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Immunology > Immunologic Tolerance and Autoimmunity (part I) > Flashcards

Immunologic Tolerance and Autoimmunity (part I) Flashcards

1
Q

immunological tolerance is specific ____ to an Ag

A

unresponsiveness

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2
Q

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

A

NOT perfect

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3
Q

central tolerance:

prevents creation of ____ lymphocytes

generated only in ____ ____ organs

A

self-reactive

primary lymphoid

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4
Q

peripheral tolerance:

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

occurs in ____ tissues

A

action

peripheral

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5
Q

peripheral Tolerance:

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

1.

2.

3.

A
  1. inactivated (anergy)
  2. deleted (apoptosis)
  3. suppressed by the Treg cells
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6
Q

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 ____ ____
A
  1. circulation
    1. clonal deletion (negative selection)
    2. BCR editing
    3. anergy
  3. circulation
  4. bone marrow
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7
Q

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

A

autoreactive

recombination

self-reactivity

RAG1 and RAG2

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8
Q

selection of nonautoreactive and autoreactive immature B cells

high avidity autoreactive, medium autoreactive, low avidity autoreactive →

low avidity autoreactive + nonautoreactive and nonautoreactive →

A

BCR editing

positive selection

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9
Q

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 ____
A
    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
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10
Q

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

A

mitochondrial (intrinsic)

apoptosis

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11
Q

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 ____
A
  1. thymus
  2. self-Ags
    1. apoptosis
    2. anti-apoptotic
  3. CD4+ and CD25+
  4. CTLA-4
  5. IL-2
  6. autoimmune
  7. periphery
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12
Q

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
A
    1. anergy
    2. suppresion
    3. deletion
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13
Q

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
A
    1. anergy
    2. inhibition
    3. deletion
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14
Q

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
A
  1. inhibitor
  2. sialic
  3. ITIM
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15
Q

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

A

mitochoondrial (intrinsic) and death receptor (extrinsic)

BAFF

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16
Q

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
A
  1. T cells
  2. Th17
  3. M1
  4. Treg cells
  5. IgA
  6. tissue collagen
17
Q

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
A
  1. outside Th0
  2. retinoic
    1. IL-6
    2. IL-2
18
Q

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
A

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)
19
Q

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
A
  1. peripheral
  2. CD4+, CD25+, FoxP3+
  3. TGF-beta
  4. IL-2
20
Q

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 ____
A
    1. CD25
    2. CTLA-4
    1. TD (thymus dependent)
    1. CD40L
  4. IL-10 and TGF-beta
21
Q

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

A

CTLA-4 or PD-1

22
Q

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

A

anti-CTLA-4 and anti-PD-1

checkpoint blockade

autoimmune

23
Q

mutations breaking the tolerance:

central tolerance: AIRE

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

A

AIRE

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

24
Q

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

A

autoimmune polyendocrine syndrome

25
Q

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 ____

A

stromal/epithelial thymus

negative selection (deletion)

autoimmunity

26
Q

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
A
  1. CD8086
    1. TCR
    2. overactivity
    1. APCs
27
Q

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
A
  1. negative
  2. APCs
  3. central
  4. transcription factor
  5. self-Ags
28
Q

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 →
A
  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
29
Q

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

Immunology (23 decks)

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