Immunologic Tolerance and Autoimmunity (part I)

Question 1

immunological tolerance is specific ____ to an Ag

Answer 1

unresponsiveness

Question 2

the negative selection of self-reactive T lymphocytes in the thymus is

Answer 2

NOT perfect

Question 3

central tolerance:

prevents creation of ____ lymphocytes

generated only in ____ ____ organs

Answer 3

self-reactive

primary lymphoid

Question 4

peripheral tolerance:

moderates ____ of lymphocytes (not just self-reactive lymphocytes)

occurs in ____ tissues

Answer 4

action

peripheral

Question 5

peripheral Tolerance:

mautre self-reactive lymphocytes in peripheral tissues may be either:

1.

2.

3.

Answer 5

1. inactivated (anergy)
2. deleted (apoptosis)
3. suppressed by the Treg cells

Question 6

Central B Cell Tolerance:

1. only a fraction of immature B cells generated in the bone marrow enter the mature B-cell pool in ____ to produce Abs
2. self-reactive immature B cells undergo:
   
   1. ____ ____
   2. ____ ____
   3. ____
3. only allows non-self reactive B cells into ____
4. occurs in the ____ ____

Answer 6

1. circulation
2. 1. clonal deletion (negative selection)
   2. BCR editing
   3. anergy
3. circulation
4. bone marrow

Question 7

BCR editing:

pre-B cells expressed rearranged IgH chains recombine the locus that encodes IgL chain yielding a lymphocyte with an ____ antigen receptors

BCR signaling promotes developmetnal arrest and continued ____

receptor editing of the IgL chain leads to expression of a distinct IgL chain, generating cell-surface immunoglobulin that lacks ____

____ and ____ are used for heavy/light chain recombination

Answer 7

autoreactive

recombination

self-reactivity

RAG1 and RAG2

Question 8

selection of nonautoreactive and autoreactive immature B cells

high avidity autoreactive, medium autoreactive, low avidity autoreactive →

low avidity autoreactive + nonautoreactive and nonautoreactive →

Answer 8

BCR editing

positive selection

Question 9

central T cell tolerance:

1. self-reactive immature T cells:
   
   1. strongly self-reactive (determined by interactions with MHC-self peptide complexes) →
   2. weakly self-reactive →
2. receptor ____ is not an option for T cells
3. only allow non-self reactive T cells or Treg cells into ____
4. only occurs in the ____

Answer 9

1. 1. clonal deletion (negative selection)
   2. express FoxP3 and become Treg cells (this is still a form of positive selection)
2. editing
3. circulation
4. thymus

Question 10

apoptosis in central tolerance:

____ pathway is used in central tolerance due to lack of survival signals given to self-reactive lymphocytes (death receptor (extrinsic) pathway does not operate in the thymus or bone marrow

in the generation of Treg cells, FoxP3 promotes anti-apoptic mechanisms allowing the Treg cell to resist undergoing ____ in the thymus

Answer 10

mitochondrial (intrinsic)

apoptosis

Question 11

Treg cells:

1. natural Treg cells develop in the ____
2. are positively selected in the thymus via strong TCR interactions with ____
   
   1. after recognition of self-Ags, they are not eliminated by ____
   2. Treg cells produce ____ molecules which protect them from negative selection in the thymus
3. express FoxP3 and are ____ and ____ positive
4. express high levels of ____
5. cytokine ____ is critical for survival and competence of Treg cells
6. serve to prevent potential ____ reactions in various tissues
7. induced Treg cells (iTreg) (Th0) differentiate in the ____

Answer 11

1. thymus
2. self-Ags
   
   1. apoptosis
   2. anti-apoptotic
3. CD4+ and CD25+
4. CTLA-4
5. IL-2
6. autoimmune
7. periphery

Question 12

peripheral T cell tolerance:

