Immunology - Week 2 - Part III - Tolerance

Question 1

Who tend to be immunologically immature?

Answer 1

Children and elderly

Question 2

What is avidity?

Answer 2

The total sum of strong or weak interactions between lymphocytes and antigens

Question 3

When are both co-receptors CD4 and CD8 expressed on T-cells?

Answer 3

After a complete TCR is expressed on the T-cell between checkpoint 2 and 3

Question 4

Where does positive selection occur for T cells?

Answer 4

thymic cortex

Question 5

what is positive selection consist of?

Answer 5

Cells that express both CD4 and CD8 are allowed to survive. Weak recognition of Class I or Class II MHC leads to survival. Also, after positive selection, the T-cells only express one class of MHC molecule (they go from double positive to single positive)

Question 6

Where does negative selection occur?

Answer 6

Thymic medulla

Question 7

What does negative selection consist of?

Answer 7

Any cell that recognizes self antigens with high avidity, either class I or class II MHC, will be killed through apoptosis Any cell that doesn’t recognize self antigen at all will also be killed through apoptosis (death by neglect)

Question 8

What do defects in negative selection lead to?

Answer 8

autoimmunity

Question 9

What is the AIRE gene?

Answer 9

AIRE is a transcription factor that drives the expression of numerous tissue-specific self peptides of peripheral organs.

Question 10

What does a loss of AIRE result in?

Answer 10

auto-immune disease because of making a lot of auto-antibodies to organ specific antigens They also make autoantibodies to IL-17, which is important in controlling fungal infections

Question 11

What is a T regulatory cell? Markers? Purpose?

Answer 11

Markers: CD4, CD25, Foxp3 Purpose: key regulatory molecules for peripheral tolerance

Question 12

What are the mechaisms of peripheral tollerence? (3)

Answer 12

Anergy, suppression and deletion

Question 13

How is ANERGY used in peripheral T cell tolerance (2 mechanisms)

Answer 13

T cell binds with MHC/self antigen: BUT 1) APC doesn’t express B7 (because there was no inflammatory event) so T cell becomes anergic or 2) T cell expresses inhibitory co-receptor CTLA4/ITIM (caused by Treg), which binds to B7 and causes T cell to become anergic

Question 14

Why would an APC not express B7?

Answer 14

If there was no inflammatory event, then the APC would not have gotten signals to express B7

Question 15

How is SUPPRESSION used in Peripheral T cell tolerance? (2 mechanisms)

Answer 15

Contact Dependent: Tregs bind to mature T cells and induce them to express CTLA-4, and thus inhibit activation Contact Independent: Treg secrete high levels of TGF-beta and IL-10 that inhibit T cell activation

Question 16

How does CTLA-4-Ig biologic immunotherapy work?

Answer 16

Fuse the extracellular domain of CTLA-4 with a modified Fc molecule. The CTLA-4 will essentially be placed on the T-cell of your choice and will inhibit that T cell by binding to CD80 of the APC and prevent 2nd signal (CD28 with B7)

Question 17

What is Immune dysregulation, polyendocrinopathy, linked syndrom (IPEX)? Cause? Who does it affect? Symptoms?

Answer 17

Cause: mutation in Foxp3 and loss of T regulatory cells Affects: boys in infancy Symptoms: broad regional hyper-inflammatory response in the mucosa

Question 18

How is DELETION used in peripheral T cell Tolerance?

Answer 18

Because of REPEATED stimulation by an antigen (likely for self peptides because they’ll be a lot of them) pro-apoptotic factors are induced and T cell is killed. There is an extrinsic as well as an intrinisic mechanism for apoptosis.

Question 19

What is Fas and FasL?

Answer 19

These are key apoptosis mechanisms used in the immune system. Used in extrinsic mechanism for T cell deletion.

Question 20

What are the mechanisms of Central B cell tolerance? What does High and Low avidity with antigens lead to? (3)

Answer 20

Strong avidity leads to: Receptor editing (rearrangement of Ig L chains Deletion (negative selection by apoptosis) Low Avidity leads to: anergy

Question 21

Where does Receptor editing take place?

Answer 21

Ig light chain of antibodies

Question 22

Peripheral B cell tolerance: Where? Differences from naive B cells? (4)

Answer 22

Where: germinal centers Differences: short lifespan, defects in BCR signaling, defects in germinal centers, low parafollicular cortex migration

Question 23

What is autoimmunity? What causes it? (2)

Answer 23

an immune response against self antigens, a failure of tolerance Cause: 1) inheritance of susceptibility genes which contribute to failure of self tolerance 2) environmental triggers may activate self reaactive lymphocites

Question 24

A confluence of what three factor would most likely lead to autoimmune diseases?

Answer 24

1) Genetic susceptibility 2) Environmental triggers 3) uncontrolled immune response

Question 25

While there are many potential causes of autoimmune problems, which gene was stressed in lecture as a common gene implicated in autoimmune diseases?

Answer 25

The gene encoding MHC

Question 26

How can the environment trigger an autoimmune response? (2)

Answer 26

1) A microbe induces a costimulatory molecule to be expressed, thus a self-reactive T cell that otherwise would have been killed, is instead activated 2) molecular mimicry –> microbial peptide is similat to self peptide