ICL 6.0: Immunologic Tolerance Flashcards
what is immunologic tolerance?
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
where is immunologic tolerance induced?
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!!
what are the three things that can happen to lymphocytes while they are developing?
- self-antigen-specific lymphocytes will be killed = apoptosis
- 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
what do regulatory T cells do?
Treg cells can inhibit immune response
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what causes a naive lymphocyte to be activated?
immunogenic antigen
they get activated and proliferate are differentiate because of the antigen
what causes a naive lymphocyte to exhibit immunologic tolerance?
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
what is anergy?
functional unresponsiveness
why is immunologic tolerance important?
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!
what are the factors that may contribute to the development of autoimmunity?
autoimmunity results from a breakdown of self-tolerance
how does the immune system maintain its unresponsiveness to self antigens?
self antigens normally induce tolerance
what is central tolerance?
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
what is the principal mechanism of central tolerance?
negative selection!
central tolerance = deletion of lymphocytes that recognize self antigens present in generative organs
what are naive T cells?
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
what two things can happen to a T cell during central tolerance?
- strong recognition of self antigens by T cells in the thymus may lead to death of the cells = negative selection
- 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….
what is peripheral tolerance?
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
what is functional inactivation?
when the lymphocyte is mature but can’t activate
all these cells will die via apoptosis or be inhibited by Treg cells
where does functional inactivation happen?
**functional activation does NOT happen in central tolerance!! only in peripheral tolerance!!
in central tolerance only cell apoptosis and inhibition by Treg cells happens
what is peripheral tolerance important for?
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
what are the mechanisms of peripheral tolerance?
self-reactive lymphocytes will undergo one of the following:
- functional inactivation
- activation-induced cell death
- suppressed by regulatory T cells
when does functional inactivation take place?
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:
- signal 1 is always antigen
- 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
what does an APC look like in the resting state?
APCs express little or no co-stimulators in the resting state
what happens during a normal response vs. functional inactivation?
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
what is activation-induced cell death?
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!
what are the apoptotic proteins involved in activation-induced cell death?
Fas and FasL