Breakout (L7)

Question 1

Only cells with antigen-specific receptors can be tolerant. This limits the effects of tolerance to ___ and ___ cells

Answer 1

B and T cells

Question 2

___: Tolerance that occurs early in lymphocyte development

Answer 2

Central Tolerance

Question 3

Where does central tolerance occur for B cells? for T cells?

Answer 3

B cells - bone marrow
T cells - thymus

Question 4

_____: allows for regulation of “escapees” of central tolerance

Answer 4

Peripheral Tolerance

Question 5

What can occur if a cell escapes from both central and peripheral tolerance?

Answer 5

Auto-immune responses

Question 6

Once a B cell starts to express ___ on the surface of the bone marrow, the immature B cell undergoes selection for self-reactivity

Answer 6

IgM

Question 7

If the immature B cell expresses a self-reactive IgM on the surface of the cell, central B cell tolerance is induced by one which two mechanisms?

Answer 7

1) Clonal Anergy
2) Clonal Deletion

Question 8

Clonal anergy typically occurs with ___ antigens
Clonal deletion typically occurs with a ___ or ___ antigens ; it involves arrested development followed by apoptosis

Answer 8

Clonal anergy = soluble antigens
Clonal deletion = particulate; cell-associated antigens

Question 9

Once in the peripheral lymphatics, self-reactive B cells that escaped central tolerance receive _______ through the B cell receptor on cell surface

Answer 9

constant, low level stimulation

Question 10

What helps maintain B cell in anergic/unresponsive state?

Answer 10

Chronic stimulation of BCR in absence of secondary signals

Question 11

All the peripheral B cells require stimulation through a receptor for the cytokine ___ for survival

Answer 11

BAFF

Question 12

Why do anergic B cells have a significantly short half life in the periphery?

Answer 12

Anergic B cells do not compete well with non-anergic mature B cells for the limited amount of BAFF in lymphatic system

Question 13

Scientists have discovered that, in tolerizing signals that induce anergy, the ITAM motifs are ____

Answer 13

hypo-phosphorylated

Question 14

In tolerizing signals that induce anergy, ITAM motifs are hypo-phosphorylated. This lack of complete ITAM phosphorylation results in altered signal, which leads to activation of ___ and ___, but not ___

Answer 14

NFAT; AP-1
NOT NF-kB

Question 15

What is a major factor that renders the immature B cell as anergized and not activated?

Answer 15

Absence of NF-kB activation in immature B cells

Question 16

Under pathological conditions, when a self-reactive, immature B cell is exposed to a membrane bound self-antigen for which they are specific, the ITAM motif becomes ______

Answer 16

hyper-phosphorylated

Question 17

What are the effects of hyper-phosphorylation of ITAM motif in self-reactive, immature B cells exposed to membrane-bound antigen that they’re specific for?

Answer 17

1) Induction of BCR signal transduction cascade
2) Inappropriate activation of ERK1/2

Question 18

The activation of ERK1/2 in the immature B cell results in the _____ and the _____

Answer 18

1) induction of apoptosis cascade
2) deletion of self-reactive B cell

Question 19

During central T cell tolerance, T cell clones whose TCR strongly recognizes self-peptides present in MHC molecules undergo ___

Answer 19

apoptosis

Question 20

Peptides presented in MHC molecules in the thymus are almost always what kind of peptides?

Answer 20

Self peptides

Question 21

Where does peripheral tolerance of T cells occur?

Answer 21

Peripheral tissues (spleen and lymph nodes)

Question 22

Primary stimulation of T cells (MHC/peptide-TCR) without secondary stimulation (B7-CD28) can result in functional inactivation of the T cell called ____

Answer 22

clonal anergy

Question 23

What is required in peripheral T cell tolerance to stabilize IL-2 mRNA and stop it from being degraded?

Answer 23

B7-CD28 interaction

Question 24

What renders a T cell anergic?

Answer 24

1_

Question 25

True or False: Once T cells become anergic, they cannot be activated even if they encounter their specific foreign peptide/MHC molecule

Answer 25

True
(this is thought to be MAIN mechanism for induction of unresponsiveness to antigens in the periphery)

Question 26

Repeated stimulation of activated T cells can cause T cells to die via _____

Answer 26

apoptosis (clonal deletion)

Question 27

True or False: T cell tolerance is usually less rapid and prolonged compared to B cell tolerance

Answer 27

False - T cell tolerance is usually more rapid and prolonged compared to B cell tolerance

Question 28

What subpopulation of T cells can inhibit activation of T cells by self peptide/MHC

Answer 28

Regulatory T cells

Question 29

___: a protein initially found to be expressed in the thymus and shown to be responsible for increasing the expression of tissue-specific antigens in the thymus

Answer 29

AIRE

Question 30

Where is AIRE expressed in high levels? low levels?

Answer 30

high levels: mTECS (Medullary thymic epithelial cells) of thymus
low levels: dendritic cells (thymus)

Question 31

What three mechanisms does AIRE use to increase the expression of tissue-specific antigens?

Answer 31

1) works with chromatin-remodeling proteins to modify large parts of the chromosome, leading to increase in accessibility to TF
2) Directly increases transcription of genes by acting as a TF
3) Interacts w protein compexes on “stalled” tissue-specific promoters to induce RNAPII to complete transcription of tissue-specific gene

Question 32

Tissue specific proteins that are expressed in the mTEC’s can be expressed on the ____ to induce deletion of developing T cells that are exposed to self antigen

Answer 32

HLA-Class 1

Question 33

When mTECS secrete tissue specific proteins, these proteins are taken up by ____ cells

Answer 33

local thymic dendritic cells

• dendritic cells endocytose proteins and present them in HLA Class II, leading to deletion of developing T cells that are specific for self antigen in context of HLA class II

Question 34

AIRE expression in the thymus leads to expression of self-antigens that are found ___ in the body and leads to deletion of these ____ T cells

Answer 34

thymus; self-reactive

Question 35

Autoimmune Poly-endocrinopathy-candidiasis ectodermal dystrophy (APECED) is related to mutations in ___

Answer 35

AIRE

Question 36

Three symptoms of APECED?

Answer 36

1) chronic mucocutaneous candidias
2) hypoparathyroidism
3) adrenal insufficiency