1. T cell function is regulated by:
   
   1. ____ : lack of costimulation (CD80/86) from APCs
   2. ____ : Treg cells block activation by competing for IL-2 and CD80/86 in addition to inhibiting APC function
   3. ____ : unduced apoptosis

Answer 12

1. 1. anergy
   2. suppresion
   3. deletion

Question 13

peripheral B cell tolerance:

1. B cell function if regulated by:
   
   1. ____ : insufficient signaling by Th cells preventing TD activation
   2. ____ : activation of CD22 on inhibitory surface protein on B cells
   3. ____ : induced apoptosis

Answer 13

1. 1. anergy
   2. inhibition
   3. deletion

Question 14

CD22 in B cell regulation:

1. functions as an ____ of B cell activationo
2. binds ____ acids which is found on mammalian cell membranes (identifies self from non-self)
3. has an ____ that when activated binds SHP-1, a phosphoyrlase, that dephosphoyrlates ITAMS of the BCR complex

Answer 14

1. inhibitor
2. sialic
3. ITIM

Question 15

apoptosis in peripheral tolerance:

____ and ____ pathways can be used

____ is a survival signal for B cells; without it, immature B cells that are being activtaed undergo apoptosis via the intrinsic pathway

Answer 15

mitochoondrial (intrinsic) and death receptor (extrinsic)

BAFF

Question 16

transforming growth factor-beta:

1. inhibits the proliferation and effector functions of ____
2. inhibits development of Th1 and Th2 subsets but promotes ____ (with IL-1 and IL-6)
3. inhibits activtion of ____ macrophages
4. regulates the differenitation of induced FoxP3+ ____
5. stimulates production of ____ by inducing B cells to switch to this isotype
6. promotes ____ repair after local immune and inflammatory reactions subside stimulating ____ synthesis and matrix-modifying enzyme production by macrophages and fibroblasts

Answer 16

1. T cells
2. Th17
3. M1
4. Treg cells
5. IgA
6. tissue collagen

Question 17

iTreg and Th17 production:

1. occurs ____ the thymus with ____ cells
2. both are stimulated by ____ acid and TGF-beta however:
   
   1. ____ promtoes Th17 and inhibits iTreg
   2. ____ promotes iTreg and inhibits Th17
   3. easy way to remember: IL-6 and Th17 cells are both pro-inflammatory -or- IL-2 is required by all Treg cells

Answer 17

1. outside Th0
2. retinoic
   
   1. IL-6
   2. IL-2

Question 18

natural Treg cells:

1. produced in the ____
2. generated by ____ tolerance
3. inhibit responses only to ____

iTreg cells:

1. prouced in ____
2. generated as part of ____ tolerance
3. can inhibit response to ____ Ag

Answer 18

natural Treg cells:

1. thymus
2. central
3. self-Ag

iTreg cells:

1. LNs or periphery (digestive tract)
2. peripheral
3. non-self Ags (such as food Ags)

Question 19

both natural Treg and iTreg cells:

1. mediate ____ tolerance
2. surface markers:
3. differentiation stimulated by ____ and IL-2
4. ____ is required for surviva/function

Answer 19

1. peripheral
2. CD4+, CD25+, FoxP3+
3. TGF-beta
4. IL-2

Question 20

role of Treg cells in peripheral tolerance:

1. inhibits T cells:
   
   1. consume IL-2 via constitutive expression of ____ (IL-2 receptor alpha)
   2. blocks costimulation by APC CD80/86 via constitutive epxression of ____
2. inhibits B cells:
   
   1. inhibition of T cells prevents ____ B cell activation
3. inhibits APCs:
   
   1. binds APCs but does not express ____ and blocks effector T cells with their CD40L
4. generates an anti-inflammatory cytokine state via ____ and ____

Answer 20

1. 1. CD25
   2. CTLA-4
2. 1. TD (thymus dependent)
3. 1. CD40L
4. IL-10 and TGF-beta

Question 21

T cell may engage inhibitory receptors ____ or ____ that causes suppression of T cell response

