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PATH3308 > 21. Immunotolerance > Flashcards

21. Immunotolerance Flashcards

1
Q

Define Immunotolerance?

A

Lack of immunological reactions towards and antigen

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2
Q

What are three examples of tolerance?

A

Tolerance to self antigens

Tolerance to Environmental Antigens
- Failure leads to coeliac etc

Tolerance to antigens that previously invoked and immune response
- Allograft

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3
Q

What are the two types of T cell tolerance and where do they develop?

A 
Central Tolerance
  - Thymus
   - Self reactive cells deleted
   - Thymic education
Peripheral Tolerance
   - Peripheral tissues
   - Self reactive cells are subsequently incapable of    responding to those antigens
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4
Q

What are the two ways central tolerance of T cells is achieved?

A

1) Thymic deletion of self reactive T-cells

2) Generation of Tregs

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5
Q

What is negative selection?

A

T cells that bind with high avidity to self antigens are deleted
Results in CD4 and CD8 cells being self-tolerant

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6
Q

How are self-reactive T cells deleted?

A

Apoptosis via Bim

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7
Q

What self-antigens are located in the thymus?

A

Lots of antigens distributed in tissues

Even peripheral tissue antigens are expressed in the thymus so immature T cells reactive can be deleted via AIRE

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8
Q

What is AIRE?

A

Autoimmune Regulator Protein
Causes self antigens - organ specific antigens to be transcribed at a low level in the thymus. allowing presentation to maturing T cells

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9
Q

What could be the cause of a multiorgan autoimmune disease then?

A

You guessed it!!
Mutations in the AIRE

  • Autoimmune polyendocrine syndrome (APS)
  • Characterised by antibody + lymphocyte mediated injury to multiple endocrine organs
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10
Q

What is positive selection in the thymus?

A

If TCR binds with low affinity - self - MHC molecule

It is rescued from cell death

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11
Q

What order do the selections go in?

A

Positive selection

Negative Selection

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12
Q

CD4 cells that are self reactive but arent deleted, what do they develop into?

A

TREGs!
Express CD25 and FoxP3
Inhibit responses against self tissues in periphery

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13
Q

Does deficiency of AIRE prevent development of thymic Tregs?

A

No

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14
Q

So what the hec determines the fate of self reactive Tregs?

A

Dunno

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15
Q

So t cells emerging from the thymus, how do they feel about self MHC and self peptides?

A

Low enough affinity so they are not self reactive

Some probablity of high affinity interaction with self - MHC + foreign peptide

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16
Q

If a T cell coming from the thymus has high affinity for self-MHC + self peptide, what sort of cell is it probs gonna be?

A

Treg (CD25 + FoxP3)

~10% of CD4 T cell population

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17
Q

What are the 3 ways in which T cells can develop peripheral tolerance?

A

Anergy
Supression
Deletion

18
Q

What is the mechanism of T cell anergy?

A

Recognition of TCR + costimulators (B7-1, B7-2 by CD28)

If CD4 T cell exposed to antigen in absence of costimulation, may be incapable of responding to antigen

When T cels recognise self antigens, may engage inhibitory receptors of CD28 FAMILY (CTLA4), terminates T cell response

19
Q

What growth factor do Tregs primarily use?

A

IL-2 have IL-2 receptor (CD25) not IL-7

20
Q

What transcription factor do Tregs express?

A

FoXp3

21
Q

What is IPEX?

A

A rare autoimmune disease in humans

Immunodysregulation Polyendocrinopathy Enteropathy X-Linked syndrome

Mutation in FOXP3 gene

Fatal - Hectic autoimmunity
- Commonly seen as type 1 diabetes

22
Q

What are some other examples of autoimmune phenomena?

A

Coombs, thrombocytopenia, tubular nephropathy

23
Q

What are the mechanisms of Treg action?

A

Express high levels of CTLA-4
- Inhibit APC stimulation of T cells by binding B7 via CTLA4, blocking CD28

Consume IL-2
- Starves responding T-cells of this factor

Produce high levels of IL-10

  • Inhibits IL-12 - mediates IFN-y
  • Inhibits expression of costimulators and class 2 MHC molecules on APC

Produces high levels of TGF-B

  • Inhibits proliferation and effector functions of T cells
  • Regulates differentiation of Th1 and Th2 cell subsets
  • Inhibit macrophages
24
Q

Do Treg cells inhibit the proliferative responses of other T cells in vitro?

A

Yes

25
Q

What are the primary cellular markers that define Treg cells?

A

CD25+ and CD4+

26
Q

What are the primary cell markers that define TH cells?

A

CD4+ and CD25-

27
Q

Is suppression of proliferation by CD4+ and CD25+ Tregs contact dependent?

A

Yes

28
Q

How is peripheral tolerance determined by deletion?

A

T cells that recognize self antigens in absence of inflammation, or those that are repeatedly stimulated by antigens undergo apoptosis

29
Q

What are the two major pathways to cell deletion?

A

Mitochondrial (intrinsic) pathway

Death Receptor (Extrinsic) pathway

30
Q

What is the mitochondrial pathway to cell deletion?

A

Normally, costimulation results in expression of bcl-2 and bcl-Xl, preventing apoptosis

Absence of co-stimulation, results in low bc-2 and bcl-XL exression = Bim activation promoting apoptosis

31
Q

What is the Death Receptor (extrinisc) pathway to cell deletion?

A

When T cells repeatedly stimulated
Expression of death receptors (FAS)
Expresses FasL ligand
Triggers cascade of caspases = apoptosis

32
Q

Could the death receptor/extrinsic pathway be present in B cells?

A

Yes

33
Q

What are the two types of B-cell tolerance?

A

Central Tolerance

Peripheral Tolerance

34
Q

What is B-cell central tolerance?

A

Mechanism involving changing or deletion of self reactive B cells in the bone marrow

35
Q

What is B-cell peripheral tolerance?

A

Mechanism rendering cells unresponsive or apoptotic due to the recognizing self antigens in absence of helper T cells

36
Q

What can B cells undergo when becoming tolerant in the bone marrow (central tolerance)?

A

Receptor editing
Deletion
Anergy

37
Q

What is receptor editing in B cell central tolerance development?

A

If B cells recognize self antigens with high avidity, they can reactivate RAG1 and RAG2 genes, initiating a new round of VJ combination

New light Ig chain expressed - creating new specificity

38
Q

What is deletion in B cell central tolerance development?

A

Failure of receptor editing leads to B cell apoptosis

We dunno though

39
Q

What is Anergy in B cell tolerance development?

A

If B cells recognise self antigens, they become functionally unresponsive. Leave bone marrow in anergic state

40
Q

What occurs in peripheral B cell tolerance?

A

B cells that encounter self antigens in peripheral tissues become anergic or apoptotic

May also express inhibitory receptors that prevent B cell activation (CD22)

41
Q

The abundant knowledge we have about tolerance of the immune system, how can we apply this knowledge clinically?

A

Suppress organ transplant rejection
Treating patients with autoimmune disorders
- LUPUS + type 1 diabetes
Asthma and other “immediate”-type allergies

42
Q

plz save

A

no

PATH3308 (21 decks)

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