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No 13 Immunological Tolerance
No 13 Immunological Tolerance
Immunological Tolerance
Chapter 10.
Tolerance
Our own bodies produce some 100,000
different proteins and one of the longstanding
conundrums of immunology has been to
understand how the immune system
produces a virtual repertoire against
pathogens while at the same time avoiding
reacting to self.
The strict definition of immunological
tolerance occurs when an immunocompetent
host fails to respond to an immunogenic
challenge with a specific antigen.
Tolerance
The mechanisms the immune system uses
to ensure the absence of self-reactivity
(autoimmunity) include:
Central Tolerance - this occurs during
lymphocyte development.
Peripheral Tolerance - occurs after
lymphocytes leave the primary lymphoid
organs.
Central Tolerance
Peripheral Tolerance
TOLERANCE
Introduction
Tolerance refers to the specific
immunological non-reactivity to an antigen
resulting from a previous exposure to the
same antigen.
While the most important form of tolerance
is non-reactivity to self antigens, it is
possible to induce tolerance to non-self
antigens. When an antigen induces
tolerance, it is termed tolerogen.
TOLERANCE
Tolerance is different from non-specific
immunosuppression and immunodeficiency.
It is an active antigen-dependent process in
response to the antigen.
Like immune response, tolerance is specific
and like immunological memory, it can exist
in T-cells, B cells or both and like
immunological memory, tolerance at the T
cell level is longer lasting than tolerance at
the B cell level.
Tolerance to tissues and cells
Tolerance to tissue and cell antigens can be
induced by injection of hemopoietic (stem) cells
in neonatal or severely immunocompromised (by
lethal irradiation or drug treatment) animals.
Also, grafting of allogeneic bone marrow or
thymus in early life results in tolerance to the
donor type cells and tissues. Such animals are
known as chimeras. These findings are of
significant practical application in bone marrow
grafting.
Tolerance to soluble antigens
A state of tolerance to a variety of T-
dependent and T-independent antigens
has been achieved in various experimental
models.
Based on these observations it is clear
that a number of factors determine
whether an antigen will stimulate an
immune response or tolerance
Tolerance
Clonal deletion:
Functionally immature cells of a clone
encountering antigen undergo a programmed
cell death, as auto-reactive T-cells are
eliminated in the thymus following interaction
with self antigen during their differentiation
(negative selection).
Mechanism of tolerance induction
Clonal deletion:
Likewise, differentiating early B cells become
tolerant when they encounter cell-associated
or soluble self antigen.
Clonal deletion has been shown to occur
also in the periphery.
Mechanism of tolerance induction
Clonal anergy:
Auto-reactive T cells, when exposed to
antigenic peptides which do not possess co-
stimulatory molecules (B7-1 or B7-2),
become anergic to the antigen.
Mechanism of tolerance induction
Clonal anergy:
Also, B cells when exposed to large amounts
of soluble antigen down regulate their
surface IgM and become anergic. These
cells also up-regulate the Fas molecules on
their surface. An interaction of these B cells
with Fas-ligand-bearing cells results in their
death via apoptosis.
Mechanism of tolerance induction
Receptor editing:
B cells which encounter large amounts of
soluble antigen, as they do in the body, and
bind to this antigen with very low affinity
become activated to re-express their RAG-1
and RAG-2 genes.
These genes cause them to undergo DNA
recombination and change their antigen
specificity.
What are RAG-1 RAG-2?
Recombination signal sequences
(RAG).
RAG-1 is a specific endonuclease and is
only active when complexed with RAG-2.
Specific DNA sequences (heptamers)
found adjacent to the V, D, and J
segments in the antigen receptor loci and
recognized by the RAG-1/RAG-2
component of the V(D)J recombinase.
(see figure 7-11)
RAG-1/RAG-2
Mechanism of tolerance induction
Anti-idiotype antibody:
Anti-idiotype antibodies produced experimentally
have been demonstrated to inhibit immune
response to specific antigens.
Anti-idiotype antibodies are produced during the
process of tolerization.
Such antibodies may respond to the unique
receptors of other lymphocytes and serve to shut
off antigen specific responses.
Therefore, these antibodies prevent the receptor
from combining with antigen.
Mechanism of tolerance induction
Termination of tolerance
Experimentally induced tolerance can be
terminated by prolonged absence of exposure to
the tolerogen, by treatments which severely
damage the immune system (x-irradiation) or by
immunization with cross reactive antigens.
These observations are of significance in the
conceptualization of autoimmune diseases.
Dendritic cells: regulators of alloimmunity and
opportunities for tolerance induction
Dendritic cells (DCs) are uniquely well-
equipped antigen-presenting cells (APCs)
regarded classically as sentinels of the
immune response, which induce and
regulate T-cell reactivity.
They play critical roles in central tolerance
and in the maintenance of peripheral
tolerance in the normal steady state.
Regulatory T cells
Mechanism of tolerance induction
Suppressor cells:
Both low and high doses of antigen may
induce suppressor T cells (Regulatory T
cells) which can specifically suppress
immune responses of both B and T cells,
either directly or by production of
cytokines, most importantly, TGF-b and IL-
10.
Regulatory T cells
CD4+ T lymphocytes that express high
levels of IL-2r a chain (CD25) but not other
markers of activation.
Regulatory T cells may be generated by
self antigen recognition in the thymus or in
the periphery.
These cells induce immunosuppression by
secreting TGF-b and IL-10 and thereby
inhibit Mf function and IFN-g activity.
Fig 10-10
Oral tolerance
The gastrointestinal tract is the largest
immunologic organ in the body.
It is constantly bombarded by a myriad of dietary
proteins.
Despite the extent of protein exposure, very few
patients have food allergies because of
development of oral tolerance to these antigens.
Once proteins contact the intestinal surface, they
are sampled by different cells and, depending on
their characteristics, result in different responses.
Oral tolerance
Antigens might be taken up by Microfold cells
overlying Peyer's patches, dendritic cells, or
epithelial cells.
Different cells of the immune system participate
in oral tolerance induction, with regulatory T
cells being the most important.
Several factors can influence tolerance
induction.
Some are antigen related, and others are
inherent to the host. Disturbances at different
steps in the path to oral tolerance have been
described in food hypersensitivity.
Oral tolerance
T regulatory cell family
The idea of specific suppressor T cell
populations that counteract harmful
autoaggressive immune responses in the
periphery was first described in the 1970s
by Gershon et al.
However, at that time neither the cells nor
the hypothetical soluble suppressor factors
responsible for the observed effects could
be identified.
T regulatory cell family