L9 - K Okkenhaug - Tolerance

Question 1

Answer 1

Question 2

why is tolerance important?

(2)

Answer 2

avoid responding to self materials

avoid responding to innoculous substances

Question 3

is tolerance aquired or hard wired?

Answer 3

aquired

Question 4

Strong adaptive immune responses almost always require the antigen to be injected in,….

Answer 4

Strong adaptive immune responses almost always require the antigen to be injected in a mixture known as an adjuvant

Question 5

how do adjuvants work?

Answer 5

• cue an infection is taking place
• convert soluble protein into particular material
  
  • which can be ingested by APC (eg macrophage)

Question 6

what is actually in adjuvant?

Answer 6

Many of them contain bacterial products, which stimulate macrophages or dendritic cells through Pattern Recognition Receptors. Complete Freund’s Adjuvant (CFA) for example, contains ground-up mycobacteria.

Question 7

describe central tolerance? for t cells

Answer 7

• T cells:
• Negative selection leads to deletion of those T cells with strong affinity for self

Question 8

describe central tolerance ofr B cells

Answer 8

since need activating by T cells - shouldnt need tolerating

B cells that react to abundant antigens on self cells are eliminated as they develop. Self-reactive cells have an opportunity to avoid apoptosis by replacing the light chain in a process called receptor editing. High doses of soluble proteins result in anergy rather than apoptosis.

Question 9

what is anergy?

Answer 9

A state of immune unresponsiveness

Question 10

why isnt central tolerance enough?

Answer 10

thymus doesnt present all self antigens

so we have peripherla tolerance too

Some antigens are not expressed until after the immune system has matured

Question 11

what is AIRE

Answer 11

a transcription factor called AIRE, which turns on many ‘peripheral’ genes in the thymus, so that the developing T cells may be exposed to their products.

allows thymus to express most peripherla proteins for tolerance to be calibrated againstq

Question 12

what happens in individuals which lack AIRE

Answer 12

suffer from a wide range of autoimmune conditions. The condition is called APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Question 13

4 proposed mechanisms for peripheral tolerance?

Answer 13

1. ignorance
2. split tolerance
3. anergy
4. Suppression

Question 14

describe split tolerance?

Answer 14

since immune pathways are interdependant - dont all need tolerising.

ie, since B cells rely on T cells, if T cells are tolerised - thats enough

The explanation of this is that it takes 100-1000- times more antigen to tolerise B cells than it does T cells. As a result, this type of split tolerance situation is reasonably common for self serum proteins.

Question 15

describe what Anergy is - as an explanation for peripheral tolerance

Answer 15

an be induced in T cells if the receptor is engaged by the MHC molecule but the second signal is absent

constantly occurs wiht self proteins.

Large amounts of soluble antigen lead to anergy if it is not cross-linked at the cell surface.

Question 16

what is meant by supression - peripheral tolerance wise

Answer 16

Idea that Treg can supress the activation of T cells bound to self antigens on MHC II - supress proliferation

secretion of IL-10 and TGF beta

Regulatory T cells express high levels of CTLA-4 - which binds B7 more strongly

not too sure on this one tbh

Question 17

what is IPEX

Answer 17

• X linked
• congenital lack of Treg
• mutations in FOXP3
• die under age of 2 unless given bone marrow transplant
• shows peripheral tolerance is essential

Question 18

what is meant by ignorance? - peripheral tolerance

Answer 18

when potentially self-reactive T cells are not activated. This could be because antigens are hidden from the immune system in locations that are not freely exposed to surveillance. These immunologically privileged sites include the brain, eye and testis.

Question 19

CTLA-4 and PD-1 are ……

Answer 19

CTLA-4 and PD-1 are inhibitory receptors that antagonise T cell activation and co-stimulation

Question 20

give some facotrs which affect tolerance

Answer 20

timing, dose of antigen, amount of costimulation and location

Question 21

does tolerance only operate in early loife?

Answer 21

no - bone marrow transplants can lead to the host developing a chimerism - which is needed to allow grafts to be accepted

check the notesa dn read ofr this one

Question 22

why dont mothers reject their babies?

Answer 22

1. Physical barrier to the mother’s T cells.
2. Lack of MHC class I expression on trophoblasts. Trophoblast cells that form the outer layer of the placenta in contact with maternal tissues do not express classical class I molecules and so are not targets for cytotoxic T cells.
3. Production of immunosuppressive factors such as 􏰀-fetal protein and IDO (indoleamine 2,3-dioxygenase, a tryptophan catabolising enzyme).

Question 23

describe a co-receptor blockade?

Answer 23

CD28 costimulation is essential - blocking blocks immune repsonse.

Abetacept (soluble CTLA4 fusion protein) blocks CD28

use to treat rheumatoid arthritis and to prevent graft rejection.

Question 24

can anti-PD1 and Canti-CTLA4 antibodies be used in cancer therapy?

Answer 24

yep - they blockimmune check points - allowing cancers new neopeptides (cancer mutations make self peptides different) to look foreign - elciting an immune repsonse.

Question 25

T or F

Antibodies against CTLA-4 or PD-1 are used to elicit anti-tumour immune responses.

Answer 25

T

Question 26

Side effects of anti-CTLA-4 and anti-PD-1

Answer 26

Because anti-CTLA-4 and anti-PD-1 break immunological tolerance, they also cause autoimmunity.

Question 27

fat

Answer 27

mamba