L22 - Immune System and the brain

Question 1

What are TLRs used for? Where are they found mostly?

Answer 1

In periphery for innate immunity - pathogen sensor sensing bacteria and viruses, leading to an immune response

Mostly microglia - not as much in neurons and astrocytes

Question 2

There is homology between Toll and?

Answer 2

IL-1

Question 3

What adaptor protein is used by TLR and IL-1 signalling?

Answer 3

MyD88 (Myeloid differentiating factor 88)

Question 4

1, 2, 3, 4 - which is the main TLR for bacteria and endogenous ligands?

Answer 4

TLR-4

Question 5

Know that they are various activators of TLRs

No TLR antagonists currently for clinical use as TLR discovered recently - TLR antag is able to lead to possible decrease in inflammation

Answer 5

Know that they are various activators of TLRs

No TLR antagonists currently for clinical use as TLR discovered recently - TLR antag is able to lead to possible decrease in inflammation

Question 6

Two types of Stroke - what are they? Which is less fatal?

Answer 6

Two types of Stroke

1) Ischemic (80%) - Blood clot and blood gets into an area of the brain
2) Hemorrhagic (20%) - burst blood vessel and brain is flooded with blood

*Ischemic is less fatal as 80% of people live, where else 20% live in hemorrhagic

Question 7

What is the only drug for treatment of stroke? Must be administered within __ hour of stroke onset

Answer 7

Tissue plasminogen activator (tPA) - a serise protease that converts plasminogen into plasmin (enzyme for clot breakdown)

4. 5 hour of stroke onset - anyone getting tPA pass that time leads to ROS building up in the brain HENCE tPA is only suitable for 10% of stroke patients
   * ONLY for ischemic stroke, if used for hemorrhagic stroke, people die

Question 8

What happens after stroke in the brain?

Answer 8

Excitotoxicity then inflammation

Question 9

What is the purpose of inflammation?

Answer 9

To limit the spread of infection by removing damaged cells and promotion healing

Question 10

!Inflammation is initiated by immune cells present in the tissue - mainly resident macrophages that express ___ that lead to inflammation. They also recognize ____ and ____

Answer 10

PRRs - pattern recognition receptors
PAMPs -pathogen-associated molecular patterns
DAMPS - danger-associated molecular patters released by injured cells

Question 11

!Unlike resident macrophages of most tissue, which are regularly used up and replaced by their circulating precursors, microglia have low/high turnover rates and low/high capacity to rapidly proliferate. They express several PRRs including?

Answer 11

Low, high, TLRs, NOD-like receptor family - pyrin domain containing 3 (NLRP3)

Question 12

Neuronal death causes activation of?

Answer 12

Microglia

Question 13

During stroke, chemokines promote ____ infiltration - why?

Answer 13

Leucocyte, to clear dead tissue away after stroke

Question 14

After leucocyte clears dead/injured tissue, there is neurogenesis occurring but it is not enough to repopulate it

Answer 14

After leucocyte clears dead/injured tissue, there is neurogenesis occurring but it is not enough to repopulate it

Question 15

In the periphery, T lymphocyte activation targets cells affected by bacteria and virus to kill them but in the brain, due to TLR this process is turned off

Answer 15

In the periphery, T lymphocyte activation targets cells affected by bacteria and virus to kill them but in the brain, due to TLR this process is turned off

Question 16

Apoptosis and necrosis, which comes first in a stroke?

Answer 16

Necrosis (less regulated, significant impact) first in the core of the infarct and contributes to its increasing size (a small localized area of dead tissue resulting from failure of blood supply)

Question 17

All TLRs use MyD88 except

Answer 17

TLR3

Question 18

Does MyD88 play a role in neuronal survival following ischemia? Glial survival?

Answer 18

NO NO

Question 19

A mouse lacking MyD88 is given a stroke and TLRs cannot work so we are not activating TLRs but why are we getting a bigger infarct?

Answer 19

The experiment is looking at neurons only but we need to look at BRAIN as a whole because there is BLOOD present - the vascular system changes during a stroke and influences the brain.

In vitro - it is detrimental
In vivo - it is protective following stroke

*Suggests that inhibiting TLR system in the blood, stops the beneficial response of these blood cells

Question 20

What does the MyD88 KO lack?

Answer 20

Ability to get infiltrating cells there - you need TLR to get them to infarct as they are beneficial