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S ECTION 20
TOLERANCE AND
AUTOIMMUNITY
C ONTACT I NFORMATION
Abul Abbas, MD (Email)
R EADING
Basic Immunology: Functions
and Disorders of the Immune System. Abbas,
Abul K., and Andrew H. Lichtman. -- Chapter 9
O BJECTIVES
K EY WORDS :
IMMUNOLOGICAL TOLERANCE
AUTOIMMUNITY
AUTOIMMUNE DISEASE
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M AIN IDEAS :
Lymphocytes with receptors for self antigens are generated in all individuals, and have to be killed or controlled in order to prevent autoimmunity. The failure of
lymphocytes to respond to an antigen after encountering that antigen is called tolerance (and is the opposite of activation).
Central tolerance: many of the immature lymphocytes that see self antigens in the central (generative)
lymphoid organs (thymus, bone marrow) are killed.
Peripheral tolerance: lymphocytes that recognize
self antigens in peripheral tissues are shut off, suppressed by regulatory T lymphocytes, or kille.
Failure in the mechanisms of tolerance to self antigens
results in autoimmunity. The major factors in the development of autoimmunity are the inheritance of suscep-
A BUL A BBAS
tibility genes and environmental factors, such as infections.
Tolerance: unresponsiveness to an antigen induced
by prior exposure to that antigen
Significance:
- self-tolerance is a fundamental property of the immune system; it is induced when self-reactive lymphocytes encounter self antigens; its failure leads
to autoimmunity
- strategies for inducing tolerance may be useful for
treating allergic and autoimmune diseases, and for
preventing graft rejection and immune responses
in gene therapy and stem cell therapy
Mechanisms of immunological tolerance: the
principal mechanisms are divided into central tolerance and peripheral tolerance. At times, the immune
system may fail to recognize or react against some self
antigens; this phenomenon is called "ignorance".
Central tolerance: immature lymphocytes recognize,
with high affinity, antigen in generative lymphoid organs (typically self antigens); this results in death of
the lymphocytes by apoptosis, also called negative selection.
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Understanding the mechanisms of peripheral tolerance
is leading to new strategies for shutting off harmful immune responses and restoring the normal balance of
lymphocyte activation and tolerance. Many trials of
these therapeutic strategies are under way.
Development of autoimmunity is a consequence
of the failure of self-tolerance; usually results from a
combination of genetic susceptibility and environmental triggers (e.g. infections).
Genetic susceptibility
Multiples genes influence susceptibility to autoimmune
disease; MHC (HLA in humans) is the most important.
Many non-MHC genes are known to be involved. Recent genetic analyses are beginning to reveal some of
the polymorphic genes that are associated with autoimmune diseases, but it has proved difficult to use this genetic information to better understand the diseases, or
to develop novel therapies, or to predict who will get a
particular disease and how it will progress.
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Environmental triggers
Infections usually trigger and/or exacerbate autoimmunity; likely mechanisms include induction of costimulators on APCs, and "molecular mimicry" of foreign antigens with self.
Surprisingly, some infections appear to protect individuals from certain autoimmune diseases; the mechanisms are not known. Despite our growing knowledge
of the mechanisms of self-tolerance, the etiologies of
human autoimmune diseases are still not established,
and this remains one of the major challenges in Immunology.
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