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Chapter 7
The Complement System
Dr. Capers
Kindt • Goldsby • Osborne
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
Functions of Complement
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
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
 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
○ However, proceeds more like classical
- Uses C4 and C2
Activated by binding of mannose-binding
lectin (MBL) to mannose residues on
glycoproteins or carbs on surface of
Membrane Attack Complex (MAC)
Forms pores in cell membrane
 Ions and small molecules can freely
pass through pores
 Cell cannot maintain osmotic stability
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
Mediating Inflammation
Cleavage products of complement
components mediate inflammation
○ Smaller fragments bind to basophils and mast
○ C3a and C5a (anaphylatoxins) induce smooth
muscle contraction and increase vascular
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
○ 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