
cause phagocytosis
Viral Neutralization

Binding of antibody and complement to
viruses blocks attachment to susceptible
host cells
Clearing of Immune Complexes


Tissue damage can
result from build up of
immune complexes
C3b coats immune
complexes
○ RBC have capability of
binding C3b coated
complexes and carrying
them to liver and spleen
to be cleared
○ Deficiencies with any of
complement may result
in improper binding of
C3b and loss of clearing
may occur