Janeway 9.49

part 2

Roitt

12.22

Roitt

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

Roitt

4.2

Janeway 9.36

Activation of C4ACTIVATION OF C4

C4b

C4

C1s

Ucker, 2003

C4a

C4

C1s

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

Roitt

4.7

Thioester mediated binding of C3b

Pathogen

C3

C3a

C3b

THIOESTER-MEDIATED BINDING OF C3b TO THE SURFACE OF A PATHOGEN

Ucker, 2003

C3bC3b

Roitt

4.16

Roitt

12.13A

Roitt

4.13

panel 1

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)

Janeway 9.32

Glycan structures

N-Acetyl Glucosamine

ComplexSialylated

Fucosylated Glycan

Sialic Acid

Galactose

Mannose

Fucose

High MannoseGlycan

Ucker, 2003

Roitt 4.8

Thioester mediated binding of C3b

Pathogen

C3

C3a

C3b

THIOESTER-MEDIATED BINDING OF C3b TO THE SURFACE OF A PATHOGEN

Ucker, 2003

C3bC3b

Roitt 12.10

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

Roitt 12.13b

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

Ucker, 2000

Complement is a self-limiting cycle

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

Roitt 4.7

Roitt 4.12

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

Activation of C3ACTIVATION OF C3

C3

C2a4b

C3a

C3b

Ucker, 2003 Pathogen

Roitt 18.16

Roitt 12.22

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

Janeway 9.31