Transcript File

Aims
• Describe the activation of the complement cascade via:
– Classical pathway
– Alternative pathway
• Explain how activation of the complement cascade can
impact other immunologic processes.
• Describe clinical implications of complement
deficiencies.
• Readings: Abbas & Lichtman, Chapter 8
The Complement Activation Pathways
• There are three activation pathways
– Classical - C1, C4, C2, C3
– Alternate - properdin pathway
– Mannose binding lectin or Lectin – uses MBL to
initiate the pathway
• All three activation pathways result in the
formation of C3 & C5 convertases
• They converge at a single terminal pathway
Classical Pathway
EC
RBC
antibody
bacteria
Classical Pathway
• C1 complex
– C1q has the antibody binding sites
– C1r and C1s are serine proteases
C1-Inhibitor is released upon
binding to Ab and this
activates C1r & C1s.
Roitt’s Essential Immunology 2-2
C1s
C1r
C1q
C1
C1’
C4a
C4b
C1’
C4b
C1’
C2a
C2b
C4b
C1’
C3
C4b2b
C3 Convertase
b
a
C1’
Explosive amplification
C4b2b
C3a
C3b
C1’
C5
a
b
C4b2b3b
C5 Convertase
C1’
C5a
C5b
C4b2b3b
C1’
C4b2b3b
C5b
Terminal Pathway
Na+ and H2O
K+
6
C4b2b3b
999
7
C5b
8
9
9
9 9
9
Membrane Attack Complex
Activators of the Alternative
Complement Pathway
• Anything that hydrolyzes C3
– leukocyte proteases
– plasmin
– bacteria or bacteral products (LPS, bacterial
cell wall components)
– aggregated IgA
– cobra venom factor
– Cellophane
– Water “Ticking over”
Alternative Pathway
EC
RBC
C3
bacteria
Alternative Pathway
EC
C3a
RBC
C3b
bacteria
Alternative Pathway
EC
RBC
C3b
bacteria
Alternative Pathway
Factor D
Factor B
a b C3b
bacterium
Alternative Pathway
Ba Bb
C3b
bacterium
Alternative Pathway
Properdin
C3a
C3b C3bBb
bacterium
C3 Convertase
Alternative Pathway
Roitt’s Essential Immunology 2-3
Alternative Pathway
C3 binding and cleavage is repeated over and over
(explosive amplification)
Properdin
C3a
C3b C3bBb
bacterium
Alternative Pathway
Properdin
C3bnBb
C5 Convertase
bacterium
Alternative Pathway
C5a
C5b
C3bnBb
C5 Convertase
bacterium
Terminal Pathway
Na+ and H2O
K+
6
C3bnBb
999
7
C5b
8
9
9
9 9
9
Membrane Attack Complex
Terminal Pathway
• Formation of
the MAC is
identical in
classical and
alternative
pathway once
C5 convertase
is formed.
Abbas & Lichtman’s Basic Immunology 8-6
Lectin Pathway
EC
RBC
MBL
bacteria
Mannose Binding Lectin (MBL) binds terminal mannose
residues of proteins and polysaccharides found on bacteria.
Only real difference from the classical pathway is that
MBL is substituted for C1 complex during initiation.
MBL
Terminal Mannose residues
Complement Pathway Regulation
• C3b by itself has a short half-life (ms)
• C3b inactivator (Factor H, DAF, and Factor I)
– Break apart stable structures and enzymatically cleave C3b
• C1 Inhibitor
– Regulates classical pathway by dissociating C1r and C1s from C1q
– Can also regulate Lectin pathway by dissociating components of MBL
C1’
999
9 9
7
C4b2b3b
6
C5b
8
999
Complement Pathway Regulation
• C4 binding protein
– Breaks apart C4b2b (classical C3 convertase)
• Anaphylatoxin inactivator or serum carboxypeptidase B
– Removes terminal arginine residue from C3a,C4a, and C5a.
• Vitronectin (S protein)
– Serum protein which can bind C567 preventing complete MAC formation
C1’
999
9 9
7
C4b2b3b
6
C5b
8
999
Cells with Complement Receptors
Receptor Specificity
Functions
Cell types
CR1
C3b, C4b
stimulates phagocytosis
removal of IC by RBCs
RBCs, Mf, PMN, B cells
CR2
C3b, EBV
B cell receptor complex
Epstein-Barr virus receptor
B cells
CR3
C3b
stimulates phagocytosis
Mf, PMNs
CR4
C3b
stimulates phagocytosis
Mf, PMNs
C1q
C1q
binds IC to phagocytes
B cells, Mf, platelets
endothelial cells
Complement Deficiencies
• Deficiency of early cascade members (C1,
C4, C2, and C3)
– Deficiency in opsonization
• Poor phagocytosis resulting in increased
infection with encapsulated bacteria.
• Poor clearance of IC associated with
autoimmune diseases.
Complement Deficiencies
Type I Hereditary angioedema
– Stress and trauma provoked vasodilatation and
edema usually of the skin, extremities, or GI
mucosa.
– Can be fatal if it involve larynx resulting in
asphyxiation.
– Deficiency of C1INH
• spontaneous generation of bradykinin
• spontaneous activation of C1  C4a
• production of C2a  C2a kinin
Complement Deficiencies
• Deficiency of late cascade members (C5, C6,
C7, C8 and C9)
– Deficiency in the formation of MAC
– C5, C6, C7 or C8 deficiency results in difficulty
killing gram negative bacteria (Neisseria
meningitidis)
Summary
• Complement is a group of serum proteins – activated in
an orderly fashion from inactive forms. This leads to
“spin-off” peptides that have biological activity.
• Three main activation pathways and one terminal
pathway that leads to the formation of the MAC.
• Complement activation is highly regulated.
• Possession of complement component receptors lends
cells certain biological activities through interaction
with complement.
• Deficiencies in complement components exist.
Next Lecture
• Antigen capture and presentation
• Exogenous and Endogenous antigens.
• Readings: Abbas & Lichtman, Chapter 3
Objectives
1. Describe the similarities and differences
between the 3 complement cascade activation
pathways.
1. Classical
2. Alternative
3. Lectin (Mannose Binding Lectin)
2. Describe complement regulation and
deficiencies.