Autoimmunity

Question 1

What is central tolerance

Answer 1

Autoreactive B and T cells are killed in the thymus to prevent auto-reactive lymphocytes from making it to the periphery (clonal deletion)

Question 2

What is peripheral tolerance?

Answer 2

B and T cells that escape negative selection and encounter self-Ags in the periphery:
1) become overstimulated; undergo activation-induced apoptosis
2) enter a state of anergy (functional un-responsiveness), where lack of co-stimulation results in inability to activate

Question 3

What are 4 mechanisms for autoimmunity

Answer 3

1) auto-reactive T cells escape thymic deletion
2) failure of peripheral tolerance
3) polyclonal/bystander activation
4) molecular mimicry

Question 4

Sequestered antigens

Answer 4

1) Antigens normally hidden in the immune system (e.g., inside cells, or from cells of immune-privileged organs) can become exposed during infection
2) Since they are normally sequestered, they aren’t shown to T cells as self-Ags in the process of clonal deletion
3) Release and binding will thereby activate T/B cells

Question 5

Molecular mimicry

Answer 5

1) In some cases, Ag from pathogens look like self-Ags (cross-reactivity)
2) Can lead to autoimmune response against self-Ags

Question 6

Polyclonal/bystander activation

Answer 6

1) Typically, autoreactive T-cells do not receive the secondary signal to activate
2) During an infection, autoreactive T cells can receive the signal to activate

Question 7

What methods are used to treat autoimmunity?

Answer 7

1) Carpet bombing
2) Focused attack
3) Precision guided weapons
4) Nuke (BM transplant)

Question 8

Carpet bombing

Answer 8

Corticosteroids and cyclophosphamide

Question 9

Cyclophosphamide

Answer 9

Alkylating agent that cross-links DNA and results in death of ALL proliferating immune cells

Question 10

Focused attack

Answer 10

Cyclosporin A, FK506, plasmapheresis, anti-CD4

Question 11

Cyclosporin A, FK506

Answer 11

Inhibits calcineurin/NFAT signaling which inhibits T cell activation
-non-T leukocytes are still functional but ALL T-cell activation is inhibited

Question 12

Palsmapheresis

Answer 12

Remove either all Ab (total plasma exchange) or specifically remove the autoimmune Ab from blood (plasma absorption - traps antibodies such that they do not re-enter the patient)

Question 13

Precision guided method

Answer 13

Anti-TCR clones

Question 14

Anti-TCR clones

Answer 14

Anti-CD4 targets T-cells to stabilize disease
-Depletion of all CD4+ cells = immunocompromised
-Depletion must take place during the correct stage of disease development

Question 15

Depletion of Ag-specific T cells

Answer 15

Generation of Ab against specific autoimmune TCRs (based on Valpha and Vbeta gene)

Question 16

BM transplant

Answer 16

1) Deplete patients BM and peripheral leukocytes via chemotherapy and radiation
2) Autologous or allogenic transplant

Question 17

Allogenic vs autologous BM transplant

Answer 17

Autologous - rejection less likely, but higher chance for autoimmune disease to return
Allogenic - risky due to graft failure, though less likely for autoimmunity to return

Question 18

Autograft

Answer 18

Transplant self-tissue (e.g., bone reconstruction, burn victims)

Question 19

Isograft (syngeneic graft)

Answer 19

Transplant tissue from genetically identical individual

Question 20

Allograft

Answer 20

Tissue from a genetically different member of the same species (express non-self Ags and therefore can be rejected)

Question 21

Xenograft

Answer 21

Transplant tissue between species

Question 22

What are the 3 mechanisms of graft rejection?

Answer 22

1) Hyperacute - mediated by pre-existing Abs
2) Acute - mediated by T cells (treated via immunosuppresive drugs)
3) Chronic - unknown mediator

Question 23

Process of BM transplants

Answer 23

1) Patients are placed on immunosuppressive drugs, radiation, or chemotherapy
2) Patients receive either donor BM or HSCT
3) Transplanted cells engraft in BM niches, proliferate and differentiate
4) T cell precursors traffic to recipient’s thymus where they are educated and tolerized to self-MHC

Question 24

Graft vs Host disease (GVH)

Answer 24

-Mature T cells can be transferred from donor to recipient
-Recipient does not have an immune system
-Transplanted T cells recognize “foreign” MHC and attack recipient tissues

Question 25

What is the GVH paradox?

Answer 25

In order to avoid GVH, mature T cells must be screened out prior to transplantation
However, mature T cells are required for successful engraftment
Mature T-cells may also be required to prevent malignancies from developing in the new BM