L2-

Question 1

What can we see about inflammation in evolution?

Answer 1

It is very well conserved. It is an ancient branch of immunology existing to at least some extent in all metazoan organisms.

Question 2

What are the characteristics of inflammation?

Answer 2

Swelling, redness, recruitment of leukocytes

Question 3

How is inflammation classified?

Answer 3

Acute or Chronic depending upon duration and cellular responses (chronic doesn’t get down to resolving part)

Question 4

Summarise the first, second and third lines of defense?

Answer 4

1st: skin, mucous membranes, normal microbiota
2nd: phagocytes, inflammation, fever, antimicrobial peptides
3rd: specialized lymphocytes, antibodies

Question 5

What are the two groups of danger signals?

Answer 5

Pathogenic: PAMPs

Non-pathogenic: DAMPs

Question 6

Examples of Pathogen Associated Molecular Patterns? (PAMPs)

Answer 6

Bacterial endotoxin (TLR4)
Peptidoglycan (TLR2)
Flagellin (TLR5)
Single stranded viral RNA (TLR7/8)
Double stranded viral DNA (TLR9)

Question 7

Examples of Damage Associated Molecular Patterns? (DAMPs)

Answer 7

Heat shock proteins (HSPs)
Uric acid crystals (gout)
ATP (shouldn't be extracellular)
DNA
Beta-amyloid (alzheimer)
Some cytokines (IL1, HMGB1)

Question 8

How do innate cells recognize threats?

Answer 8

Pattern Recognition Receptors (PRRs)

Question 9

What are the main 4 groups of innate immune cells?

Answer 9

1. Macrophages and monocytes (includes tissue-specific macrophages i.e. microglia)
2. Granulocytes: Eosinophil, Neutrophil, Basophil
3. Dendritic cells (DCs)
4. Innate Lymphoid cells

Question 10

How does phagocytosis happen?

Answer 10

Bound material is internalized in phagosomes fuses with lysosome and broken down in this phagolysosomes

Question 11

What are some examples of cytokines?

Answer 11

Lymphokines- produced by lymphocytes, coordinate T cell responses

Interleukins- produced by mainly leukocytes.

Chemokines- induce chemotaxis. Required for recruitment of immune cells to infected/injured tissue

Question 12

What are the two main groups of phagocytic receptors?

Answer 12

1. C-type lectins:
   - dectin-1:bind to beta-1,3-linked glucans (fungi?)
   - mannose receptor:bind to mannosylated ligands
2. Scavenger receptors:
   recognise anionic polymers and acetylated low density lipoproteins.
   Class A: SR-A I, SR-A II. MARCO
   Class B: CD36

Question 13

What are the three main structural parts of Membrane bound receptors: (TLRs)Toll-like receptor?

Answer 13

Leucine-Reach Repeats LRRs)
Transmembrane domains
Toll-IL-1 receptor (TIR) domain
(it’s a dimer)

Question 14

As a general rule what do TLRs recognise at the plasma membrane, or the endosome membrane?

Answer 14

Plasma membrane- recognise Bacterial and Fungal PAMPs

Endosomal membrane- recognise viral PAMPs

Question 15

What do TLRs activate?

Answer 15

transcription factors: NF-kb, AP-1 and IRF to induce expression of cytokines and interferon.
They can stimulate anti-viral or anti-bacterial responses, depending which one they activate.

Question 16

signalling tlrs IKK complex mechanism…

Answer 16

.

Question 17

What are the main cytosolic receptors?

Answer 17

1. RIG-like helicases (retinoic acid inducible gene 1): viral recognition.
2. cGAS (cyclic-CMP-GMP synthase): viral recognition, self-recognition (self DNA).
3. Nod-like receptors (NLRs): bacterial and endogenous DAMPs, NOD1/2s, inflammasome forming

Question 18

What are the RIG-1 helicases?

Answer 18

Can find two of them:

1. RIG-1: recognises mainly ssRNA
2. MDA-5: recognises mainly dsRNA.

They both need an adaptive protein called MAVS. MAVS is in the mitochondria

Question 19

What does cGAS do?

Answer 19

Contains a nucleotidyltransferase domain and two major DNA-binding domains.
Absence of DNA, cGAS exists in an autoinhibited state.

(protein called sting induces the inflammatory response in this process)

Question 20

Nod-like receptors:

NOD1 and NOD2?

Answer 20

Cytosolic.
Have LRR, NOD and CARD domains. (nod2 has 2 card domains)
They recognise bacterial proteins.
nod1 recognises dipeptide in peptidoglycan, nod2 recognises muramyl dipeptide which is in all bacteria.

Question 21

NOD2 mechanism?

Answer 21

Needs to form complex in the cytosol,

… 36 minutes.

Question 22

Nod2 mutations and disease?

Answer 22

Loss of function- If nod2 is mutated, you can’t recognise mdp anymore (muramyl dipeptide) in your gut so there’s no NF-kB signalling.
Causes Crohn’s Disease. (inflammatory bowel disease)

Can also have gain of function- sense mdp, excessice NF-kB signalling. Blau syndrome. Overinflammation, spontaneous inflammation of eyes, skin other places.

Question 23

How does IL1B get secreted?

Answer 23

Doesnt have secretory signal. Pro-IL-1B needs processing and release to perform biological actions.
This is done by Caspase1.
Caspase1 is activated with the inflammasome.

Needs a second signal to be activated. big difference.

Question 24

What’s different about Inflammasome forming NLRs (cytosolic receptors)?

Answer 24

Most cytokines present signals to be secreted by the classical secretory pathway (er, golgi, secretary vesicle)
But IL-1B and IL-18 (pro-inflammatory) do not have secretory signals.
Need second signal for inflammasome to be activated.

Question 25

What is the inflammasome?

Answer 25

Molecular complex formed by:
NLR + Adaptor molecule + Effector molecule

NLRP3 + ASC + Caspase-1

Question 26

CAPS: Cryopyrin Associated Periodic Syndromes?

Answer 26

Autosomal dominant.
Presence of just one copy of a mutated gene can cause the disease.
Leads to high levels of IL-1B secretion.

Question 27

What is the treatment for CAPS?

Answer 27

Canakinumab- a monoclonal antibody.
Injected every 8 weeks.
Binds IL-1B so it can;t bind to the receptor.