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Cellular Week 4 > Self Tolerance II > Flashcards

Self Tolerance II Flashcards

1
Q

Anergy is an active state - turns off the cell in a ways that it can no longer be turned on

A

….

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2
Q

What is the main mechanism of central tolerance in T cells?

A

negative selection (clonal deletion - death by apoptosis)

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3
Q

Downregulation of Immune Responses…

Signal 1 plus signal 2 (B7-CD28) leads to activation of T cell…. Later in the T cell response, what does the activated T cell express?

A

CTLA4

This binds to B7 with higher affinity than CD28 - This leads to a negative signal to down-regulate T cell activation

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4
Q

CD28 - pos signal
CTLA4 - neg signal!

LA = “late antigen” - leads to cell-cycle arrest

A

…

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5
Q

What two levels can CTLA be expressed at?

A

Can be used to block T cell activation, or Tregs can sequester B7 on the APC

Limiting amounts of B7 ensure that only the high affinity receptor for B7 (CTLA-4) will bind, and the lower CD28 will not be engaged - try to understand this concept

T Regs express CTLA-4 at all times!!

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6
Q

When B7-CD28 interaction is blocked by CTLA-4 - there is functional inactivation!! Creates an unresponsive (anergic) T cell

A

…

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7
Q

T cell peripheral tolerance mechanisms:

A

clonal anergy

inactivation via inhibitory receptors

suppression by Tregs

clonal ‘exhaustion’ or clonal deletion (may involve inactivation via inhib receptors and activation induced death or suppression by t regs)

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8
Q

What are some markers for Tregs?

A

Transcription facto - FoxP4

CD25 on resting surface (high affinity IL-2 receptor)

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9
Q

What do Tregs tend to secrete?

A

anti-inflamm cytokines (TGFbeta and IL-10)

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10
Q

Tregs can act on the APC (inhibit T cell activation) or at the effector T cell stage (inhibition of effector functions)

A

…

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11
Q

What does IL-10 inhibit

A

TH1 responses

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12
Q

What is clonal exhaustion?

A

chronically stimulated T cells - keep going on and on - eventually those responses might be detrimental to the host

immune system recognizes this and undergoes clonal exhaustion - STOP RESPONDING TO ANTIGEN!

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13
Q

What is apoptosis - activation induced death?

A

When a T cell is activated, it begins the apoptotic pathway

When it receives signal for IL-2, it stops this pathway and is a growth fact

Lack of IL-2 = mechanism of cell death!!!

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14
Q

Absence of FoxP3+ (marker for Treg cells) - leads to autoimmune disease!

A

..

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15
Q

Central tolerance is primarily based on signals received via what?

A

Ag-specific receptor on lymphocytes and the fact that cells at diff developmental stages respond differently to such signals. Peripheral tolerance is more varied

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16
Q

Negative selection is the main mechanism for T cell tolerance!

A

…

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17
Q

What are the three checkpoints in T cell central tolerance?

A

survival signals via pre-TcR

positive selection

negative selection - main mechanism for T cell central tolerance

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18
Q

negative selection is really deletion! OR it can also create Tregs that can go out into the periphery

A

…

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19
Q

Inactivation via inhibitory receptors in the periphery for T cells happens by what two receptors?

A

CTLA-4 and PD1

Originally thought to be mainly involved in dampening chronic inflammation and controlling acute (foreign-Ag-specific) T cells responses; an important role in maintaining self-tolerance only just beginning to be widely appreciated

20
Q

Failure of any of the mechanisms of self tolerance can…

A

lead to pathogenic immune responses to self antigens (autoimmunity)

21
Q

Autoimmune disease are what type of hypersensitivity?

A

Types II, III, IV (not type I)

22
Q

What are four mechanisms for loss of self-tolerance?

A

loss of antigen compartmentalization (true tolerance never existed)

(single) genetic defects in tolerance-generating mechanisms

polygenic/multifactorial autoimmune diseases

potential role for infection? (cross-reactivity/molecular mimicry)

23
Q

potential mechanisms for loss of self-tolerance: loss of Ag sequestration… where do these happen?

A

immunologically privileged sites! (like in the eye)

Immunologically priveled because has TGF-beta - produced by stromal cells (not T cell mediated phenomenon)

loss of Ag sequestration can lead to immune attack

24
Q

Specific example of loss of Ag sequesteration/disease?

what is this disease specifically called?!?

A

Trauma to one eye results in the release of sequestered intraocular protein antigens

released intraocular antigens are carried to lymph nodes and activate T cells

Effector T cells return via bloodstream and attack antigen in BOTH eyes

This is called sympathetic opthalmia!!!

activated T cells don’t distinguish between the two eyes

Tolerance never existed, just immunologically privileged

25
Q

What other place besides the eye could you include in loss of antigen compartmentalization?

A

oral tolerance! don’t normally get sick to oral antigens (for ex. indians eating the poison ivy)

26
Q

It is estimated that only a small proportion of lymphocytes (few percent) survive positive and negative selection to make it to the periphery as mature lymphocytes. Thus, MHC molecules have a great influence on the T cell repertoire of each individual.

