Tolerance, Autoimmunity and Transplant

Question 1

Discuss the two-signal model of T cell activation

Answer 1

Signal 1: TCR/CD3 with the MHC Class II receptor holding the antigen.

Signal 2: CD28 of the Naive T Cell and the APC receptor, such as the B7 receptor.

Thus only a “professional” APC will successfully activate a naive T Cell

Question 2

How do we become self tolerant in regards to our B Cells?

Answer 2

Only one way! Self-reactive B cells are deleted in the bone marrow during development.

Question 3

Review Central Thymus tolerance. What two steps occur?

Answer 3

Let’s reach way back here…

Firstly, the thymocyte has a TCR, and there is a positive selection. a:b T cells are tested against an epithelial MHC receptor in the thymus. If it can’t bind MHC, it’s useless, doesn’t receive signal to survive, and dies off. Only those with moderate or strong binding make it beyond this first step.

Next, Dendritic cells replace the epithelial cells. They are more picky! Moderate binding of MHC allows the T cell to live, and tight binding, a precursor to autoimmune issues, leads to that T cell dying off (negative selection)

All in the thymus!

Question 4

So we leave the Thymus and now we have perfect T cells that react with MHC and self antigen!

Wait…this sounds bad…that means we will have a lot of autoimmunity…WHAT HAPPENS NEXT TO CONTROL THE MADNESS

Answer 4

Peripheral selection

Remember, to activate properly, a T cell must bind both MHC and the other APC presenting receptor, such as B7. If the T cell just binds the MHC receptor, then its just reacting to random cells. The T cell will be signaled to anergize, which means shut down for life, even if the correct receptors are activated in the future.

Thus only the T cells that bind both parts of APC are able o proliferate.

Question 5

TH1 cells release what cytokines?

Answer 5

• IFN-y
• GM-CSF
• TNF-a
• LT
• IL-2

Question 6

TH1 cells are responsible for what?

Answer 6

Help macrophages to suppress intracellular infections

Question 7

TH2 cells release what cytokines?

Answer 7

• IL-4
• IL-5
• IL-10
• IL-13
• TGF-B

Question 8

TH2 cells are responsible for what?

Answer 8

Help basophils, mast cells, eosinophils, and B cells respond to parasite infections

Question 9

T-FH cells make what cytokines?

Answer 9

• IL-21
• IL-4
• IFN-y

Question 10

T-FH cells are responsible for what?

Answer 10

Help B cells become activated, switch isotype, and increase antibody affinity

Question 11

TH17 cells make what cytokines?

Answer 11

• IL-17
• IL-21
• IL-22
• IL-26

Question 12

TH17 cells are responsible for what?

Answer 12

Enhance the neutrophil response to fungal and extracellular bacterial infections

Question 13

T reg cells make what cytokines?

Answer 13

• TGF-B
• IL-10
• IL-35

Question 14

T reg cells are responsible for what?

Answer 14

Suppress the activities of other effector T-cell populations

Question 15

How do T reg cells slow down other T cells?

Answer 15

Two methods

1. Release cytokines that are immunomodulatory
2. Bind to an APC that a CD4 T cell is bound to and suppress it

Question 16

What do we mean by privileged sites and how might autoimmunity happen there?

Answer 16

Privileged sites are ones where the immune system is not present. Exposure of these sites to the immune system causes confuson, because the immune system doesn’t recognize them.

Most common occurrence is in the eye after an eye trauma

Question 17

Discuss that causes APECED and what general issue is leading to the autoimmunity

Answer 17

This is an AIRE gene issue leading to decreased expression of self antigen in the thymus, resulting in defective negative selection of self reactive T cells

Question 18

How is autoimmunity triggered in Group A Strep?

Answer 18

Molecular mimicry causes T cells to react to GAS, as well as cells in our body that look a lot like it.

Consequence is Rheumatic fever, carditis, polyarthritis.

Question 19

Discuss what mediates Type I hypersensitivity and what diseases we associate with it?

Answer 19

IgE mediated Immediate Hypersensitivity

Associated with Atopy
Anaphylaxis
Asthma

Question 20

Discuss what mediates Type II hypersensitivity and what diseases we associate with it?

