Self Tolerance II

Question 1

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

Answer 1

….

Question 2

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

Answer 2

negative selection (clonal deletion - death by apoptosis)

Question 3

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?

Answer 3

CTLA4

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

Question 4

CD28 - pos signal
CTLA4 - neg signal!

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

Answer 4

…

Question 5

What two levels can CTLA be expressed at?

Answer 5

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!!

Question 6

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

Answer 6

…

Question 7

T cell peripheral tolerance mechanisms:

Answer 7

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)

Question 8

What are some markers for Tregs?

Answer 8

Transcription facto - FoxP4

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

Question 9

What do Tregs tend to secrete?

Answer 9

anti-inflamm cytokines (TGFbeta and IL-10)

Question 10

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

Answer 10

…

Question 11

What does IL-10 inhibit

Answer 11

TH1 responses

Question 12

What is clonal exhaustion?

Answer 12

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!

Question 13

What is apoptosis - activation induced death?

Answer 13

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!!!

Question 14

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

Answer 14

..

Question 15

Central tolerance is primarily based on signals received via what?

Answer 15

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

Question 16

Negative selection is the main mechanism for T cell tolerance!

Answer 16

…

Question 17

What are the three checkpoints in T cell central tolerance?

Answer 17

survival signals via pre-TcR

positive selection

negative selection - main mechanism for T cell central tolerance

Question 18

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

Answer 18

…

Question 19

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

Answer 19

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

Question 20

Failure of any of the mechanisms of self tolerance can…

Answer 20

lead to pathogenic immune responses to self antigens (autoimmunity)

Question 21

Autoimmune disease are what type of hypersensitivity?

Answer 21

Types II, III, IV (not type I)

Question 22

What are four mechanisms for loss of self-tolerance?

Answer 22

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)

Question 23

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

Answer 23

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

Question 24

Specific example of loss of Ag sequesteration/disease?

what is this disease specifically called?!?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

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.

Answer 26

...

Question 27

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?

Answer 27

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!

Question 28

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

Answer 28

T cells reactive to tissue specific antigens mature and leave the thymus! its loss leads to a defect in central T cell tolerance!

Question 29

Defect in AIRE leads to what condition? How many genes/how many organ systems?

Answer 29

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

Question 30

What is AIRE?

Answer 30

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???

Question 31

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

Answer 31

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

Question 32

What mutations lead to IPEX? What does it lead to the loss of? Defect in what mechanism?

Answer 32

Due to mutations in the FoxP3 gene - transcription factor of Treg cells! Leads to loss of Treg development Defect in mechanisms of peripheral tolerance!

Question 33

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

Answer 33

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

Question 34

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

Answer 34

systemic or multi-organ disease

Question 35

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

Answer 35

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

Question 36

Which is more common...multifactorial or single gene defects?

Answer 36

multifactorial!

Question 37

What does multifactorial mean? what is a major genetic risk factor? what do they tend to involve?

Answer 37

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

Question 38

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

Answer 38

streptococcal cell wall stimulates antibody response some antibodies cross-react with heart tissue causing rheumatic fever

Question 39

What cytokines can up regulate MHC molecules? What other infection agents are involved with autoimmunity?

Answer 39

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

Question 40

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

Answer 40

....

Question 41

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?

Answer 41

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!

Question 42

Tumors can be what?

Answer 42

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

Question 43

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

Answer 43

activation (works at APC level) effetor function

Question 44

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

Answer 44

....

Question 45

PD-L1/PD-1 binding inhibits what?

Answer 45

T cell killing of tumor cell

Question 46

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

Answer 46

T cell killing of tumor cell

Question 47

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

Answer 47

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