Answer 21

CTLA-4 or PD-1

Question 22

T cell anergy and suppression

therapeutic application: treatment of cancer patients with ____ and ____ that block CTLA-4 and PD-1 receptors

leads to enhance antitumor immune responses and tumor regression, this type of therapy is known as ____ ____

checkpoint blockade often develop ____ reactions

Answer 22

anti-CTLA-4 and anti-PD-1

checkpoint blockade

autoimmune

Question 23

mutations breaking the tolerance:

central tolerance: AIRE

peripheral tolerance: C4, CTLA-4, Fas/FasL, FoxP3, IL-2; IL-2R-alpha/beta, and SHP-1

Answer 23

AIRE

C4, CTLA-4, Fas/FasL, FoxP3, IL-2; IL-2R-alpha/beta, and SHP-1

Question 24

incomplete induction of tolerance in the thymus (AIRE deficiency) causes

Answer 24

autoimmune polyendocrine syndrome

Question 25

AIRE as a component of central tolerance:

AIRE is expressed in ____/____ cells of the ____ and allows presentation of Ags that are normally restricted to only elsewhere in the body leads to ____ selection

without AIRE, T cells cannot be tested against tissue restricted self-Ag and therefore central tolerance is never established to these proteins and leads to ____

Answer 25

stromal/epithelial thymus

negative selection (deletion)

autoimmunity

Question 26

CTLA-4 as a component of peripheral tolerance:

1. binds ____ just like CD28 (costim for T cell activation)
2. intrinsic function (CTLA-4 is on the cell trying to activate)
   
   1. CTLA-4 binds SHP-2 which cause inhibition of ____ signaling
   2. activation of T cell increases expression of CTLA-4 preventing ____
3. extrinsic function (CTLA-4 is on a different cell than the one trying to activate)
   
   1. CTLA-4 on the Treg cells binds CD80/86 on ____ preventing effector T cell from receiving CD28 costimulation

Answer 26

1. CD8086
2. 1. TCR
   2. overactivity
3. 1. APCs

Question 27

AIRE in central tolerance:

1. ____ selection of T cells in the thymus is necessary for the maintenance of self tolerance
2. medullary thymic epithelial cells have a key function as ____ (presenting tissue-restricted antigens - TRAs)
3. mutations in AIRE cuase a breakdown of ____ tolerance
4. AIRE has been proposed to function as a ____ ____
5. mutation in AIRE is associated with decreased expression of ____ in the thymus

Answer 27

1. negative
2. APCs
3. central
4. transcription factor
5. self-Ags

Question 28

mutations breaking the tolerance: peripheral tolerance:

1. C4 →
2. CTLA-4 →
3. Fas/FasL →
4. FoxP3 →
5. IL-2; IL-2Ra/b →
6. SHP-1 →

Answer 28

1. C4 → defective clearance of immune complexes → SLE
2. CTLA-4 → failure of anergy in CD4+ cells → autoimmune diseases
3. Fas/FasL → defecgtive deletion of anergic self-reactive B cells; reduced deletionof mature CD4+ cells → ALPS
4. FoxP3 → deficiency of Treg cells → IPEX
5. IL-2; IL-2Ra/b → defective development, survival, or function of regulatory T cells → none known
6. SHP-1 → failure of negative regulation of B cells → none known

Question 29

functions of CTLA-4

1. two important functions:
   
   1. expression is low on ____ T cells until the cells are activated by Ag
   2. once expressed, CTLA-4 terminates continuing ____ of these responding T cells
2. CTLA-4 is expressed on ____ and mediates the suppressive function of these cells by inhibiting the activation of naive T cells
3. blocking of CTLA-4 with Abs enhances ____ diseases
4. polymorphisms in CTLA-4 are associated with several autoimmune diseases in humans, including ____ and ____

Answer 29

1. 1. resting
   2. activation
2. Treg cells
3. autoimmune
4. type I diabetes and Graves’