Ch5 - Complement System

Complement

Group of circulating blood proteins often synthesized by the liver that are inactive but induce many different effects once activated

• 7 different complement categories

Complement Activation Paths

There are 3 ways in which the complement cascade may be activated in order to assist with an immune response

• classical, lectin, and alternative

Classical Pathway

Was discovered first, but given its involvement with antibodies of the adaptive immune system, it is unlikely that it was the first to evolve - involves binding to antigen/antibody complexes 

1. antibody/antigen complex binds with complement 

2. C4 and C2 are cleaved 

3. C3 cleavage 

4. C5 cleavage and MAC 

Classical: Step 1

Antibody/Antigen complex consisting of IgG or IgM allows C1q pentamer to bind to the Fc invariable region of the antibody 

• Singular C1r associated with C1q imitates cleavage and activation of remaining C1r and the two C1s molecules

Classical: Step 2

Cleavage of C4 and C2

• C1s cleaves C4 into a/b components 

• C4b binds to membrane surface which allows C2 to be cleaved 

• C4b2a forms the C3 convertase

Classical: Step 3

Cleavage of C3

• C3 convertase hydrolyzes C3, some of which binds to the C4b2a complex 

• C4b2a3b forms C5 convertase

Classical: Step 4

C5 cleavage

• C5 binds to C3 portion of the convertase 

• C5 is cleaved 

• C5b binds to membrane to begin MAC formation

Lectin Pathway

Similar to the classical pathway but instead is able to bind directly to the microbe rather that the antigen/antibody complex through polysaccharide recognition 

1. Carb Recognition

2. C4/C2 cleavage 

3. C3 Cleavage

4. C5 Cleavage and MAC

Lectin: Step 1

Mannose Binding Lectin (MBL) recognizes carbs on the surface of microbes 

• Allows MBL-Associated serine protease docking (MASPs) 

Lectin: Step 2

Cleavage of C4 and C2

• MASPs cleave C4 into component parts

• C4b binds to surface 

• C2 cleaved 

• C4b2a complex forms C3 convertase 

Lectin: Step 3

Cleavage of C3

• C3 convertase hydrolyzes C3, some of which binds to the C4b2a complex 

• C4b2a3b forms C5 convertase

Lectin: Step 4

C5 cleavage

• C5 binds to C3 portion of the convertase 

• C5 is cleaved 

• C5b binds to membrane to begin MAC formation

Alternative Pathway

Differs from the other two pathways in that it relies on different forms of C3 and C5 convertases and has 3 separate modes of activation

1. C3 Fluid Convertase formation 

2. C3 membrane bound convertase 

3. C5 Convertase formation 

4. MAC creation

Alternative: Step 1

C3 fluid convertase formation

• C3 spontaneously hydrolyzes to form C3(H2O)

• Molecule associates with Factor B 

• Factor B is cleaved by Factor D to for the C3(H2O)Bb Fluid-Phase C3 convertase

Alternative: Step 2

C3 membrane bound convertase formation

• Fluid Phase convertase cleaves a circulating C3 

• Resulting C3b binds to membrane surface 

• Associates with Factor B 

• Factor D cleaves Factor B resulting in C3Bb membrane-bound C3 convertase 

Alternative: Step 3

C5 convertase formation

• At this point the alternative path may diverge 

• Alike in that they result in the cleavage of C3 to for the C3bBbC3b C5 convertase

Alternative: Step 4

C5 cleavage

• C5 is cleaved and C5b binds to induce MAC formation

Alternative Properdin

Pathway utilizes Properdin(Factor P) to stabilize the membrane bound C3 convertase 

• Properdin is already bound to membrane 

• C3 convertase is formed on top of Properdin

Alternative Tickover

Pathway also utilizes Properdin to stabilize the membrane-bound C3 convertase and increase its half-life 

• properdin binds to fully formed membrane-bound C3 convertase to stabilize it 

Alternative Protease

Pathway capitalizes on clotting cascades to stimulate cleavage

• Thrombin cleaves C3 and C5 

• Platelet activation releases ATP etc that stabilize fluid phase C3 

MAC 

Membrane attack complex is formed by subsequent C6,7,8,9 binding to membrane bound C5b 

• Multiple C9 components form a pore structure in membrane that disrupts the osmotic integrity to induce lysis

Complement Receptors

Connect complement-tagged pathogens to effector cells

• host receptors allow for discrete and differentiated responses 

CR1

• On leukocytes and erythrocytes

• Often responds to C3b ligands

• Erythrocytic functions to bring immune complexes to liver for clearance and reduction of prolonged inflammation 

• Phagocytic functions for opsonization 

• B-Cell functions to enhance T-cell presentation

CR2

• Otherwise known as CD21

• Binds to C3d on opsonized bacteria/antigens 

• Helps provide secondary signals to B-Cells through BCR complex for increased efficiency 

CR3

• Found on cells of myeloid and lymphoid lineages

• Responds to factor H

• Binds to adhesion molecules on leukocytes to facilitate extravasation 

C3aR/C5aR

• On granulocytes

• Responds to anaphylatoxins

• Induces degranulation and subsequent death

Complement Outcomes

Helps to enhance host defense against infection

• MAC-induced cell death

• Promotion of inflammation

• Promotion of opsonization

  • Opsonized microbes easier to ingest/destroy

  • Opsonized immune complexes easier to clear

Complement as Immune Systems Mediation

Mediates at interface between the innate and adaptive immune

• enhances antigen uptake

• enhances B-cell response

• lyse immature t-cells

• facilitates T-cell maturation

Complement and Contraction

Complement aids in resolving immune inflammation to avoid damaging inflammation in the absence of antigens 

• aids in the disposal of lymphocyte apoptotic cells and bodies 

• aids in immune complex removal/disposal 

Complement Regulation

Multiple ways that the complement system is regulated to prevent harm to self-cells

• short C3 Convertase half-life unless otherwise stabilized

• self cells have different carbohydrate structures

C1 Inhibitor

Otherwise known as C1INH

• promotes C1 dissociation

DAF

Promotes decay of C3 convertases

• requires CR1 and C4BP for classical/lectin

• requires CR1 and Factor H for alternative

CR1

Membrane bound protein found in all pathways that blocks formation of C3 convertases

Factor H

Binds negatively charged eukaryotic cell surface sialic acid and heparin

Factor I

Degrades C3b and C4b

• Soluble and constituent active serine protease

• Cleaves membrane-associated C3b and C4b into inactive fragments

  • requires MCP and CR1 to function

  • C3 further requires Factor H and C4 further requires C4BP

CD 59

Otherwise known as Protectin

• Binds to deposited C5b678 complexes to prevent insertion and C9 recruitment

S Protein

Otherwise known as Vitronectin

• binds fluid-phase C5b67 to prevent insertion into the host plasma cell membrane

Carboxypetidase

May inactivate C5a/C3a anaphylatoxins

• remove arginine residues to create des-Arg inactive forms

• shuts down unnecessary or dangerous inflammation

Deficiencies

Have varied outcomes 

• C1q,C1r,C1s,C4 or C2 deficiency may result in immune complex disorders due to inadequate clearance 

• MBL deficiency may exhibit more encapsulated bacteria infections due to lack of coat recognition, opsonization, and phagocytosis 

Microbial Evasion

Many different and varied strategies to avoid complement

• Some interfere with Ig-mediated complement activation

• Microbial proteins may bind and inactivate complement proteins

• Microbial proteases destroy complement proteins

• Some microbes mimic or bind complement reg proteins

S. pyogenes

Accelerates decay of C3 convertases by binding to C4BP and Factor I