ICL 6.0: Immunologic Tolerance

Question 1

what is immunologic tolerance?

Answer 1

a state of specific immunologic unresponsiveness to an antigen

your body develops a tolerance for own tissue and does not produce a rejection response

immunologic tolerance is the reason our immune system doesn’t attack our own cells

Question 2

where is immunologic tolerance induced?

Answer 2

immunologic tolerance may be induced at various
stages of lymphocyte development both in central
and peripheral sites

central vs. peripheral tolerance

autoimmunity results from the breakdown of self-tolerance!!

Question 3

what are the three things that can happen to lymphocytes while they are developing?

Answer 3

1. self-antigen-specific lymphocytes will be killed = apoptosis
2. sometimes, lymphocytes may not react in any way = functional inactivation

the choice among lymphocyte activation or tolerance
is determined by the nature of the antigen-specific
lymphocytes and by the nature of the antigen and
how it is displayed to the immune system

Question 4

what do regulatory T cells do?

Answer 4

Treg cells can inhibit immune response

specif

Question 5

what causes a naive lymphocyte to be activated?

Answer 5

immunogenic antigen

they get activated and proliferate are differentiate because of the antigen

Question 6

what causes a naive lymphocyte to exhibit immunologic tolerance?

Answer 6

tolerogenic antigen = capable of producing immunologic tolerance aka your self-antigens

when a naive lymphocyte is exposed to a tolerogenic antigen then it will either undergo apoptosis or anergy = functional unresponsiveness

Question 7

what is anergy?

Answer 7

functional unresponsiveness

Question 8

why is immunologic tolerance important?

Answer 8

it explains why our immune system doesn’t destroy our own cells

also if we understand how to induce immunologic tolerance in lymphocytes, we can specifically induce immunological tolerance to treat a certain disease!

for example, 3 types of immune responses we don’t want are allergies, autoimmune diseases and organ transplant rejection

so if someone is allergic to fish and we figure out how to induce immunological tolerance for fish in this person, we would allow them to eat fish!

Question 9

what are the factors that may contribute to the development of autoimmunity?

Answer 9

autoimmunity results from a breakdown of self-tolerance

Question 10

how does the immune system maintain its unresponsiveness to self antigens?

Answer 10

self antigens normally induce tolerance

Question 11

what is central tolerance?

Answer 11

if an IMMATURE T cell in the THYMUS recognizes self antigens
present in the thymus, then that lymphocyte will die by apoptosis

central tolerance = deletion of lymphocytes that recognize self antigens present in generative organs

anything that involves the thymus or immature T cells has to do with central tolerance!!

**sidenote: naive T cells are mature lymphocytes, they are NOT immature cells

Question 12

what is the principal mechanism of central tolerance?

Answer 12

negative selection!

central tolerance = deletion of lymphocytes that recognize self antigens present in generative organs

Question 13

what are naive T cells?

Answer 13

naive T cells are mature lymphocytes! they are NOT immature cells!!

naive T cells are just cells that haven’t interacted with antigens

once they interact with antigens, they become active and are no longer naive

since naive T cells are mature, they are NOT related to central tolerance

Question 14

what two things can happen to a T cell during central tolerance?

Answer 14

1. strong recognition of self antigens by T cells in the thymus may lead to death of the cells = negative selection
2. self-antigen recognition in the thymus may also lead to the development of regulatory T cells that enter peripheral tissue

what determines whether self antigens will induce negative selection or the development of regulatory T cells is not known….

Question 15

what is peripheral tolerance?

Answer 15

immunologic tolerance to different self-antigens may be induced when MATURE lymphocytes encounter self antigens in peripheral tissues, leading to functional inactivation (anergy) or death

or when the self-reactive lymphocytes are suppressed by regulatory T cells

peripheral tolerance = deletion or anergy of lymphocytes that recognize self antigens in peripheral tissues

Question 16

what is functional inactivation?

Answer 16

when the lymphocyte is mature but can’t activate

all these cells will die via apoptosis or be inhibited by Treg cells

Question 17

where does functional inactivation happen?

Answer 17

**functional activation does NOT happen in central tolerance!! only in peripheral tolerance!!

in central tolerance only cell apoptosis and inhibition by Treg cells happens

Question 18

what is peripheral tolerance important for?

Answer 18

peripheral tolerance is important for preventing
lymphocyte responses to self antigens that are present mainly in peripheral tissue and not in the thymus

peripheral tolerance may also provide “back up” mechanisms for preventing autoimmunity in situations where central tolerance is incomplete

Question 19

what are the mechanisms of peripheral tolerance?

