Autoimmunity

Question 1

Central tolerance

Answer 1

Induced in immature self-reactive lymphocytes in primary lymphoid organs.

Question 2

Peripheral tolerance

Answer 2

Induced in mature self-reactive lymphocytes in peripheral sites.

Question 3

Fate of cells w/ central tolerance

Answer 3

Apoptosis
Develop into Treg cells
B cells can attempt a change in BCR specificity

Question 4

Fate of cells w/ peripheral tolerance

Answer 4

Anergy
Apoptosis
Suppressed by Treg cells

Question 5

AIRE

Answer 5

Found in the thymus and exposes T cells to antigens from all kinds of cell types.
Helps to protect against autoimmunity.

Question 6

Central tolerance curve explanation

Answer 6

Cells with weak avidity undergo apoptosis (nonfunctional)
Cells with high self- reactivity are deleted.
Thymocytes activated below a threshold are postively selected to become mature T cells.
A small percentage express FOXp3 and develop into Treg cells.

Question 7

Mechanism of anergy

Answer 7

T cells engage inhibitory receptors CTLA-4 or PD-1 that block activation.

Question 8

Checkpoint blockade

Answer 8

Treatment of cancer patients with anti-CTLA-4 and anti-PD-1. This can also cause autoimmune reactions.

Question 9

Cytokines affecting Treg

Answer 9

Generation of Treg requires TGF-beta
Express FOXp3 and are CD4+CD25+.
Express high levels of CTLA-4.
Cells are long-lived.
IL-2 IS CRITICAL FOR THEIR SURVIVAL.

Question 10

Inducible Treg cells (iTreg)

Answer 10

FOXp3 can be induced in mature T cells by presence of TGF-beta IF IL-6 is not present (hence a strong relationship between Th17 and iTreg).

Question 11

Retinoic acid receptor (RAR)

Answer 11

Inhibits formation of Th17 but promotes FOXp3 expression.

Question 12

Basic mechanisms for Treg cells (4)

Answer 12

Secrete inhibitory cytokines (TGF-beta and IL-10)
Cell-to-cell contact to block DC function
Metabolic disruption (death of target by deprivation of cytokines, specifically IL-22)
Cytolysis via granzyme and perforin

Question 13

Targeting of DCs by Treg mechanism

Answer 13

Binding of CTLA-4 and B7 inhibits DC maturation AND induction of IDO, which degrades Trp (an essential AA).

Question 14

B cell Central Tolerance

Answer 14

Immature B cells that recognize self-ags undergo receptor editing (further rearrangement and replacement of IgL-chain genes). If this fails, cells undergo apoptosis.
Weak recognition leads to anergy.

Question 15

Retinoic acid in Treg development

Answer 15

DCs secrete RA which stimulates developmento of Treg cells from naive CD4+CD25- T cells.

Question 16

CD22 receptor

Answer 16

An inhibitory receptor that is phosphorylated by Lyn and recruits SHP-1 to inhibit BCR signaling.
Defects in Lyn, SHP-1, and CD22 inhibitory receptor can lead to autoimmunity.

Question 17

AIRE gene causes a failure of what?

Answer 17

Central tolerance. All others cause failure of peripheral tolerance.

Question 18

AIRE Deficiency causes:

Answer 18

Autoimmune polyendocrine syndrome

Question 19

FOXp3 causes

Answer 19

IPEX Syndrome

Question 20

Mutations in AIRE are associated with:

Answer 20

Decreased expression of self-Ags in the thymus.

Question 21

Diseases associated with polymorphisms in CTLA-4 (know 2)

Answer 21

Type I Diabetes

Grave’s Disease

Question 22

2 improtant properties of CTLA-4

Answer 22

CTLA-4 expression is low on resting T cellls until activated by Ag.
CTLA-4 terminates continuing activation of responding T cells (the brakes of the system).

Question 23

CTLA-4 has both intrinsic and extrinsic actions. Explain.

Answer 23

Engagement of CTLA-4 can deliver inhibitory signals that terminate activation (intrinsic).
CTLA-4 on Treg (or any responding T cell) can bind to B7 molecules and make them unavailable to CD28.

Question 24

Polymorphisms of what genes has the strongest association with autoimmunity?

Answer 24

MHC/HLA genes

Non-HLA genes can also play a role.

Question 25

3 ways microbial Ags can elicit autoimmunity:

Answer 25

1. Molecular mimicry (Rheumatic fever, MS) 2. Polyclonal (bystander) activation to actiavte autoreactive lymphocytes (create cytokine field). 3. Release of previously sequestered Ags.

Question 26

MS molecular mimicry by microbial Ag

Answer 26

T cells react w/ myelin basic protein and peptides from EBV, influenza A and HPV

Question 27

Rheumatic fever

Answer 27

Triggered by Streptococcal infection and mediated by cross-reactivity between strep Ags and cardiac myosin.

Question 28

Estrogens exacerbate:

Answer 28

Systemic lupus erythematosus by altering B-cell repitoire in absence of inflammation.

Question 29

Penicillins can bind RBCs and:

Answer 29

Generate a neoantigen and cause hemolytic anemia.

Question 30

Immune privileged sites (7)

Answer 30

``` Eye Brain Pregnant uterus Ovary Testes Adrenal cortex Hair follicle ```

Question 31

Immune privilege

Answer 31

These tissues are able to tolerate the introduction of antigens without eliciting an inflammatory immune response.

Question 32

Strongest associations with MHC genes 1-4 ATRP

Answer 32

Ankylosing spondylitis (MHC I) Type I DM (MHC II) RA (MHC II) Pemphigus vulgaris (MHC II)