Complement system

Complement system contains more than 30 glycoprotein present in the serum in the form of components and factors Activation involves the sequential proteolysis of proteins to generate proteolytic enzymes The products of complement activation become covalently attached to microbial cell surface or to antibodies bound to microbial surface or other antigens Complement activation is inhibited by regulatory proteins present on normal host cell to minimize complement mediated damage to host cell Complement cascade also interact with other trigered-enzyme cascade : coagulation, kinin and fibrinolysis

MERCK Manual 2000

MERCK Manual 2000

Complement activation
The central event of complement activation is proteolysis of complement protein C3 to generate biologically active product C3b

Pathways of complement activation : The classical pathway The alternative pathway

Lectin pathway

Clasical Pathway
C1q

Lectin Pathway
MBP

Alternative Pathway
C3b

C1r C1s C4 C2

C1r MASP C1s C4 C4 C2 C2

C3 C3b C5b6789 / MAC / Membrane Attack Complex

P D B

COMPLEMENT ACTIVATORS

Classical Pathway : immune complex : IgG & IgM Alternative Pathway : endotoxin , CVF virus , parasite , bacteria

Lectin pathway :
carbohydrate(mannose)

MAC : Membrane Attack Complex

C5 a
C5

C9
C 6 C 7

C8

C5 convertase

C5 b

C5 b
C 7

C 6

C5 b
C 7

C 6

C5 b
C8
C 7

C6 C 6

C9 C8

Alternative-pathway

C3 a

C3

D B

C3B

C3 C3
D Bb Ba

C3

C3B

C3 convertase

C3 a

C3 a

C3 a

C3 a

C3B C3B C3B

Bb

C3B

C5 convertase

Classical-pathway
Antigen

C1q r s

C4

C2

C4 a

C4b

C2a

C4 a

C3
C3 convertase
C4b
C2b

C2a

C3 a C3 b

C4 a

C4b
C5 convertase C2b

C3 b

MASP : MBL associated serine protease

MAC : Membrane Attack Complex

C9
C 6 C 7

C8

C5

C5 convertase

MAC : Membrane Attack Complex

C5 a

C9
C 6 C 7

C8

C5 convertase

C5 b

MAC : Membrane Attack Complex

C9 C8

C5 convertase

C5 b
C 7

C 6

MAC : Membrane Attack Complex

C9

C5 convertase

C5 b
C 7

C 6

C8

MAC : Membrane Attack Complex

C6 C6

C5 convertase

C5 b
C 7

C9 C8

MAC : Membrane Attack Complex

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

MAC : Membrane Attack Complex

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

MAC : Membrane Attack Complex

LYSIS
C5 b
C 7
C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

C5 b
C 7

C 6

C9 C8

Complement mediated damage

A C

ABBAS 2000

A. B.

Complement lesions on the erythrocyte membrane Membrane lesions induced by CTL

C.

Model of MAC

Complement regulatory mechanisms

C1INH

: inhibits proteolytic activity of C1r and C1s

DAF

: binds C4b and C3b

Factor I

: degrades cell associated C4b and C3b

C59

: inhibits formation of MAC

Classical Pathway
Antigen-antibody complex C1,4,2 C3/C5 convertase
C 4a , C 5a , C3a C 3b

Alternative Pathway
Pathogen surfaces C3,B,D

C 5b , C 6 --- C 9

Inflammation Phagocyte recruitment

Opsonization of pathogens

MAC Lysis of pathogens and cells

Biological effects of Complement system

Lysis of microbes

Inflammation

Phagocytosis of opsonized microbes

Biological effects of Complement system

Lysis of microbes

Inflammation

Phagocytosis of opsonized microbes

Regulators / inhibitors of complement

Complement Receptors
Receptors
CR1/CD35

Ligands
C3b,C4b,iC3b

Cell distributions
MNC,neutrophils erythrocytes, B and T FDCs, eosinophils

Functions
Phagocytosis Clearance of I.C

CR2/CD21

C3d, iC3b

B lymphocytes

Co-receptor for B cell activation

CR3/Mac-1 C11b-C18

iC3b, ICAM-1

MNC, neutrophils NK cells

Phagocytosis Adhesion mol.

CR4/C11c-CD18

iC3b

MNC, neutrophils NK cells

Phagocytosis

Activity Increase of vascular permeability Smooth muscle contraction Degranulation of mast cells / basophils Neutrophil activation and chemotaxis Stimulation of prostagladin and leukotrien production Opsonization of bacteria and immune complexes leading to phagocytosis Stimulation of respiratory burst Lysis of bacteria and foreign cells Solubilization of circulating immune complexes

Components and fragments C5a, C3a, C4a, C5adesArg

C5a C5adesArg

C3b, C4b

C3b, C5a, C5adesArg, C1q C5b6789 C36, CR1

The Complement system in Disease Two general ways : 1. Deficiencies of complement components or its regulators 2. Activation of normally functioning complement in response to abnormal stimuli

Complement deficiencies :

1. Failure to clear up circulating I.C 2. Failure in solubilization of large I.C 3. Failure in antigen mediated signal for B cell which may induce autoimmunity 4. Increased susceptibility to infection

Classical Pathway deficiencies Ciq, C1r, C1r, C4, C2, C3

C4 and C2 deficiencies : 50% associated with Auto Immune Disease (SLE) Not usually associated with increased susceptibility to infection

C3 deficiency :
Frequent pyogenic bacterial infection

Alternative Pathway deficiencies Factor D, B and Properdin Increased susceptibility to pyogenic bacterial infection Terminal complement components deficiencies C5, C6, C7, C8, C9

Increased susceptibility to Neisseria bacterium

Complement Regulators deficiencies : DAF deficiency : Paroxysmal nocturnal Hburia C1INH deficiency Hereditary angioneurotic edema