Download Tolerance

Tolerance
• Weapons are designed to
attack the enemy while
ensuring the self defense
• Lack of skill or
malfunctioning of a
weapon may lead to self
damage
• Therefore in order to avoid
self damage our body’s
immune system must be
educated against self and
non-self
• Physiologic meaning of
tolerance is the nonreactivity of the immune
system against body’s own
or self proteins
Immunological tolerance and
associated terms…
• Immunologic tolerance is defined as unresponsiveness to an antigen that is
induced by previous exposure to that antigen
• Antigens that induce tolerance are called tolerogens, or tolerogenic antigens
• Antigens that induce immunity are called immunogens
• A single antigen may be an immunogen or a tolerogen, depending on the
conditions in which it is displayed to specific lymphocytes (e.g., in the presence
or absence, respectively, of inflammation and innate immune responses)
• Tolerance to self antigens, also called self-tolerance, is a fundamental property
of the normal immune system, and failure of self-tolerance results in immune
reactions against self (autologous) antigens
• Such reactions are called autoimmunity, and the diseases they cause are
called autoimmune diseases
• Tolerance unlike immunosuppression is antigen specific
RECOGNITION OF MICROBES AND DAMAGED
SELF BY THE INNATE IMMUNE SYSTEM
• The innate immune system recognizes molecular
structures that are characteristic of microbial
pathogens but not mammalian cells
• The microbial substances that stimulate innate
immunity are called pathogen-associated molecular
patterns (PAMPs)
• These PAMPs recognize a limited number of
fundamental differences between microbial molecules
and the molecules that higher organisms produce
PAMPs
The innate immune
system recognizes
microbial products that
are often essential for
survival of the
microbes!!!
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The innate immune system also recognizes
endogenous
molecules that are produced by or released
from damaged
and dying cells
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These substances are called damage associated
molecular patterns (DAMPs)
•
DAMPs may be produced as a result of cell
damage caused by infections, but they may
also indicate sterile injury to cells caused by
any of myriad reasons, such as
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chemical toxins,
burns,
trauma,
or decreased blood supply.
DAMPs are generally not released from cells
dying by apoptosis
In some cases, healthy cells of the immune
system are stimulated to produce and release
DAMPs, which enhances an innate immune
response to infections
DAMPs
RECOGNITION OF MICROBES AND DAMAGED SELF BY
THE ADAPTIVE IMMUNE SYSTEM
• In contrast to the innate immune system, the
adaptive immune system is capable of
recognizing a much wider array of foreign
substances whether or not they are products of
microbes
• Adaptive immune system may recognize the
microbial components which may be dispensable
for the survival of the microbe
• With what biological consequences?
microbe may mutate or lose many of the antigens that are
recognized by the adaptive immune system, thereby
enabling the microbes to evade host defense without
compromising their own survival
• How can a large number of diverse
lymphocytic receptors be generated?
General features of physiological
tolerance
• The immune system must learn or be
educated to discriminate between self and
non-self
• Normal individuals are tolerant of their own
(self) antigens
• All individuals inherit essentially the same
antigen receptor gene segments, and these
recombine and are expressed in
lymphocytes as they arise from stem cells
• The specificities of the receptors encoded by
the recombined genes are irrespective of
foreign or self
• Therefore, there is a risk for lymphocytes to
react against that individual’s cells and
tissues, causing disease
• The mechanisms of immunologic tolerance
are designed to prevent such reactions
OVERVIEW OF LYMPHOCYTE
DEVELOPMENT
• The maturation of B and T lymphocytes involves a series of events that
occur in the generative lymphoid organs
• These events include the following:
– The commitment of progenitor cells to the B cell or T cell lineage
– Proliferation of progenitors and immature committed cells at specific early
stages of development, providing a large pool of cells that can generate useful
lymphocytes.
– The sequential and ordered rearrangement of antigen receptor genes and the
expression of antigen receptor proteins
– Selection events that preserve cells that have produced correct antigen
receptor proteins and eliminate potentially dangerous cells that strongly
recognize self antigens.
• These checkpoints during development ensure that lymphocytes that
express functional receptors with useful specificities will mature and enter
the peripheral immune system
• Differentiation of B and T cells into functionally and phenotypically
distinct subpopulations
– B cells develop into follicular, marginal zone, and B-1 B cells,
– and T cells develop into CD4+ and CD8+ T lymphocytes and γδ T cells
Checkpoints in lymphocyte maturation. During development,
the lymphocytes that express receptors required for continued proliferation and maturation are selected to survive,
and cells that do not express functional receptors die by apoptosis
Positive selection and negative selection further preserve cells with useful specificities.
The presence of multiple checkpoints ensures that only cells with useful receptors complete their maturation.
Positive selection
•The process called positive selection facilitates the survival of
potentially useful lymphocytes
•Positive selection is linked to the lineage commitment, the
process by which lymphocyte subsets are generated
•In the T cell lineage, positive selection ensures the maturation
of T cells whose receptors recognize self MHC molecules and
also that the expression of the appropriate co-receptor on a T
cell (CD8 or CD4) is matched to the recognition of the
appropriate type of MHC molecule (MHC class I or MHC class II)
•Mature T cells whose precursors were positively selected by self
MHC molecules in the thymus by the same self MHC molecules on
antigen-presenting cells in peripheral tissues.
