The Complement System

The Complement System

Complement: Complement: history history

Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min

The complement system is the major effector of the humoral branch of the immune system.

The Complement Components • 1. Complement components are designated by numerals (C1–C9), by letter symbols (e.g., factor D), or by trivial names (e.g., homologous restriction factor). 2. Peptide fragments formed by activation of a component are denoted by small letters. In most cases, the smaller fragment resulting from cleavage of a component is designated “a” and the larger fragment designated “b” (e.g., C3a, C3b; note that C2 is an exception: C2a is the larger cleavage fragment). • 3 .Those complexes that have enzymatic activity are designated by a bar over the number or symbol (e.g., C4b2a, C3bBb).

Complement Activation • The Classical Pathway • Alternative pathway • Lectin pathway

The Classical Pathway • Begins with Antigen-Antibody(IgM,IgG) Binding • The formation of an antigen-antibody complex induces conformational changes in the Fc portion of antibody that expose a binding site for the C1 component of the complement system.

• The initial stage of activation involves C1, C2, C3, and C4.

Components of the Classical Pathway C1r

C1s

Ca++ C1q

C2

C1 complex

C3

C4

Classical Pathway Generation of C3-convertase C1r

Ca++ C1q

C1s C4 b

C4a

Classical Pathway Generation of C3-convertase C4a

C1r

C1s

Ca++

a 2 C

C2b

C1q Mg++

C4b2a is C3 convertase C4b

C2a

Classical Pathway Generation of C5-convertase C4a

C1r

C3a

C1s

Ca++ C1q Mg++

C2b C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway C3

C4b

C2a

b

The Alternative Pathway • the alternative pathway is a component of the innate immune system • The alternative pathway is initiated in most cases by cellsurface constituents that are foreign to the host • involve four serum proteins: C3, factor B, factor D, and properdin. • serum C3 is subject to slow spontaneous hydrolysis to yield C3a and C3b.

Components of the alternative pathway

D

C3

B P

Spontaneous C3 activation Generation of C3 convertase H2O

C3 i

D

Bb

C3 b

C3a

This C3b molecule has a very short half life

C3-activation

the amplification loop

If spontaneously-generated C3b is not degraded

D

C3a

C3b

Bb

C3 b

C3-activation the amplification loop D

C3 b

C3a C3a

C3b

Bb

Bb

C3b

C3-activation the amplification loop D

Bb

C3 b

C3a C3a

C3a

Bb

C3b

C3b

Bb

C3b

C3-activation

the amplification loop

Bb

C3a C3a

C3a

Bb

C3b

C3b

Bb

C3b

The Lectin Pathway • The lectin pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues • After MBL binds to the surface of a cell or pathogen, MBL-associated serine proteases,MASP-1 and MASP-2, bind to MBL. The active complex formed by this association causes cleavage and activation of C4 and C2. • activating the C2–C4 components to form a C5 convertase doesn,t need for specific antibody

Components of mannose-binding lectin pathway

C4 MASP2

MBL

C2

MASP

Mannose-binding lectin pathway C4a

C4b2a is C3 convertase; C2b MASP

MASP2

MBL

it will lead to the generation of C5 convertase

C4b C4 2a CC2

C4b

C2a

The Three Complement Pathways Converge at the Membrane-Attack Complex

. • The terminal sequence of complement activation involves C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called the membrane-attack complex (MAC).

Lytic pathway

Generation of C5 convertase leads to the activation of the

Lytic pathway

Components of the lytic pathway C7

C6

C 5

8 C

C 9

Lytic pathway C5-activation C5a

5 C b

C4b

C2 a

C3b

Lytic pathway assembly of the lytic complex

C6 C7

5 C b

Lytic pathway:

insertion of lytic complex into cell membrane

C6 8 C

CC C C C9 9 9 9C 9C C C9 9 9 9

C7

5 C b

The Function of MAC • MAC forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane. • So the cell cannot maintain its osmotic stability and is killed by an influx of water and loss of electrolytes.

Regulation of the Complement System

C1qrs breakdown C1Inh

C1r

C1q

C1s

C1r

C1s

Biological effects of C5a

Opsonization and phagocytosis

Biological Consequences of Complement Activation • The Membrane-Attack Complex Can Lyse a Broad Spectrum of Cells • Cleavage Products of Complement Components Mediate Inflammation • C3b and C4b Binding Facilitates Opsonization • The Complement System Also Neutralizes Viral Infectivity • The Complement System Clears Immune Complexes from Circulation

The Functions of Complement •

Lysis of cells, bacteria, and viruses

•

Opsonization, which promotes phagocytosis of particulate antigens

•

Binding to specific complement receptors on cells of the immune system, triggering specific cell functions, inflammation, and secretion of immunoregulatory molecules

•

Immune clearance, which removes immune complexes from the circulation and deposits them in the spleen and liver