COMPLEMENTTHE LINK BETWEEN NON-SPECIFIC AND SPECIFIC IMMUNITY

Complement: History

• Discovered in 1894 by Bordet

• It represents lytic activity of fresh serum

• Its lytic activity is destroyed when heated at 56°C for 30 min

The Nobel Prize in Physiology or Medicine 1919

resistant

active immunization

serum (antisera)

bloodsample

Fresh serum

Serum(Heat inactivated at 56º C)

Bordet's Classical Experiment

Hans Joaquim Muller-Eberhard(May 5, 1927- March 3, 1998).

The first part of the immune system that meets invaders such as bacteria is a group of proteins called the complement system. These proteins flow freely in the blood and can quickly reach the site of an invasion where they can react directly with antigens - molecules that the body recognizes as foreign substances. When activated, the complement proteins can

• trigger inflammation

• attract eater cells such as macrophages to the area

• coat intruders so that eater cells are more likely to devour them

• kill intruders

Complement Functions

Host benefit:• opsonization to enhance phagocytosis• phagocyte attraction and activation• lysis of bacteria and infected cells• regulation of antibody responses• clearance of immune complexes• clearance of apoptotic cells

Host detriment:• Inflammation, anaphylaxis

Complement Components

Classical

• C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9

Alternative

• Factors B, D, H and I, properdin (P)

Lectin Pathway

• Mannose binding protein (MBP), MASP-1 MASP-2

Pathways of Complement Activation

CLASSICALPATHWAY

LECTINPATHWAY

Activationof C5

MEMBRANE ATTACK

COMPLEX (MAC)

antibodydependent

(Ac-Ag)

ALTERNATIVEPATHWAY

antibodyIndependent(No Ac-Ag)

Activation of C3 andgeneration of C5 convertase

Classical Pathway.C1

C1r

C1s

1

2

3

45

6

Collagen-like tails

C1q

Classical Pathway.Intact C1

Classical Pathway.Intact C1

Classical Pathway.Interaction with Ac

Ac

Ac

Cell membrane

Ag

AbAb C1qrsC1qrs

C4C4 bb C4aC4a

Classical PathwayClassical Pathway

AbAb

C1qrsC1qrsC4C4 bb C2C2 bbaa

AbAb

C1qrsC1qrsC2C2 bb

C4C4 bb

C4b2bC4b2b(C3 convertase)(C3 convertase)

The Third Component of the Complement (C3)The Third Component of the Complement (C3)

• It is the most important component of the complementIt is the most important component of the complement

• It is synthezised by the liver and the macrophagesIt is synthezised by the liver and the macrophages

• It exists in high concentration in serumIt exists in high concentration in serum

• C4b2bC4b2b (C3 convertase) can activate as many as 200 C3 molecules (C3 convertase) can activate as many as 200 C3 molecules

C3C3 bb

C2C2 bb

C4C4 bb

C3C3

C3C3

C3C3

C3C3

C2C2 bb

C4C4 bb

C3C3

C3C3

C3C3

C3C3

bbaa

C4b2b3bC4b2b3b(C5 convertase)(C5 convertase)

Generation of C5 convertase

leads to the activation of the

lytic pathway

Lytic pathway

C2C2 bb

C4C4 bb

C3C3 bb C3C3 bbC5C5 bbaa C5C5 bbaa

bb C5bC5b

C6C6

C7C7

C8C8C9C9

Lysis andLysis andcell deathcell death

Membrane Attack Complex

Membrane Attack Complex

Membrane Attack Complex

Membrane Attack Complex

IV_9_2_Complement_System.mov

Alternative PathwayAlternative PathwayC3 is spontaneously formed in serumC3 is spontaneously formed in serum

C3C3 bb

C3C3 bb

C3C3 bbC3C3 bb

C3C3 bb

C3C3 bb

C3C3 bb

LPSLPS

C3C3 bb

LPSLPS

Bacterial surfaceBacterial surface

LipopolysaccharideLipopolysaccharide

C3C3 bbLPSLPS

Bacterial surfaceBacterial surface

BB

C3bBbC3bBb(C3 convertase)(C3 convertase)

aa

bb

DD

C3C3 bbPPC5bC5b

C6C6

C7C7

C8C8C9C9

Mannose-Binding Protein Pathway

Macrophages

MBPMBP

MASP-1MASP-1 MASP-2MASP-2

Mannose-Binding Protein PathwayMannose-Binding Protein Pathway

Bacterial SurfaceBacterial Surface(rich in carbohydrates)(rich in carbohydrates)

C4C4 bb C4aC4a

MBPMBP

MASP-1MASP-1 MASP-2MASP-2

Mannose-Binding Protein PathwayMannose-Binding Protein Pathway

Bacterial SurfaceBacterial Surface(rich in carbohydrates)(rich in carbohydrates)

bbC4C4 bb C2C2 bbaa

Opsonization and Phagocytosis

Biological Effects of C5a

Product Biological Effects Regulation

Biological Properties of C-activation Products

C2b (prokinin) edema C1-INH

C3a (anaphylatoxin)

mast cell degranulation; enhanced vascular permeability; anaphylaxis

carboxy-peptidase- B (C3-INA)

Product Biological Effects Regulation

as C3, but less potent

(C3-INA)C4a (anaphylatoxin)

opsonization; phagocytosis

C4b (opsonin)

C4-BP, factor I

C3b (opsonin)

opsonization; phagocyte activation

factors H & I

Biological Properties of C-activation Products

Product Biological Effects Regulation

anaphylactic as C3, but much more potent;attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release

C5a (chemotactic factor)

carboxy-peptidase-C (C3-INA)

C5b67 protein-Schemotaxis, attaches to other membranes

Biological Properties of C-activation Products

C1-inhibitor deficiency:angioedema