•In the B cell lineage, positive selection preserves receptorexpressing cells and is coupled to the generation of different
subsets,
Negative selection
• Negative selection of immature lymphocytes is an important
mechanism for maintaining tolerance to many self antigens; this is
also called central tolerance because it develops in the central
(generative) lymphoid organs
• Negative selection is the process that eliminates or alters
developing lymphocytes whose antigen receptors bind strongly to
self antigens present in the generative lymphoid organs
• Both developing B and T cells are susceptible to negative selection
during a short period after antigen receptors are first expressed
– Developing T cells with a high affinity for self antigens are eliminated
by apoptosis, a phenomenon known as clonal deletion
– Strongly self-reactive immature B cells may be induced to make
further Ig gene rearrangements and thus evade self-reactivity. This
phenomenon is called receptor editing
– If editing fails, the self-reactive B cells die, also called clonal deletion
Positive and negative selection during
lymphocyte maturation
•After immature clones of lymphocytes in generative
lymphoid organs express antigen receptors, they are subject
to both positive and negative selection processes.
•In positive selection, lymphocyte precursors with antigen
receptors that bind some self ligand with low avidity are
selected to survive and mature further
•Developing B cells receive survival signals simply because of
expression of complete antigen receptors, without
recognition of a self antigen.
•However, as in T cells, self antigen of different affinities can
drive the differentiation of different B cell subsets.
•Positive selection in both B and T lineages is therefore
tightly linked to the process of generating lymphocyte
subsets, also referred to as lineage commitment.
•Positively selected lymphocytes enter peripheral lymphoid
tissues,
•where they respond to foreign antigens.
•In negative selection, cells that bind antigens present
within the generative organs, with high avidity, receive
signals that either lead to cell death or induce further
rearrangement of antigen receptor genes, a process known
as receptor editing.
•As a result, the repertoire of mature lymphocytes lacks cells
capable of responding to these self antigens.
•The diagram illustrates selection of B cells; the principles
are the same for T lymphocytes, except that there is no
receptor editing in the T lineage.
• Macfarlane Burnet added to his clonal selection
hypothesis the corollary that lymphocytes specific for
self antigens are eliminated to prevent immune
reactions against one’s own tissues.
• As we shall see later in this chapter, self tolerance is
maintained by several different mechanisms that
prevent the maturation and activation of potentially
harmful self-reactive lymphocytes.
• Tolerance results from the recognition of antigens by
specific lymphocytes
• In other words, tolerance, in its strict definition, is
antigen specific
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FIGURE 14–1 Central and peripheral
tolerance to self antigens.
Immature lymphocytes specific for self
antigens may encounter these antigens
in the generative lymphoid organs and
are deleted, change their specificity (B
cells only), or (in the case of CD4+ T
cells) develop into regulatory
lymphocytes (central tolerance).
Some self-reactive lymphocytes may
mature and enter peripheral tissues
and may be inactivated or deleted by
encounter with self antigens in these
tissues or are suppressed by the
regulatory T cells (peripheral
tolerance).
(Note that T cells recognize antigens
presented by antigen-presenting cells,
which are not shown.)
• FIGURE 14–2 Central
T cell tolerance.
• Recognition of self
antigens by
immature T cells in
• the thymus may lead
to death of the cells
(negative selection,
or deletion) or the
development of
regulatory T cells
that enter peripheral
tissues
FIGURE 14–3 Mechanisms of
peripheral T cell tolerance.
The signals involved in a
normal immune response
and the three major
mechanisms of peripheral
T cell tolerance
•FIGURE 14–4 Mechanisms of T cell
anergy.
•T cell responses are induced when the
cells recognize an antigen presented by a
professional antigen-presenting cell (APC)
and activating receptors on the T cells
(such as CD28) recognize costimulators on
the APCs (such as B7).
•If the T cell recognizes a self antigen
without costimulation, the T cell becomes
unresponsive to the antigen because of a
block in signaling from the TCR complex
or engagement of inhibitory receptors
(such as CTLA-4)
•The signaling block may be the result of
recruitment of phosphatases to the TCR
complex or the activation of ubiquitin
ligases that degrade signaling proteins
•The T cell remains viable but is unable to
respond to the self antigen
FIGURE 14–5 Mechanisms of action
of CTLA-4. A, The top panel shows
the activation of T cells by antigen
recognition and costimulation
through CD28.
B, The bottom panel shows the two
postulated mechanisms of action of
CTLA-4: delivery of inhibitory signals
that block TCR- and CD28-mediated
signals, and engagement of B7
molecules on APCs so they are
inaccessible to CD28.
Note that regulatory T cells may also
use CTLA-4 to block B7 and thus
inhibit immune responses.
There is some evidence that in
addition to blocking B7, CTLA-4 may
remove these molecules from the
APC surface and internalize them
FIGURE 14–6 Regulatory T cells.
•Regulatory T cells are generated by self antigen recognition in the thymus (
•sometimes called natural regulatory cells)
•and (probably to a lesser extent) by antigen recognition in peripheral lymphoid organs (called
inducible or adaptive regulatory cells)
•The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3
•In peripheral tissues, regulatory T cells suppress the activation and effector functions of other, self-reactive
and potentially pathogenic lymphocytes