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Lecture 6
IMMUNOLOGICAL
TOLERANCE
Jan Żeromski
2007/2008
BASIC FACTS ABOUT TOLERANCE
• Tolerance – a state of
unresponsiveness specific for a given
antigen
• It is specific (negative) immune
response
• It is induced by prior exposure to that
antigen
BASIC FACTS ABOUT TOLERANCE-2
• Self tolerance – prevents the body to
elicit an immune attack against its own
tissues
• Mechanisms of active tolerance
prevent inflammatory reactions to many
innocuous airborne and food antigens
found at mucosal surfaces
Features of self-tolerance
• Self-non-self discrimination is learned
during development
• Tolerance is NOT genetically programmed
• The time of first encounter is critical in
determining responsiveness
FACTORS IMPORTANT IN THE
INDUCTION OF TOLERANCE
1. The stage of differentiation of lymphocytes
at the time of antigen confrontation
2. The site of encounter
3. The nature of cells presenting antigenic
epitopes
4. The number of lymphocytes able to respond
5. Microenvironment of encounter (expression
of cell adhesion molecules, influence of
cytokines etc.)
TOLERANCE – GENERAL PROPERTIES
1. Immature or developing lymphocyte is more
susceptible to tolerance induction than
mature one
2. Tolerance to foreign antigens is induced
even in mature lymphocytes under special
conditions
3. Tolerance of T lymphocytes is a particularly
effective for maintaining long-lived
unresponsiveness to self antigens
POSSIBLE WAYS OF PREVENTION OF
SELF-REACTIVITY
• Clonal deletion – physical elimination of cells
from the repertoire during their lifespan
• Clonal anergy – downregulating the intrinsic
mechanism of the immune response such as
lack of costimulatory molecules or insufficient
second signal for cell activation
• Suppression – inhibition of cellular activation
by interaction with other cells:
(Treg – CD4+, CD25+ T lymphocytes)
DIVISION OF TOLERANCE
Central
• The site for T cells is
the thymus
• The site for B cells
is the bone marrow
• The mechanism –
clonal deletion
Peripheral
• The site – everywhere
in the body
• Cells – both T and B
• Mechanisms – anergy,
cell death, immune
deviation
IMPORTANT OPPOSED TERMS
• Central tolerance (self-tolerance)
versus peripheral tolerance
• Active tolerance vs. passive tolerance
(ignorance)
• T-cell tolerance vs. B-cell tolerance
• Natural vs. artificial tolerance
• Complete vs. incomplete tolerance
IMMUNOLOGICALLY PRIVILEGED SITES
• Sites in the body where foreign
antigens or tissue grafts do not elicit
immune responses
• These antigens do interact with T cells,
but instead of destructive IR they
induce tolerance or a response
innocent to the tissue
IMMUNOLOGICALLY PRIVILEGED SITES - 2
• Immunosuppressive cytokines such as
TGF-beta seem to be resposible for
such unusual response
• The sites include: brain, eye, testis,
uterus (fetus)
IMPORTANT OPPOSED TERMS
• Central tolerance (self-tolerance)
versus peripheral tolerance
• Active tolerance vs. passive tolerance (ignorance)
• T-cell tolerance vs. B-cell tolerance
• Natural vs. artificial tolerance
IGNORANCE OF SELF ANTIGENS
•
•
It is a passive form of immunological
tolerance
It occurs when:
1. T cells can not contact with self –
antigens,
2. if self antigen is present in too low an
amount to be detected,
3. if it is present on cells with few or no MHC
molecules
4. if there are not enough T cells to respond
5. if there is the absence of co-stimulation
FEATURES OF B-CELL TOLERANCE
1. Binding soluble self antigens is tolerogenic
for B cells
2. Immature B cells that encounter self antigen
undergo clonal abortion
3. The fate of self-reactive B cells depends on
the affinity of the B cell antigen receptor and
the nature of the antigen
4. Receptor editing - autoreactive B cells
escape anergy or deletion by further
rearranging their immunoglobulin genes
IMPORTANT OPPOSED TERMS
• Central tolerance (self-tolerance)
versus peripheral tolerance
• Active tolerance vs. passive tolerance (ignorance)
• T-cell tolerance vs. B-cell tolerance
• Natural vs. artificial tolerance
ARTIFICIAL INDUCTION OF TOLERANCE
1. By chimerism in immunocompromized hosts
2. By antibodies to T cell receptors
3. By injection of soluble antigens
ARTIFICIAL INDUCTION OF TOLERANCE - 2
4. By oral administration of antigens
5. By clonal exhaustion via extensive clonal
proliferation after repeated antigenic
challenge
6. Anti-idiotypic antibody – partial result, affects
B cells only
FUTURE APPLICATIONS OF
TOLERANCE
• To promote tolerance to foreign tissue grafts
• To control the damaging immune responses
in hypersensitivity states and autoimmune
diseases
--{ THANK YOU }—
and be tolerant to our
imperfections!