Lecture 20: Perturbations in the Super System

Question 1

What is a superantigen?

Answer 1

a bacteria or virus that has developed ways to circumvent our immune system

Question 2

What 3 major ways do superantigens differ from conventional peptide antigens?

Answer 2

1) React with MHC class II in UNPROCESSED form (is not taken up, digested, and presented)
2) the binding portion of the TCR that reacts with them is NOT within the classic peptide binding groove or antigen specific antibody receptor on B cells but on the SIDE of mononuclear MHC Class II TCR complex
3) elicit massive, immediate primary polyclonal response in T cells

Question 3

Go over the 3 differences present in a superantigen again?

Answer 3

1) binds to MHC sideways
2) binds to MHC unprocessed
3) elicits massive polyclonal T cell response

Question 4

What is the effect of superantigens?

Answer 4

cause MASSIVE outpouring of pro-inflammatory cytokines (can lead to severe cytokine storms)

essentially starts a huge TMMI which leads to huge macrophage activation

Question 5

What is toxic shock syndrome?

Answer 5

massive release of TNFa in response to a superantigen (releases IFNy which activates macs which release TNFa)

TNFa leads to loss of endothelial integrity, decreased vascular resistance, and ultimately shock

Question 6

What are 3 ways viruses can mediate their effects to evade immune response?

Answer 6

1) increase/decrease production of cytokines
2) upregulate or suppress cytokine receptor display
3) make soluble decoys

Question 7

shock sydromes are usually caused by _____________

Answer 7

superantigens

Question 8

What causes cytokine storm?

Answer 8

rapid activation of T cells

Question 9

The intensity of the superantigen response is dependent on what?

Answer 9

host’s MHC Class II polymorphism

Question 10

Why are superantigens an ineloquent way to get around the immune response?

Answer 10

because the host doesnt last long (dies soon)

problematic for viruses which require living host

Question 11

Successful viruses are those that evolved ways to do what?

Answer 11

1) sneak past innate alarm systems like TLRs

2) hijack host genes that are used to modify for suppress immune responses

Question 12

What is the third highest cause of morbidity and mortality?

Answer 12

autoimmune disease

Question 13

True or False: autoimmune disease is caused by self reactive T and B cells

Answer 13

true

Question 14

Do genetics play any role in autoimmune disease?

Answer 14

yes! (why monozygotic twins are at greater risk)

Question 15

Does environment play a role in autoimmune disease?

Answer 15

yes! gluten/celiacs, MS/higher latitudes, etc

Question 16

What are the 2 major types of tolerance?

Answer 16

Central and peripheral

Question 17

Describe central tolerance for T cells in the thymus

Answer 17

• negative and positive selection. Positive selects for T cells that recognize host MHC while negative selection selects against those that recognize host (self-reactive T cells)

AIRE driven development of Tregs

Question 18

How stringent is central tolerance for T cells in the thymus?

Answer 18

VERY 98% of T cells die

Question 19

What is a main way the thymus prevents autoimmunity?

Answer 19

AIRE (gene expressed and shows maturing T cells host antigens to make sure they won’t react)

Question 20

What happens if a self-epitope is missing from the AIRE presentation?

Answer 20

an auto-reactive cell slips through the thymus and goes out into the periphery

Question 21

What is the MAIN effector of peripheral tolerance for T cells?

Answer 21

Tregs

Question 22

What are the CD markers of Tregs?

Answer 22

4 and 25

Question 23

What two cytokines can produce Tregs in the periphery during immune reactions?

Answer 23

IL-10 and TGFb

Question 24

When you see TGFb out in the periphery, what should you think?

Answer 24

it is trying to turn the immune response down

Question 25

What controls/mediates Treg function?

Answer 25

CTLA4 (controlled by FoxP3) acts as a break

Question 26

Tregs are influenced by the ratio of _____ to _____

Answer 26

IL-6 to TGFb

Question 27

Tregs are dependent on which cytokine for growth?

Answer 27

IL-2

Question 28

What is HUGE site of peripheral tolerance (relatively new)?

Answer 28

the gut

Question 29

How is tolerance established in the gut?

Answer 29

symbiont PAMPs drive TLRs to induce tolerance

Question 30

What happens if you are missing AIRE gene?

Answer 30

multiple autoimmune diseases

Question 31

What happens if you don’t have the FoxP3 gene?

Answer 31

widespread T and B autoimmune reactions

Question 32

True or False: complete loss of the CTLA4 gene is fatal

Answer 32

true (partial loss causes extensive autoimmunity)

Question 33

Is tolerance limited to T and B cells?

Answer 33

NO it depends on everything including TLRs and DCs (over or under expression can lead to autoimmunity, if for example TLRs start presenting nuclei acid antigens)

Question 34

How are viruses linked to T1DM? (3 ways)

Answer 34

1) viruses can directly infect pancreatic beta cells and initiate CD8 attack against them
2) viruses can exhibit antigens that mimic beta cell antigens so CD8 cells mistakenly attack beta cells as well
3) infect non beta cell sites in the pancreas and incite collateral damage to beta cells

Question 35

The new sub-lineage of Th cells that are Th1 but produce IL-17 (NOT IFNy) and express ROR not T-bet will produce Tregs if what happens?

Answer 35

ONLY TGFb is present

co-presence of IL-6 and 23 PREVENT Tregs and allow Th17 differentiation

Question 36

What prevents the development of IL-17?

Answer 36

If either IFNy or IL-4 are present (therefore found in high conc at autoimmune inflammatory sites to prevent Th17)

Question 37

What conditions favor DC signaling with IL-23? (aka what favors autoimmune vs Treg development)

Answer 37

NO ONE KNOWS

genetic differences in TLR, DC? AIRE defects?

Question 38

Which cytokine mediates the effects of Th17 responses?

Answer 38

IL-17

IL23 starts Th17

Question 39

True or false: most of us have autoreactive B cell clones

Answer 39

TRUE but they are not productive

Question 40

Why aren’t our autoreactive B cell clones productive?

Answer 40

most cases, parallel auto-reactive T cell will not be there or a Treg will be there (no T cell help = no autoantibody formation because no B cell proliferation)