Download Activation of the Alternative Pathway

Elements of the Immune System:
Complement
S. Barbour
03.31.09
Hallmarks of Complement
• Sequential Activation
• Amplification
• Regulation
Overview of Complement
Activation
(adaptive immunity)
Activation
(innate immunity)
Activation
(innate immunity)
Lectin Pathway
Alternative Pathway
Mannose-binding protein
binds pathogen surface
Pathogen surface creates
environment conducive to
complement activation
Classical Pathway
Antibody binds to specific
antigen on pathogen surface
a series of enzyme
(protease) reactions
Complement Activation
Formation of C3 and C5 convertases
Inflammatory response
Membrane Attack Pathway
Cytolysis of some pathogens
effecter function
effecter function
Opsonization & phagocytosis
of some pathogens
effecter function
Activation of
B cells
effecter function
Clearance of
immune complexes
effecter function
Complement Nomenclature
1. CX (X = 1-9); example: C5
2. Factor X (alternative pathway);
example: Factor B (B)
3. complement fragments (usually a and b);
example: C3 → C3a + C3b
Note: the “b” fragment remains surface associated;
“a” fragment is soluble
Note: “i” denotes “inactive” fragments that do not support
complement activation. However, these fragments
can have other biological functions. (eg. iC3b or C3bi)
Complement Activation
Activation of the Classical Pathway
IgG
IgM
C3 convertase
YYY
Y
Y
C3b
C3 convertase
C1
YY
C3
(IgG1, IgG2, IgG3)
C1
C3
C3b
Antigen
(bacterial or yeast cell surface)
-Note: only antigen-antibodies complexes can activate the classical pathway! Antibody
alone cannot
-Classical pathway results in formation of a C3 convertase that generates C3b
-C3b forms a covalent bond with the surface of the pathogen and is part of C5 convertase
Activation of the Alternative Pathway
(Sources of C3b)
Soluble
C3 convertase
C3
C3b
C3 convertase
C3 tickover
C3
C3b
C3b
YY
C1
covalent bond
with surface
C3b
covalent bond
with surface
“activating surface”
(bacterial or yeast cell surface)
-the alternative pathway is initiated by C3b binding to a bacterial or yeast cell surface
-C3b preferentially interacts with bacterial or yeast cells; host cells are spared
-this is a primitive distinction of self versus non-self
Activation of the Alternative Pathway
(C3 Convertase)
Soluble
C3 convertase
C3
C3b
C3b
C3
C3 tickover
C3b
C3 convertase
C3 convertase
covalent bond
with surface
“activating surface”
(bacterial or yeast cell surface)
covalent bond
with surface
-alternative pathway results in the formation of a C3 convertase that generates C3b
-C3b forms a covalent bond with the surface of the pathogen and is part of C5 convertase
Activation of the Lectin Pathway
C3b
mannan binding lectin
(MBL)
mannose
sugars
C3 convertase
C3
MBL
covalent bond
with surface
“activating surface”
(bacterial or yeast cell surface)
-mannan binding lectin (MBL) recognizes mannose sugars on microbial cells
-host mannose is hidden and is not accessible to MBL
-lectin pathway results in the formation of a C3 convertase that generates C3b
-C3b forms a covalent bond with the surface of the pathogen and is part of C5 convertase
Regulation of Complement
Importance of C3
• Activation of Classical, Lectin, and Alternative
pathways (alternative pathway is constantly activated in serum!)
• Fragments have biological activity
• Opsonization / Phagocytosis
• B cell activation
• Inflammation
• Most abundant complement protein in serum ( > 1
mg/ml)
C3 Convertases
C3
C3a + C3b
Classical / Lectin Pathway
Alternative Pathway
receptor
subunit
catalytic
subunit
C2b
receptor
subunit
catalytic
subunit
C4b
Bb
P
C3b
covalent association
with pathogen surface
Covalent association ensures that C3 convertases remain localized to the
pathogens that activate complement!
Regulation: Dissociation of the subunits or proteolysis of receptor subunit by Factor I
Regulation of C3 Convertases
Proteolysis
Dissociation
(Factor I cofactor)
Protein
Classical/
Lectin
Alternative
C4b
C3b
Factor H
-
+
-
+
C4bp
+
-
+
-
DAF
+
+
-
-
MCP
-
-
+
+
CR1
+
+
+
+
In general, regulatory proteins are expressed on host cells, but not
on pathogens. Therefore, host cells are spared from complement
attack.
Effecter Functions of Complement
The Membrane Attack
Pathway
MAC
The MAC is especially important for the immune response against
Neisseria spp. Membrane proteins (CD59, HRF) prevent MAC
formation on host cells.
Opsonization / Phagocytosis
C3b or iC3b
CR1, CR3, or CR4
opsonized bacteria
Inflammation
anaphylotoxins
C3a, C4a---increased
vascular permeability
C5a—chemoattraction
C3a, C4a----activation
Clearance of Immune Complexes
CR1
Activation of B Cells
-microbial cell expresses antigens
recognized by B cell receptor
-microbial cell is coated with C3d or
C3dg, recognized by CR2
-simultaneous binding to B cell
receptor and CR2 results in more
efficient B cell activation
or C3dg
Complement:
Disease Correlations
Disease Correlations
-deficiency in classical pathway components is associated with accumulation of immune
complexes, autoimmune diseases.
-deficiency in terminal components (components of MAC) results in increased
susceptibility to Neisseria infections.
Disease Correlations
-C1 inhibitor (C1INH) blocks the activation of C1, the complement component that
interacts with antibody in the classical pathway. Deficiency results in uncontrolled
production of anaphylotoxins
-DAF, HRF, and CD59 are lipid (GPI) linked proteins. Deficiency in production of
lipid anchors results in loss of these regulatory proteins, complement activation on host
cells
Deficiencies in Complement Receptors
• CR3, CR4
• CR3, CR4 are integrins
• Loss of these proteins compromises functions of
phagocytes (LAD)
• Result is increased susceptibility to infection
• CR1
• Most CR1 is expressed by erythrocytes
• Loss of this protein is associated with
accumulation of immune complexes
(similar to deficiencies in classical pathway
components)
Overview of Complement
Activation
(adaptive immunity)
Activation
(innate immunity)
Activation
(innate immunity)
Lectin Pathway
Alternative Pathway
Mannose-binding protein
binds pathogen surface
Pathogen surface creates
environment conducive to
complement activation
Classical Pathway
Antibody binds to specific
antigen on pathogen surface
a series of enzyme
(protease) reactions
Complement Activation
Formation of C3 and C5 convertases
Inflammatory response
Membrane Attack Pathway
Cytolysis of some pathogens
effecter function
effecter function
Opsonization & phagocytosis
of some pathogens
effecter function
Activation of
B cells
effecter function
Clearance of
immune complexes
effecter function