Jan ew ay 9.4 9 par t 2. Roi tt 12. 22 Roi tt 4.1.
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Transcript of Jan ew ay 9.4 9 par t 2. Roi tt 12. 22 Roi tt 4.1.
The Classical Activation Pathway
Some large fragments function by binding to membranes (esp. pathogen membranes)
Some small fragments act as soluble mediators
C1sC4
Ab
C4a
C4b
C3
C3a
C5
C5a
C5b C6 C7 C8 C9
C6 C7C8 C9
MAC
Membrane
Ucker, 2003
Classical Activation Pathway
C2
C2b
C4b C2a C3b
C1
Thioester mediated binding of C4b
Pathogen
C4
C4a
C4b
THIOESTER-MEDIATED BINDING OF C4b TO THE SURFACE OF A PATHOGEN
Ucker, 2003
C4bC4b
Activation of a
C3 Convert
ase
ACTIVATION OF A C3 CONVERTASEC2
C4b
PathogenThioester-mediatedbinding to the pathogen:
Ucker, 2003
C1s C2a
C2b
C4b
C2
C4b
C4b
Thioester mediated binding of C3b
Pathogen
C3
C3a
C3b
THIOESTER-MEDIATED BINDING OF C3b TO THE SURFACE OF A PATHOGEN
Ucker, 2003
C3bC3b
Janeway 9.49
part 2 &
Mayer Figures
6,8
Relative sensitivity of nucleated and non-nucleated cells to membrane attack
C6 (relative concentration)
Ce
lls s
tain
ed
by
vita
l dye
(%
)
Time (minutes)
Ch
an
ne
ls r
em
ain
ing
(%
)
Temperature-dependent repair by nucleated cells of Complement channels
(M. Mayer 1984)
Glycan structures
N-Acetyl Glucosamine
ComplexSialylated
Fucosylated Glycan
Sialic Acid
Galactose
Mannose
Fucose
High MannoseGlycan
Ucker, 2003
Thioester mediated binding of C3b
Pathogen
C3
C3a
C3b
THIOESTER-MEDIATED BINDING OF C3b TO THE SURFACE OF A PATHOGEN
Ucker, 2003
C3bC3b
Amplification Loop
C3b B
C3bB
D
Ba
C3bBbC3
C3a
(C3 convertase)
C3
C3
One C3 convertase molecule cleaves many C3 molecules.
Properdin stabilization
C3b interacts with factor B, and more C3 convertase is generated.
Amplification Loop
Hanley, 1998
Three families of Complement
proteins
THREE FAMILIES OF COMPLEMENT PROTEINS
COLLECTINS SERINE PROTEASES THIOESTER PROTEINS
C1q C1s
MBL MASP
C2 C4
Factor B C3
Factor D C5
Ucker, 2003
Regulators Of Complement Activation
•Regulators of C3 convertase assembly and destruction: C4b-BP, MCP, CR1, Factor H, DAF (assembly), Factor I (destruction)
•Regulators of the lytic pathway (MAC assembly inhibitors): HRF, MRL
•Regulators of C1 esterase activity: C1INH (Deficiency = Hereditary Angioneurotic Edema)
Ucker, 2000
Regulators Of Complement Activation
Complement Control Proteins
Molecule Regulatory Role
C1 Inhibitor (C1INH) Binds to activated C1r and C1s, dissociating from C1q
C4 Binding Protein (C4BP) Binds to C4b, displacing C2a. Co-factor for C4b cleavage by I
Complement Receptor 1 (CR1) Binds C4b (displacing C2a) and C3b (displacing Bb); co-factor for I
Factor H (H) Binds C3b, displacing Bb, co-factor for I
Factor I (I) Cleaves C3b and C4b, aided by H, MCP, C4BP, or CR1
Decay Accelerating Factor (DAF) Membrane protein that displaces Bb from C3b, and C2a from C4b
Membrane Co-factor Protein (MCP) Membrane protein that promotes inactivation of C3b and C4b by I
CD59 (protectin) Prevents formation of Membrane Attack Complex on homologous cells
Homologous Restriction Factor (HRF) Prevents formation of Membrane Attack Complex on homologous cells
Complement
Control
Proteins
(adapted
from Janeway 9.50)
Complement Receptors (adapted from Roitt 4.15)
Complement Receptors for fragments of C3
Receptor Ligands Cellular Distribution
CR1 (CD35)
C3b>iC3b C4b
B cells, neutrophils, monocytes, macrophages, erythrocytes, follicular dendritic cells, glomerular epithelial cells
CR2 (CD21)
iC3b, C3dg
Epstein-Barr Virus
Interferon-α
,B cells ,follicular dendritic cells epithelial cells of cervix and
nasopharynx
3CR ( 18/ 11 )CD CD b
3iC b zymosan
certain bacteria fibrinogen
factor X ICAM-1
, ,monocytes macrophages , , neutrophils NK cells
follicular dendritic cells
4CR ( 18/ 11 )CD CD c
3iC b fibrinogen
, , neutrophils monocytes tissue macrophages
C1C4
C2
B
D Properdin
C3(I, H)
C5
C6
C7
C8
C9
Pyogenic infectionsImmune Complex Disease
Neisserial infections
Severe pyogenic infectionsImmune Complex Disease
Neisserial infections
Deficiencies of components within the same pathway result in similar clinical manifestations.
Hanley, 1998