Answer 19

self-reactive lymphocytes will undergo one of the following:

1. functional inactivation
2. activation-induced cell death
3. suppressed by regulatory T cells

Question 20

when does functional inactivation take place?

Answer 20

functional inactivation of lymphocytes that occurs when these cells recognize antigens without adequate levels of the costimulators (second signals) that are needed for full T cell activation

naïve T cells need at least two signals for their proliferation and differentiation into effector cells:

1. signal 1 is always antigen
2. signal 2 is provided by costimulators that are expressed on professional antigen-presenting cells (APCs) in response to microbes

APCs don’t express co-stimulators in resting state –> self-reacting lymphocytes can only receive signal one from them and won’t get the second signal and so this lymphocyte will undergo functional inactivation

so if a lymphocyte interacts with these APC while they’re in their resting state or during the early stages of infection where they haven’t expressed co-stimulators yet, then they will undergo functional activation since there’s no signal 2

Question 21

what does an APC look like in the resting state?

Answer 21

APCs express little or no co-stimulators in the resting state

Question 22

what happens during a normal response vs. functional inactivation?

Answer 22

normal response:

APC has antigen on MHCII receptor that binds to TCR on T cell = signal 1

APC expresses costimulators like B7 that binds to C28 on T cell = signal 2

these two signal combined will lead to T cell proliferation and differentiation!

functional inactivation:

APC has antigen on MHCII receptor that binds to TCR on T cell = signal 1

but the APC doesn’t express B7 so there is no B7 to bind to CD28 on the T cell = no signal 2

the cell will undergo functional inactivation

so an antigen presented by costimulators-expressing APCs induces a normal T cell response. If the T cell recognizes antigen without costimulation the T cell fails to respond

Question 23

what is activation-induced cell death?

Answer 23

repeated activation of lymphocytes by self antigen, or recognition of self antigens without second signals, induces pathways of apoptosis that result in elimination (deletion) of the self-reactive lymphocytes

apoptotic proteins = Fas and FasL

repeated signal 1 without signal 2 will lead to activation-induced cell death!

Question 24

what are the apoptotic proteins involved in activation-induced cell death?

Answer 24

Fas and FasL

Question 25

what is the mechanism of activation-induced cell death?

Answer 25

antigen recognition (signal 1) induces the production of pro-apoptotic proteins in lymphocytes

the activity of these proteins is counteractive by anti-apoptotic proteins that are induced by co-stimulation (signal 2)

but without second signals, lymphocytes do not stimulate production of anti-apoptotic proteins, resulting in death of the cells that recognize the self antigens

if there’s only signal 1 = pro-apoptosis proteins and no signal 2 = anti-apoptosis proteins to balance it out, the cell will undergo apoptosis!

Question 26

what is the death receptor?

Answer 26

Fas

FasL binds to Fas and generates signals through the Fas death receptor that induce apoptosis

repeatedly interacting with signal 1 induces Fas-FasL which leads to apoptosis

Question 27

what do Treg cells do?

Answer 27

they prevent or suppress the activation of other self-reactive lymphocytes

self-antigen recognition in the thymus can lead to the development of Treg cells

we don’t know what special features of antigen recognition lead to the development of regulatory cells!

Question 28

what happens if a person doesn’t have Treg cells?

Answer 28

they’ll develop autoimmune diseases!

if T cells depleted of CD25+ lymphocytes are transferred into a mouse that does not have any lymphocytes of its own, this mouse develops a autoimmune disease involving multiple organs

Treg cells are contained within the CD25+ cell population, normally control auto-reactive lymphocytes and, in the absence of the regulators, the auto-reactive lymphocytes are released from their control and attack self tissue

Question 29

what CD classification do Treg cells have?

Answer 29

CD4

CD25

Question 30

what are the two mechanisms through which Treg cells inhibit immune responses?

Answer 30

1. some regulatory cells produce cytokines, such as TGFβ and IL-10, which block the activation of lymphocytes and macrophages
2. regulatory cells may also directly interact with and suppress other lymphocytes or APCs, by undefined mechanisms that do not involve cytokines

Question 31

which cytokines inhibit T cell response?

Answer 31

IL-10

TGFβ

these get released by Treg cells

Question 32

which cytokine activates macrophages?

Answer 32

IFNγ

Question 33

what are the 3 mechanisms of peripheral tolerance?

Answer 33

1. functional inactivation (anergy)
2. activation-induced cell death
3. suppression by Treg cells

Question 34

what causes autoimmunity?

