Chapter 2: The innate immune system

Question 1

Innate immune system

Answer 1

Complement proteins, professional phagocytes and natural killer cells which defend our body against everyday invaders and activates the adaptive system if more complicate invaders enter

Question 2

Complement system

Answer 2

Born with it, produced by the liver and present in high concentration in blood and tissues. 20 proteins: destroy invaders and signal other parts of the immune system

3 different ways of activation:
1. Classical pathway: antibody dependent
2. Alternative pathway: antibody dependent, C3b
3. Lectin activation pathway: MBL

Question 3

Alternative pathway

Answer 3

C3 most abundant complement protein.

• Cleaved spontaneously –> C3a and C3b
• C3b: very reactive; binds easily to amino or hydroxyl group of an invader
• B complement protein binds –> C3bB
• Complement protein D cliffs of B protein –> C3bBb: slices other C3 proteins (snowball effect) and cleave other complement proteins like C5
• C5b can form with C6, C7, C8 or C9 a membrane attack complex (MAC)
• C5b, C6, C7 and C8 anchors the complex in the cell membrane of the invader
• C9 proteins make a hole in the surface of the invader

To prevent this from happening to our own cells: MCP enzyme, DAF protein, CD59 (protecti, prevents incorporation of C9 molecules)

Question 4

Lectin activation pathway

Answer 4

Depends on mannose-binding lectin (MBL) made in the liver. Mannose (carbohydrate) found on the surface of pathogens.

• MBL binds to MASP in the blood
• When MBL finds mannose –> MASP functions like a saw lo cleave C3 proteins

Question 5

3 main functions of the complement system

Answer 5

1. Building membrane attack complexes (MACs)
2. Opsonize invaders: C3b –> iC3b (cannot make MAC’s anymore) –> attaches to invader which causes better grip to slimy invaders
3. Serves as chemoattractants: C3a and C5a are set free in the tissue: anaphylatoxins (contribute to anaphylactic shock)

Question 6

3 stages of readiness in macrophages

Answer 6

1. Resting state: garbage collectors (e.g. death cells), have very few MHC II presenting cells
2. Activated: received alarm signal by IFN-y (produced by Th-cells and NK cells): MHC II upregulated
3. Hyperactivation: direct signal from invader via e.g. LPS (lipopolysaccharide) or mannose –> stops proliferation and starts killing only.
   Also produces tumour necrosis factor (TNF): kills tumour and infected cells and activates the rest of the system. The number of lysosomes and ROS increase. Can also dump its lysosomes on the invader when it’s too big to digest

Question 7

Neutrophils

Answer 7

About 70% of all white blood cells; short half life of 5 days. They can only kill on the call; arrives in half an hour fully activated to site of action; phagocytose and kill very efficiently.
Also produce cytokines and give off destructive chemicals from cells –> turn tissue into a toxic soup; lethal to invaders (so also damaged the normal tissue)

3 types of molecules necessary to arrive at site of action (fail-safe):

• Endothelial cells: ICAMs on surface and express SEL (selectin)
• Neutrophils: SLIGs (selectin ligand)
• Activated macrophages secrete IL-1 and TNF
• SLIGs + SEL –> sniff for inflammatory signals like C5a and LPS –> makes new protein to surface: INT (integrin).
• INT + ICAM –> neutrophil stops rolling
• Chemoattractants (C5a and fragments of bacterial proteins (f-ment peptide)) help neutrophils to migrate to site of inflammation while activated by cytokines like TNF.

Question 8

Natural killer (NK) cells at site of action

Answer 8

Use same technique as neutrophils to leave the blood (roll, stop, exit).

Two roles on site of action:

1. Give off cytokines like IFN-y
2. Kill by forcing cells to commit suicide; activated by IFN type I or LPS of bacterial membrane. Identifies targets by activating receptors that are unusual carbohydrates or proteins on the surface of a target cell.

Macrophages produce TNF which upregulates the expression of IL-2 receptors –> neutrophils proliferate

Question 9

Recognition of invaders

Answer 9

PRRs (pattern-recognition receptors): recognize danger signals which are released by dying cells.

• PAMPs (pathogen-associated molecular patterns)
• DAMPs (damage-associated molecular patterns)
• MAMPs (microbe-associated molecular patterns)

TLR (toll-like receptor) is best known PRR:

• Inside the cell: TLR7 (recognizes ssRNA) and TLR9 (recognizes dsRNA)
• Outside the cell: TLR4

Properties of PRRs:

1. Recognize general characteristics of classes of invaders (not just a single)
2. Recognize structures of the pathogen that are so important they cannot easily be altered by mutation

Question 10

Interferon system

Answer 10

Interfere with viral reproduction; produced in mainly pDCs (plasmacytoid dendritic cells). Use TLR7 and 9 to detect viral RNA and DNA –> produce lots of type I interferons which can warn nearby cells. Will continue normal function unless attacked by the virus –> beneficial suicide

Type I interferons: interferon alfa/beta produced as warning signal when PRRs detect a virus attack