Tolerance and Autoimmunity

Question 1

What is central tolerance?

Answer 1

T-cell selection

Question 2

Where does central tolerance occur?

Answer 2

Thymus

Question 3

How does a thymocyte become a DP cell?

Answer 3

Thymocyte migrates from bone marrow to thymus and undergoes a 20-fold expansion to become a DN cell which is rearranged to form a DP cell; CD4+ or CD8+

Question 4

What is positive selection?

Answer 4

Efficient TCRb and TCRa rearrangements which can bind MHC

Question 5

What is negative selection?

Answer 5

Death by neglect, if the SP T cells cannot bind self-MHC they receive no survival signals and will undergo apoptosis. Then if they cannot bind strongly to self-peptides presented by self-MHC they will also undergo apoptosis.

Question 6

What are the products of centraltolerance?

Answer 6

Naive CD8 T cells and naive CD4 T cells

Question 7

What is peripheral tolerance?

Answer 7

Production of T reg cells which act to suppress immune responses, maintain homeostasis and self tolerance, inhibit T cell proliferation, inhibit cytokine production and prevent autoimmunity

Question 8

What is the two signal model of T cell activation?

Answer 8

Activation-signal 1 increases intercellular Ca, signal 2 CD80:CD28 activation, both for productive T cell activation via NFAT/AP1

Question 9

What is anergy?

Answer 9

No signal 2 so NFAT drives anergic response which inc IL10 and dec IL2

Question 10

What is ignorance?

Answer 10

Neither signals 1 or 2 present

Question 11

What are the. autoimmunity checkpoints?

Answer 11

Failure of central tolerance, failure of peripheral tolerance, presentation of autoantigen and co-stimulation

Question 12

What is bystander activation? (presentation of autoantigen)

Answer 12

Cytokines and PAMPS cause activation of dendritic cells causing damage which releases auto-antigens that trigger an immune response resulting in auto-reactive T cell activation and pathogen reactive T cell activation

Question 13

What is AIRE?

Answer 13

An autoimmune regulator expressed in the medullar of the thymus

Question 14

What is the cell life of B cells?

Answer 14

Pre B cell becomes an immature cell, then virgin B cell, to mature B cell which becomes either a memory B cell of a plasma cell

Question 15

How can autoimmune diseases be classified?

Answer 15

Organ specific-directed to a target antigen unique to a single organ or gland
Systemic-involves a number of target organs and tissues and response is directed towards a wider range of target antigens

Question 16

What are some examples of organ specific autoimmune diseases?

Answer 16

IDDM, hashimoto, addisons, pemphigus, vulgaris, autoimmune, haemolytic, anaemia and MS

Question 17

What are some examples of systemic autoimmune diseases?

Answer 17

SLE, sjorgrens, schleroderma, RA and polymyositis

Question 18

What is the criteria for an autoimmune disease?

Answer 18

Major
1) evidence of loss of tolerance
2) clinical response to appropriate immunosuppression
3) passive transfer of the putative immune effector
Minor
1) Animal model with similar loss of tolerance
2) evidence that putative immune effectors reproduces the disease in a naive animal
3) HLA association

Question 19

What are autoantibodies?

Answer 19

Antibodies that react with self antigens

Question 20

Evidence for autoimmunity?

Answer 20

Hyperthyroidism in the womb, Mother with Graves disease will give a baby with Graves disease due to IgG crossing the placenta

Question 21

What causes autoimmunity? (genetic and environmental)

Answer 21

Genetic susceptibility-mutations, female
Environmental-infections, hormones, drugs and toxins