Answer 34

a breakdown of self-tolerance

Question 35

what 3 factors effect autoimmunity?

Answer 35

1. genes
2. infections
3. environment

Question 36

which gene mutation predisposes you to autoimmune disease?

Answer 36

MHC genes

the incidence of a particular autoimmune disease is often greater in individuals who inherit a particular HLA allele(s) than in the general population.

this incidence is called the “relative risk” of an HLA-disease association

Question 37

how can genetics effect autoimmunity?

Answer 37

genetic predisposition to autoimmunity was appreciated when it was noted that if one of two identical twins develops an autoimmune disease, the other twin is more likely to develop the same disease than an unrelated member of the general population

the second twin has a 50% chance to develop the same disease

the reason it’s no 100% chance is due to different environments

Question 38

which two gene mutations are related to certain autoimmune disease?

Answer 38

1. people with HLA-B27 allele are 100x more likely to get ankylosing spondylitis disease than B27-negative people
2. HLA-DR3/DR4 = 25x more likely to get insulin-dependent diabetes mellitus

Question 39

why can certain MHC alleles lead to autoimmune diseases?

Answer 39

a certain HLA allele may increase the risk of developing a particular autoimmune disease, but the HLA allele is NOT, by itself, the cause of the disease

particular MHC alleles may contribute to the development of autoimmunity because they are inefficient at displaying self antigens, leading to defective negative selection of T cells, or because peptide antigens presented by these HLA alleles may fail to stimulate regulatory T cells

Question 40

what are the three ways infections can cause autoimmune disease?

Answer 40

infections may activate self-reactive lymphocytes and lead to the development of autoimmune diseases in several ways

1. co-stimulators
2. molecular mimicry
3. antigen release

Question 41

how do infections effect co-stimulators and cause autoimmunity?

Answer 41

an infection of a tissue may lead to increased expression of co-stimulators and cytokines by tissue APCs

as a result, these activated tissue APCs may be able to stimulate self-reactive T cells

resting APCs don’t express co-stimulator molecules so naive t cells that interact with this APC would undergo functional inactivation – however, if you have bacterial infection and the infection can induce APC to express co-stimulator molecules

Question 42

what is molecular mimicry?

Answer 42

some infectious microbes may produce peptide antigens that are similar to, and cross-react with, self antigens.

in these cases, immune responses to the microbial peptide may result in an immune attack against self antigens

ex. a man comes into your office complaining of heart problems and two weeks ago he had a throat infection – the antibody against this bacteria can somehow cause a reaction to the heart tissue!

this same antibody that was generated from the infection will recognize the bacteria in the heart and bind to heart tissue….this is so bad because it can cause rheumatic fever, murmurs and other heart problems

Question 43

how can infections effect antigen release and lead to autoimmunity?

Answer 43

infection may also injure tissue and release antigens that are normally sequestered from the immune system

ex. some antigens in the testis and eye are normally not seen by the immune system and are ignored

release of sequestered intraocular protein antigens by trauma or infection may by carried to lymph nodes and initiate an autoimmune reaction against the tissue – effector T cells return via the bloodstream and attack antigen in both eyes

ex. if a couple came to your office and they haven’t been able to have a baby for 5 years but you realize that 6 years ago the man was in a car accident that effected his testes, maybe what’s happening is that the testes antigen released during the accident caused the immune system to make antibodies against his sperm which is why they can’t get pregnant

Question 44

what is the definition of immunologic tolerance?

Answer 44

immunologic tolerance is a state of specific immunologic unresponsiveness to an antigen

immunologic tolerance may be induced at various stages of lymphocyte development both in central and peripheral sites

Question 45

what is the definition of central tolerance?

Answer 45

immature T cells in the thymus recognize with self antigens present in the thymus, the lymphocytes die by apoptosis

principle mechanism of central tolerance is negative selection

Question 46

what is the definition of peripheral tolerance?

Answer 46

immunologic tolerance may be induced when:

1. mature lymphocytes encounter self antigens in peripheral tissues, leading to functional inactivation (signal 1 and signal 2)

or

2. activation-induced cell death (pro-apoptotic protein & anti-apoptotic protein; Fas/ FasL)

or

3. when the self-reactive lymphocytes are suppressed by regulatory T cells

Question 47

why do infections predispose us to autoimmunity problems?

Answer 47

infections predispose to autoimmunity, by inducing the expression of co-stimulators, or because of cross-reactions between microbial and self antigens

infection may also injure tissue and release antigens that are normally sequestered from the immune system