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Tolerance
Tolerance is a state of immunologic unresponsivness to particular antigens or sets of
antigens
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Rather than simply ignoring self,
the immune system recognises and promotes self compounds and beneficial commensals
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Sequestration allows these antigens to evade encounters
with reactive lymphocytes under normal circumstances; if the antigen is not exposed to
immune cells, there is little possibility of reactivity
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Thus, when the barriers are breached, by trauma for example, the newly exposed antigen
may be seen as forgein and aggressively attacked
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Microenvironments where
inflammation can be highly destructive are structured in ways that, under normal conditions,
bias immune engagement toward tolerance rather than assault
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Elimination is the first developmental step in central tolerance;
negative selection results in the induction of apoptosis in many developing lymphocytes with
high affinity T cell receptors (TCRs) or B cell receptors (BCRs) that recognise antigen
expressed in primary lymphoid organs (PLOs)
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This expression mediates deletion of potentially harmful
self-reactive T cells recognizing these antigens
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short , high
affinity but transient engagement of the TCR with MHC-antigen in the thymic medulla favors
the generation of regulatory cells
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Peripheral tolerance
Despite central tolerance some potentially self-destructive lymphocytes escape PLOs
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Peripheral tolerance is the process by which self
reactive lymphocytes in circulation are eliminated, rendered anergic, or otherwise inhibited
from producing an immune response
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Antigens that induce tolerance are

called tolergens rather than immunogens
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A cell engaged by a telerogen or in a
tolerogenic setting has other dates besides apoptosis, including energy (unresponsiveness)
or regulation (engagement leading to suppression)
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This could occur due to lack of costimulation, the
presence of inhibitory cytokines, or surface molecules, or in connection with time and place
of exposure
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Inactivation of an immune response does not
result in general immune suppression, but rather inhibition specific for the tolerogenic
antigen
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The possibility of damage from
self reactive lymphocytes is further limited by the need for coordination between multiple cell
types
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In order for T cells to become activated, the TCR must bind antigen presented by
self MHC molecules (signal 1), and the T cell must undergo costimulatory engagement
(signal 2)
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Immunomodulatory molecules are any compounds or inducers that change the behaviour of
immune cells, immunomodulatory is most often used to refer to the activity of costimulatory
or co inhibitory molecules
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CTLA-4 binds to CD80/86 inhibiting T cell activation
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CD28), and reduced
expression of proinflammatory cytokines (eg
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As a result of the
engagement of CTLA-4 and APC, Treg cells secrete immune inhibiting cytokines, such as
IL-10, TGF-beta, and IL-35, suppressing the activity of other nearby T-cells and APCs
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IL-2 is a growth- and survival- promoting cytokine, thus absorption of IL-2 by Treg cells
discourages expansion of local immunostimulatory effector T cells
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FoxP3 expression is
both essential and sufficient for the induction of immunosuppressive function
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Some
CD8+Treg cells recognize antigen using conventional MHC molecules, whereas others as
restricted to the nonclassical MHC class I molecules, HLA-E
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The mechanisms by which Treg inhibits immune
responses include both contact dependent and contact independent processes
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CD4+ Treg cells have also been shown to suppress responses to some

non-self antigens
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It is
possible for FoxP3+ T cells to inhibit T cells recognizing other antigens, as occurs when both
the Treg cell and the bystander T cell recognizing another antigen interact with the same
APC
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This simultaneous processing and presentation of different
antigens might happen naturally in vivo when the antigens in question are parts of the same
pathogen
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Regulatory B cells also play an important role in maintaining tolerance
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Breg cells have been shown to suppress
inflammatory cascades associated with IL-1
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MDSC secrete inhibitory compounds, such as IL-10, indoleamine
2,3-dioxygenase, arginase-1, and inducible nitric oxide synthase, and also express
immuno-suppressive surface markers that negatively regulate T- cell proliferation, such as
PD-L1

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