Tolerance And Autoimmunity - Bowden (Completed)

Question 1

What is central tolerance? 6

Answer 1

Happens in primary lymphoid organs

Ensuring lymphocytes are tolerant to self

Question 2

Where does central tolerance for T lymphocytes occur? 8

Answer 2

In the thymus

Question 3

What will a defect in AIRE lead to? 8

Answer 3

AIRE - autoimmune regulator protein

Defects in AIRE results in autoimmune polyendocrinopathy

Question 4

What is responsible for negative selection in developing T cells? 8

Answer 4

AIRE - autoimmune regulator protein

Question 5

What can happen when a thymocyte has intermediate affinity for self Ag? 9

Answer 5

If FOXp3 is upregulated in the thymocyte it will mature into a Treg cell

Question 6

What mediates peripheral tolerance? 10

Answer 6

Treg cells

Question 7

What do Treg cells secrete? 10

Answer 7

IL-10 (anti-inflammatory)

TGF-β

Question 8

What would a loss of FOXp3 TF in the body result in? 10

Answer 8

Widespread NK cell autoimmunity

Question 9

What can Treg cells inhibit? 10

Answer 9

Effector T cells

B cells

NK cells

Naive T cell activation

Question 10

Why is B7-1/2 (CD80) down-regulated when the body is not fighting disease? 11

Answer 10

Pro-inflammatory cytokines are responsible for up regulation of B7-1/2 (CD80)

Question 11

Where would you expect ot find a high concentration of Tolerogenic self Ags and immunogenic foreign Ags? 15

Answer 11

Tolerogenic self Ags highly concentrated in primary lymphoid organs

Immunogenic foreign Ags are highly concentrated in secondary lymphoid organs

Question 12

What can contribute to autoimmune disease? 18

Answer 12

Susceptibility genes

Infections

Environmental factors/triggers

All of the above lead to breakdown of tolerance

Question 13

What are the effector mechanisms of auto-immunity? 19

Answer 13

Circulating auto-Abs

Auto-reactive T lymphocytes

Question 14

What acuity would you expect for an autoimmune disease that was organ-specific vs systemic? 20

Answer 14

Organ-specific –> acute

Systemic –> chronic and progressive

Question 15

Why can autoimmune diseases be chronic? 21

Answer 15

Because the self-Ag specific lymphocyte undergoes clonal expansion making many copies that persist and cause disease

Question 16

Why can autoimmune diseases be persistent? 21

Answer 16

With the destruction of target cells via self-reactive lymphocytes new Ags are released into inappropriate compartments and are responded against via normal healthy immune cells

Question 17

What are the main environmental inducers of autoimmune disease? 22

Answer 17

Infection - Rheumatic fever

Physical trauma - sympathetic ophthalmia

Drug induced - SLE

Question 18

What can mediate autoimmunity? 23

Answer 18

Can be mediated by both the humoral immunity and cel-mediated immunity

Question 19

What protein is most prevalent in genetic autoimmune diseases? 25

Answer 19

HLA alleles (primarily HLA Class II)

Question 20

What HLA allele has been shown to have a 90% relative risk for developing ankylosis gentlemen spondylitis when mutated? 25

Answer 20

HLA-B27

Question 21

Defects in Foxp3 results in? 26

Answer 21

Breakdown of peripheral tolerance

Question 22

Defects of FAS results in? 26

Answer 22

Defective apoptosis in B and T peripheral cells (adrenals)

Question 23

What is molecular mimicry? What’s an example? 27

Answer 23

In the process of destruction of a microbe people with certain mutations in HLA genes accidentally identifies normal tissue

Ex. Strep, immune system accidentally identifies cardiac tissue as strep because of the resemblance of the Ags

Question 24

What is the Ag, Ab, and consequence in Graves’ disease? 29

Answer 24

Ag - thyroid stimulating hormone receptor

Ab - agonist

Consequence - hyperthyroidism

Question 25

What is needed to induce SLE (systemic lupus erythromysis)? 30

Answer 25

Susceptibility genes + external triggers Immune complexes are not cleared and therefore auto-abs are eventually made

Question 26

What's happening in RA? 31

Answer 26

Inflammation of the synovium - inflammation sustained by Th17/Th1 response - auto-ab production (rheumatoid factor)

Question 27

What is rheumatoid factor? 31

Answer 27

An Ab that binds the Fc portion of IgG (prevalent in RA)

Question 28

What is a biological therapy targeted against IL-6? 33

Answer 28

Tocilizumab

Question 29

What is a biological therapy targeted against IL-1? 33

Answer 29

Anakinra Rilonacept

Question 30

What is a biological therapy targeted against IL-23? 33

Answer 30

Uztekinumab ABT874

Question 31

What is the biological therapy role of Anti-CD25? 34

Answer 31

Decreases T cell autocrine response to IL-2

Question 32

What is the biological therapy role of Anti-CD20? 34

Answer 32

Targets mature naive B cells for deletion

Question 33

What is IPEX? 40

Answer 33

Mutated FOXP3 resulting in loss of function of Treg cells (uninhibited T cell activation)

Question 34

What are the most common symptoms of IPEX? 40

Answer 34

Inflammation of gut --> colitis--> Intractable diarrhea --> failure to thrive Dermatitis Autoimmune diabetes (type I)

Question 35

What is the inheritance of IPEX? 40

Answer 35

X-linked --> male susceptibility

Question 36

What would you expect to see from a serum Ab panel taken from an IPEX patient? 40

Answer 36

Normal serum levels of all Abs except elevated IgE (hyper-IgE)