Answer 20

IgM and complement or IgG antibody mediated hypersensitivity

Associated with Autoimmune hemolytic anemia, Goodpasture’s disease, erythroblastosis fetalis

Question 21

Discuss what mediates Type III hypersensitivity and what diseases we associate with it?

Answer 21

IgG and complement immune-complex mediated hypersensitivity. This is where the complexes deposit in tissues.

Associated with serum sickness, arthus’ reaction, and lupus nephritis

Question 22

Discuss what mediates Type IV hypersensitivity and what diseases we associate with it?

Answer 22

T cells, macrophages, histiocytes - Delayed hypersensitivity

Associated with transplant rejection, contact dermatitis, tuberculosis

Question 23

What is happening with autoimmune hemolytic anemia

Answer 23

We form antibodies to RBCs, which bind the RBC. Complement get activated and also coat the RBCs, leading to macrophage digestion of them and hemolytic anemia.

Question 24

What is happening with Type I Diabetes?

Answer 24

Remember there are several cell types in the islets of langerhans.

In type 1 diabetes an effector T cell recognizes peptides from a Beta cell specific protein and kills the beta cell.

Glucagon and Somatostatin keep getting released by alpha and delta cells without beta cells

Question 25

What leads to hyperacute rejection?

Answer 25

Crossing blood groups with organ donation

If putting a kidney from Blood type B into a type A person, the preformed Type B antibodies in the recipient will cause destruction of the kidney by targeting the B antigens in the vasculature of the donated kidney, causing Kidney destruction vigorously

Type II hypersensitivity!.

Question 26

Acute rejection is what exactly?

Answer 26

Caused by T cell responses to non-self HLA alleles expressed on an allograft.

Translation: So we get this donor specific kidney. This kidney still has some immune cells in it due to the inflammation surrounding the surgery, etc. These resident cells get mobilized (turned on) and hop out of the kidney into a draining lymph node. The problem with these cells though are that they are from the donor, meaning they don’t have the self expressing HLA molecules of the recipient. T cells of the recipient respond to these cells, and thus, cause a host response onto the new kidney.

Controllable with immunosuppression. This is a type IV reaction since it is T cell mediated.

Question 27

What is chronic rejection?

Answer 27

Caused by formation of antibody/HLA immune complexes.

So we have this new kidney. As cells on this new kidney begin to die, the host begins to pick up fragments of peptides that are HLA, but have a couple amino acid differences to the host HLA. Uptake by dendritic cells leads to presentation of allo-HLA peptides to recipient CD4 T cells, some of which turn in to Tfh cells.

B cells then thus get turned to plasma cells that attack dead donor cells. This causes recruitment of inflammatory cells to the blood vessel walls of the transplanted kidney.

Recall this is Type III hypersensitivity.

Question 28

How does Belatacept work?

Answer 28

This guy is an immunosuppressive.

It plays on the two step reaction needed to cause T Cell immune response. It is a soluble chimera of Ig Fc region and CTLA4.

So our crazy alloreactive T-cell receptor binds foreign MHC and generates signal 1 YAYYYY

BUT THEN, Belatacept binds B7 and prevents engagement of CD28 and generation of signal 2

Question 29

How do Cyclosporin A and Tacrolimus work?

Answer 29

ZAP-70 signaling causes activation of NFAT, NF-kB, and AP-1. These transcription factors lead to the activation of transcription of the IL-2 gene.

CsA or FK-506 (Tacrolimus) target NFAT, thus inhibiting IL-2

Question 30

Two general immunosuppressive functions of immunosuppressive drugs?

Answer 30

They will either:

1. Deplete T-cells - We use this for preconditioning (reduces the number of T cells that can respond to the graft)
2. Interfere with T cell activation - Great for long term maintenance

Question 31

What huge issue do we need to worry about with bone marrow transplant that no other transplantation leads to?

Answer 31

Bone marrow has active mature T cells from the donor. When you put it into a recipient, these T cells wil react to the host HLA molecules, leading to massive graft vs. host disease

We handle this by depleting the T cells from the donor.