A

…

27
Q

Individual organs of the body express tissue specific antigen (like the retina and ovaries).

In the thymus, T cells arise capable of recognizing tissue-specific antigens.

Under control of what protein does the thymic medullary cells express tissue-specific proteins, deleting tissue-reactive T cells?

what happens in its absence?

A

The AIRE protein!!

Absence of the regulatory factor leads to a condition with broad autoimmune effects!

AIRE = transcription factor/autoimmune regulator…. if you lack it, you can no longer negatively select for some tissue specific antigens!

its loss leads to a defect in central t cell tolerance!

28
Q

What occurs in the absence of AIRE for T cells in thymus?

A

T cells reactive to tissue specific antigens mature and leave the thymus!

its loss leads to a defect in central T cell tolerance!

29
Q

Defect in AIRE leads to what condition?

How many genes/how many organ systems?

A

APECED

Autoimmune PolyEndocrinopathy-Candidiasis Ectodermal Dystrophy, type I

Broad spectrum autoimmune disorder

This is a SINGLE GENE DEFECT DISORDER!!! - but causes multiple organ systems to be involved

30
Q

What is AIRE?

A

transcription factor that enables the expression, in thymic medullary epithelial cells, of around 3000 proteins, including many tissue specific proteins (e.g. insulin!)

very important for endocrine tissues!!

Pts tend to get candida infections when it is gone

Also when its gone, they might make autoantibodies to IL-17???

31
Q

Besides APECED, what is another single gene defect leading to autoimmune disease?

A

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)

32
Q

What mutations lead to IPEX?

What does it lead to the loss of?

Defect in what mechanism?

A

Due to mutations in the FoxP3 gene - transcription factor of Treg cells!

Leads to loss of Treg development

Defect in mechanisms of peripheral tolerance!

33
Q

Mutations or polymorphisms in many other single genes (e.g., TGF-β, CTLA-4)
can also cause autoimmune syndromes.

A

….

TGF-beta would be an autoinflamm disorder rather than an autoimmune disorder though

34
Q

These single-gene defects in underlying mechanisms for tolerance induction are
relatively rare, and typically result in ______________.

A

systemic or multi-organ disease

35
Q

Example of a polygenic/multifactorial autoimmune disease that is common?

A

Type I (insulin dependent) diabetes mellitus

Insulitis in the pancreatic islet cell and leads to pancreatic b cell loss

Insultitis is due to infiltrating lymphocytes - eventually leads to their distraction

multitfactorial - so around two dozen or so genes contribute to it

36
Q

Which is more common…multifactorial or single gene defects?

A

multifactorial!

37
Q

What does multifactorial mean?

what is a major genetic risk factor?

what do they tend to involve?

A

genetic and non genetic factors involved (only 30-50% concordance in identical twins)

multiple genes involved in susceptibility

major genetic risk factor is usually the MHC

Tend to involve only one specific tissue type

38
Q

One potential role for infection in autoimmunity is molecular mimicry…. ex of this?

A

streptococcal cell wall stimulates antibody response

some antibodies cross-react with heart tissue causing rheumatic fever

39
Q

What cytokines can up regulate MHC molecules?

What other infection agents are involved with autoimmunity?

A

IFN-gamma and others

PAMPS can induce expression of co-stimulatory molecules on APCs too

Bacterial super antigens can also stimulate auto-reactive T cells

40
Q

There are many association of infection with autoimmunity…. rheumatic fever, reiter’s syndrome, reactive arthritis, lyme disease/arthritis, type 1 diabetes… etc

A

….

41
Q

Clinical usage of info about T cell activation and tolerance… blocking signal 2!!

A CTLA4-Ig chimeric receptor will block….?

What is this used for?

medication called?

A

B7! - CTLA-4 blockade prevents down regulation of T cells - blocks inhibitory receptors on T cells - allows you to reveal an immune response that was being blocked by the cancer cell

Used in immunosuppression for transplants

Belatacept!

42
Q

Tumors can be what?

A

immunogenic!!

changing cancer therapy with this new revelation

read slide with evidence and conclusions about tumors being immunogenic

for ex. cancers activate inhibitory responses to avoid immune system

43
Q

CTLA-4 seems to be involved in preventing T cell_______, while PD-1 is more involved with inhibiting T cell _______.

A

activation (works at APC level)

effetor function

44
Q

Dual PD-1 and CTLA-4 antagonism may be most effective

A

….

45
Q

PD-L1/PD-1 binding inhibits what?

A

T cell killing of tumor cell

46
Q

Blocking PD-L1 or PD-1 allows for what?

A

T cell killing of tumor cell

47
Q

What is beginning to be appreciated about CTLA4/PD1 inhibition therapy?

A

such tis may break tolerance to self antigens and cause autoimmune diseases!!

Cellular Week 4 (11 decks)

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