Complement

4. Phagocytosis & Phagocytosis Maturation (LTS)

How does indirect recognition occur?

Via complement or antibodies.

What are the main pathways of the complement system, and when do they all converge?

1. Classical Pathway

2. Lectin Pathway

3. Alternative Pathway

They converge at the C3 component.

What is the modern understanding of the complement’s system role beyond antimicrobial defense?

Global regulator of:

• Immunity

• Tissue homeostasis (development and repair)

It is an elaborate network of fluid-phase, cell-surface-associated, and intracellular proteins.

Where else, besides the bloodstream, are complement components found, and what is their role?

Not exclusively intravascular and extracellular.

• Secreted locally by tissue-resident and infiltrating cells.

• Co-exist intracellular with novel homeostatic and immunological functions e.g. within T cells.

How does complement influence T-cell responses?

• Activation

• Co-stimulation

• Differentiation

How does the complement system affect cellular metabolism in T cells?

Metabolic programming.

e.g. C5 activation in T cells leads to reactive oxygen species production and inflammasome activation.

How is the complement system related to inflammasome activation?

Regulates it

e.g. MAC activates the NLRP3 inflammasome.

What are inflammasomes?

Innate immune system receptors/sensors that regulate the activation of caspase-1 and induce inflammation.

What is the relationship between complement and the microbiome?

Maintains host-microbiome homeostasis.

• Modulates composition of the commensal microbiome.

• The microbiota can influence complement expression also.

What roles does complement play in neurodegenerative conditions?

• Drive tissue-destructive inflammation.

• Involved in synaptic pruning e.g. C1q and C3 deficiency reduces cognitive decline.

What are the dual roles of complement in cancer?

Pro- and anti-tumour roles.

• Regulates myeloid-derived suppressor cell differentiation and recruitment.

• Promote tumour cell motility and invasiveness.

• Protective anti-tumour activity.

Describe the classical complement pathway.

• C1 is activated upon binding to antigen-antibody complexes, causing both C2 and C4 to split into 2.

• C2a and C4b combine to form C3 convertase, which cleaves C3 into C3a and C3b.

How is C1 activated in the classical complement pathway?

Binding to antigen-antibody complexes.

• An antibody binds to a specific antigen on the pathogen surface.

What does C1 do?

Cleaves both C2 and C4 into 2 fragments each (C2a and C2b; C4a and C4b).

What does C3 convertase do?

Cleaves C3 into C3a and C3b.

What is C3 convertase made of?

C4b and C2a fragments.

How is the alternative pathway activated in the complement system?

Directly binding to pathogenic surfaces- the pathogen surface creates a local environment conducive to complement activation.

Describe the alternative pathway in the complement system.

• C3 is activated upon binding directly to the pathogenic surfaces

• C3 interacts with factors P, B and D (FP, FB, FD), leading to the cleavage of C3 to C3a and C3b.

How is the lectin pathway activated in the complement system.

The binding of mannose-binding lectin (MBL) or ficolin to carbohydrates on pathogen surfaces.

Describe the lectin pathway in the complement system.

• MBL circulates in the plasma as a MASP-1-MASP-2 complex.

• MBL or ficolin binds to carbohydrates on pathogen surfaces.

• MASP-2 cleaves both C4 and C2 into 2 fragments.

• C4b and C2a combine to form C3 convertase, which cleaves C3 to create C3a and C3b.

What happens following the cleavage of C3 in the complement system?

• C3a diffuses and recruits phagocytes, triggering inflammation.

• C3b is an opsonin, tagging pathogens by binding to the complement receptors.

• C3b cleaves C5 into C5a and C5b.

• C5b joins with C6-9, other terminal complement components, to form the membrane attack complex (MAC), leading to pathogen and cell lysis.

What does C3a do?

Diffuses and recruits phagocytes, triggering inflammation.

What does C3b do?

C3b (opsonin) covalently binds to surface components of the pathogen, leading to pathogen death via:

• Inflammatory cell recruitment.

• Pathogen opsonisation, facilitating the uptake and killing of phagocytes.

• Perforation of the pathogen cell membrane (cleaves C5 into C5a and C5b- C5b is part of the MAC that causes perforation).

What does C5b do?

Joins with C6-9, other terminal complement components, to form the membrane attack complex (MAC), leading to pathogen and cell lysis.

What makes up the membrane attack complex (MAC)?

• C5b

• C6

• C7

• C8

• C9

What recognises complement proteins? How many are there?

Complement receptors. There are 4 (CR1-4)

What does CR1 recognise?

MBL, C1q, C3b and C4b

What does CR2 do? Where is it found?

Enhances activation, found on B-cells.

What is CR3 composed of? What is its function?

Composed of CD11b and CD18.

• Major phagocytic.

• Recognises iC3b.

What is CR4 composed of? What is its function?

Composed of CD11c and CD18.

• Minor phagocytic.

• Recognises iC3b.

How does the complement system contribute to innate immunity (generally)?

A large number of distinct plasma proteins that react with each other to opsonise pathogens and activate an inflammatory response.

How is complement activated?

• Classical pathway: an antibody binds to a specific antigen on the pathogen surface.

• Lectin pathway: binding of mannose-binding lectin (MBL) or ficolin to carbohydrates on pathogen surfaces.

• Alternative pathway: pathogen surface creates a local environment conducive to complement activation; directly binding to pathogenic surfaces