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POD Exam 3 > Immunologic tolerance > Flashcards

Immunologic tolerance Flashcards

1
Q

What is important in order to have positive selection of immature T and B cells?

A

TCR or BCR have weak affinities to self-antigens

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2
Q

Where are T-cell “central” self-antigens found?

A
  • Thymus
  • expressed in periphery but brought to thymus by circulation
  • Peripheral tissue-specific Ag expressed in thymic medullary epithelial cells under control of TF Autoimmune regulator (AIRE)
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3
Q

What stage does negative selection occur? (T cell)

Does the TCR show high or low affinity to central self-Ag in order for deletion to occur?

A

Double positive CD4+ CD8+

high affinity

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4
Q

Which cells mediate negative selection of thymocytes?

A

thymic DC
Macs
thymic medullary epithelial cells

(DC and Macs are bone marrow origin)

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5
Q

Where does negative selection of thymocytes occur?

A

Cortex-medulla junction (mainly)

Medulla

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6
Q

How does deletion occur for negative selection of thymocytes? (central tolerance)

A

Deletion by apoptosis

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7
Q

Autoimmune polyendocrine syndrome

A
  • Mutation in AIRE gene
  • Leakage in negative selection
  • Affects endocrine organs: parathyroid gland, adrenal glands, pancreatic islets
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8
Q

Tolerance to “central” self Ag in B cells is induced where? in which stage?

A

Bone marrow

immature B cells

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9
Q

Does B cell have central tolerance mechanisms for high or low affinity to central self Ag?

A

BOTH

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10
Q

What is the mechanism for high affinity self Ag? (B cell)

A

Receptor editing

Clonal deletion

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11
Q

What is the mechanism for low affinity self Ag? (B cell)

A

Anergy

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12
Q

What happens during receptor editing?

A

Reactivate expression of Rag1 and Rag2 –> DNA rearrangement of Ig gene on k light chain - change specificity

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13
Q

What happens during clonal deletion?

A

Apoptosis

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14
Q

What is anergy?

A

reduced receptor expression
signaling block

basically, unresponsiveness to subsequent encounter of the self ag

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15
Q

What happens if autoreactive T cells escape negative selection?

A

become mature autoreactive T cells and exit thymus to the periphery

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16
Q

How are mature autoreactive T cells in the periphery kept under control?

A
  • Anergy
  • Deletion
  • (Foxp3+) Regulatory T cells
17
Q

Anergy in T cell peripheral tolerance is due to

A

Absence of costimulation

18
Q

Anergy in T cell peripheral tolerance

Mechanism:

A

Down regulation of TCR expression : Cbl-b ubituitin ligase-mediated degradation

Induction of inhibitory receptors:
CTLA-4 – high affinity for B7 - competitive inhibition of B7:CD28 - inhibitory signal

PD-1 – affinity for PD-L1 or PD-L2. Block T cell activation or pro-inflammatory cytokine expression on APC

19
Q

What causes a breach in T cell Anergy?

A

infection:

PAMPs interact with TLR –> APC (immature DC) express high levels of MHC II and costimulatory molecules (B7)

20
Q

Deletion of autoreactive T cells in periphery

A

apoptosis by:

  • mitochondrial pathway (activate Bim)
  • Fas-FasL mediated –> activation-induced cell death (AICD)
21
Q

What happens when Fas-FasL apoptosis is defective?

A

Autoimmune lymphoproliferative disorder (ALPS)

22
Q

What can actively suppress activation of conventional CD4 T cells and CD8 T cells?

A

Treg

23
Q

What offers best hope for curing autoimmune disease?

A

T reg

24
Q

Types of Treg cells

A
  • natural

- inducible

25
Q

Where is nTreg generated

A

in the thymus

26
Q

where is iTreg generated?

A

converted from conventional CD4 T cells in the periphery

27
Q

Distinguish Treg cells from conventional CD4 T cells

A

TF Foxp3
CD25 (high)
CTLA-4

28
Q

Function of Treg cells

A

suppress T cells reactive to self Ag and allergens – prevents autoimmune and allergic disease

29
Q

Deficiency in Treg cells results in:

A

IPEX syndrome:

Immune dysregulation
Polyendocrinopathy
Enteropathy
X-linked

30
Q

Characteristics of IPEX

A

multiple organ autoimmune and allergic disorders
death at 1-2 years of age
Males only

31
Q

What is the cause of Treg cell deficiency

A

Mutation in Foxp3 gene

32
Q

Tolerance mechanism for periphery B cells

A
  • Anergy

- Clonal deletion

33
Q

Anergy in B cell peripheral tolerance

A
  • absence of T helper, esp CD40:CD40L costimulation is missing

unresponsive autoreactive B cell
CD40L*** is on Th cells

34
Q

Clonal deletion in B cell peripheral tolerance. Name the 3 circumstances

A
  • strong avidity self Ag stimulation –> mitochondrial pathway apoptosis
  • Repeated stimulation by self Ag –> insufficient BAFF/Blys –> apoptosis (mit. pathway)
  • Somatic mutation –> deletion by Fas-FasL interaction

POD Exam 3 (6 decks)

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