Complement system

What is the function of complement

Recognises pathogen or danger signals and triggers a response

What responses does the complement system trigger

• Directly lyse pathogen to rupture target cell membranes

• Opsonise pathogens to enhance phagocytosis

• Act as chemoattractant to attract immune cells

• Trigger degranulation of mast cells

How does the complement system work

• Through recruitment and activation of zymogen-like proteins

• Happens on the cell surface

• Zymogen splits into two

• Larger enzyme is retained at surface

• Smaller part acts as chemoattractant or cell activator

Is complement potent

Extremely potent so tight regulation of complement activation is required

What are the modes of action

• Direct inhibitors and blockade

• Decay accelerator factors

• Found on many WBC surfaces speeds up the decay of convertases

• CD59 inhibits the formation of the membrane attack complex on host cell surfaces to protect host cells from being destroyed by the complement system

What does complement being non-specific mean

• It must possess very broad activation mechanisms

• The pathways to activation also give rise to differing effectors and lend their name to the 3 complement systems

What are the different effectors

• The classical pathway

• The alternative pathway

• The lectin pathway

What are the features of the classical pathway

• Activating signal - antigen antibody complex

• Effectors - cell phagocytosis, cell lysis, WBC recruitment and activation

• Targets - bacteria, viruses, parasites, fungi

• Differences - inherently longer due to need for Abs

What are the features of the MB-lectin pathway

• Activating signal - host mannose binding lectins

• Effectors - cell phagocytosis, cell lysis, WBC recruitment and activation

• Targets - bacteria, viruses, parasites, fungi

• Differences - binds surface via soluble protein

What are the features of the alternative pathway

• Activating signal - C3 binding to pathogen carbohydrates or proteins

• Effectors - cell phagocytosis, cell lysis, WBC recruitment and activation

• Targets - bacteria, viruses, parasites, fungi

• Differences - binds directly to pathogen surface

What happens in the classical pathway

• Must have lots of antibodies to activate C1

• Successive levels of activation

• One activated it becomes 2 products

• C4b2b also known as C3 convertase and is important part of pathway

• C3b5 is first stage of membrane attack complex

• Anaphlatoxin as biproduct causing inflammation and vasodilation

What happens in the alternative pathway

• C3 spontaneously coverts without C3 convertase

• Becomes activated if binding on a microbial surface

• If on host surface it isn’t activated

• Factor H binds in the blood to inactivate it

What happens in the MB-lectin pathway

What is C3 made by

Macrophages in the liver

What does C3 break down naturally into

C3a and C3b

What can C3b bind to

• Microbe surfaces via carbohydrates

• Factor H on host cells taking C3b out of circulation

What does C3a do

Acts as an anaphylatoxin or a chemoattractant

Where do all three pathways converge

On C3

How do MB- lectin and classical pathways converge

C4b + C2b → C3 convertase

How does the alternative pathway converge

C3b + Bb → C3 convertase

Why is there more C3b then C4b

Due to concentration effect as large amounts of C3 are cleaved to C3b then C4 cleaved to C4b

What are the anaphylatoxins

• C3a

• C4a

• C5a

What do the anaphylatoxins do

• Change smooth muscle

• Increases vasodilation

• Activates mast cells or neutrophils

• Increases fluid in the tissue and speeds up lymph flow

What is the membrane attack complex

• A central effector mechanism of the complement system and innate immune response

• It is an endpoint of all 3 activation pathways

• Can be referred to MAC or terminal complement complex

• Composed of C5b, C6, C7, C8 and multiple copies on C9

What happens in the membrane attack complex

1. C5 → C5a and C5b

2. C5b binds to C6

3. C5b6 is bound by C7

4. C5b:C6:C7 complex allows the insertion of C7 into the phospholipid bilayer as a hydrophobic site is exposed on the C7 protein once in a complex

5. Complex is bound by C8

6. C8ß binds C5b and joins the surface

7. C8α and C8γ inserts into the cell membrane

8. This causes 10-16 copies of C9 to polymerise on the cell surface
   
   

What does the membrane attack complex do

• Opens the bacterial cell cytosol

• Dramatic loss of cellular homeostasis

• Disrupts proton gradient

• Penetration of host lysozome and other proteases

What is canine C3 deficiency

• An inhereted disoder

• Homozygote dogs have no serum C3

• They have trouble making antibodies against certain pathogens

• Increased pyometra, pneumonia and sepsis

What is the normal level of C3

126 mg/mL

What is porcine factor H deficiency

• Inherited recessive autosomal disease

• Carriers born normal up to a few weeks so production problems

• DIe of anaemia and renal failure

• Factor H stops C3b activation

• In animals C3 accumulates on surface and basal membranes on kidneys

What does C3a and C5a do

Peptide mediators of inflammation and phagocyte recruitment

What does C3b do

• Bind to complement receptors on phagocytes

• Opsonization of pathogens

• Removal of immune complexes

What do C5b, C6, C7, C8 and C9 do

• Membrane attack complex

• Lysis of certain pathogens and cells

What does MAC punching holes in membranes cause

• Dramatic loss of cellular homeostasis

• Disrupts proton gradient

• Penetration of host lysozyme and other proteases