Lecture 23 - Complement 2

Question 1

What is Phagocytosis

Answer 1

Mediated by neutrophils and macrophages

Neutrophils 1st on scene

Microbe binds to cell surface receptors and is endocytosed

Phagosome fuses with lysosomes containing degrading
enzymes – lysozyme, collagenase & elastase plus ROIs and NO

Reactive oxygen species – superoxide, hydrogen peroxide, Nitric oxide

NO- formed from arginine by iNos (+ H2O2= peroxynitrite)

Question 2

What is the process of phagocytosis

Answer 2

Bacterium becomes attached to membrane evaginations (pseudopodia)

Bacterium is ingested, forming phagosome

Phagosome fuses with lysosome

Lysosomal enzymes digest captured material

Digestion products are released from cell

Question 3

Cellular summary

Answer 3

4 cell types involved in innate response

Recognise microbes through pattern recognition receptors on cell surface ( 4 types)

Results in
- phagocytosis of microbe,
- killing of infected cells
- antigen presentation

Question 4

What is the complement system

Answer 4

Cascade of plasma proteins activated by microbes resulting in
their destruction

Zymogens – gain enzymatic activity by cleavage

3 pathways – classical, alternative and lectin

Classical – C1 detects ab bound to microbe, cleaves C2 /4
Alternate – direct recognition of microbe
Lectin – mannose R binds lectin and cleaves C4

All result in cleavage of C3- C3a and b leading to opsonisation
and phagocytosis.

C5a chemotactic for neutrophils - localised

Question 5

What is the process of complement activation titles

Answer 5

Initiation

Acute inflammation (C3a)

Enhanced phagocytosis (C3b)

Chemotactic (C5a)

Lysis of microbe

Question 6

How is complement activation beneficial and why is excessive complement activation bad

Answer 6

enhancing the innate
immune response and rapid elimination of pathogens

However, excessive complement activation can cause high
levels of inflammation and a more severe prognosis
C3a/C5 a. Increase neutrophil infiltration, tissue damage

Excessive complement activation/ deposition/ tissue damage
observed in severe cases of COVID-induced respiratory distress

Question 7

What is the role of complement in COVID19

Answer 7

Excessive complement activation/ deposition/ tissue damage
observed in COVID-induced respiratory distress

That coronaviruses activate multiple complement pathways;

The combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19;

A subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation;

These observations created a basis for clinical trials of complement inhibitors in life-threatening illness.

Question 8

Wat is meningitis

Answer 8

Inflammation of the membrane (meninges)

Question 9

What is the therapeutic approach for meningitis

Answer 9

Developed C5 antibodies-eculizumab.

Rationale for this?

However, patients developed invasive meningococcal disease

Secondary reason (apart from lack of neutrophils?)

Question 10

What are cytokines

Answer 10

Small proteins released by immune and non-immune cells that
act on immune cells to regulate their function

Immunomodulatory agents

Aid cell-to-cell communication and stimulate the movement of cells
towards sites of inflammation, infection, and trauma

Can drive differentiation, proliferation, migration, survival and function

Active in pM concentrations and can act in autocrine, paracrine or
endocrine fashion

Target cell requires expression of appropriate cytokine receptor

Different sub families- Interleukins, chemokines, interferons, growth factors

Question 11

What are TNF / IL-1- cytokines

Answer 11

Pro-inflammatory cytokines
In innate system mainly produced by LPS challenged macrophages

Stimulate neutrophil migration to site of infection by increasing adhesion molecules and extravasation

Question 12

What are IL-12 cytokines

Answer 12

Produced by mac and dendritic cells
Promotes NK cytolysis

Stimulates IFNg production in T and NK cells
IFNg stimulates mac to kill microbe

Question 13

What are IL-10 cytokines

Answer 13

Anti inflammatory
Mainly produced by macrophages
Dampens immune response

Question 14

Why do cytokines play a role in immune regulation

Answer 14

dysregulation of expression can lead to disease

Targeting of cytokines and their receptors is a growing
therapeutic field especially in immune-related disorders

Main approaches are to

Mop up excess cytokines with abs/ soluble receptors

Stimulate or block cytokine receptors

Try to restore the homeostatic balance of
pro vs anti inflammatory cytokines