3. What is Immunologic Tolerance?
ďState in which the individual is incapable
of developing an immune response to a
specific antigen.
ďSelf tolerance: refers to the lack of
individualâs antigens.
ďAffects the ability to live in harmony with
our own cells and tissues.
4. Classification
Immunologic
tolerance
Central Peripheral
tolerance tolerance
5. Central Tolerance
ďRefers to death (deletion) of self-reactive T-
and B-lymphocyte clones during their
maturation in the central lymphoid organs
(the thymus for T cells and the bone
marrow for B cells).
ďExperiments with transgenic mice provide
abundant evidence that T lymphocytes that
bear receptors for self antigens undergo
apoptosis within the thymus during the
process of T-cell maturation
6.
7. ď T-cells that bear receptors for self antigen
undergo apoptosis within the thymus during
the process of T-cell maturation.
ď Many autologous protein antigen are
processed and presented by thymic antigen-
presenting cells in association with self MHC
(major histocompatibility complex) proteins.
ď Developing T-cells having high affinity
receptors for such antigens are negatively
selected, or deleted, and therefore the
peripheral T-cell pooling is lacking or
deficient in self reactive cells.
ď The developing thymocytes express high
levels of Fas causing negative selection.
8. ďClonal deletion of T-cells also affects B-
cells.
ďWhen developing B-cells encounter a
membrane-bound antigen within the bone
marrow, they undergo apoptosis.
ďNo self antigen present in the thymus: T-
cells and B-cells slip into the periphery.
ďB-cells bearing receptors for thyroglobulin,
collagen and DNA can be found in the
periphery.
9. PERIPHERAL TOLERANCE
ďT-cells that escape intrathymic negative
selection can cause tissue injury unless
they are deleted or muzzled in the
peripheral tissues.
ď3 âback upâ mechanisms that silence
such potentially autoreactive T-cells are:-
1.Clonal deletion by activation-induced cell
death
2.Clonal anergy
3.Peripheral suppression by T-cells
10. 1. Clonal deletion by activation-
induced cell death
ďMechanism to prevent uncontrolled T-cell
activation during normal immune response
involves apoptotic death of activated T-
cells by Fas-Fas ligand system.
ďExpression of Fas (CD95) is upregulated in
antigen activated T-cells.
ďEngagement of Fas by Fas L, coexpressed
on activated T-cells, dampens the immune
response by inducing apoptosis of
activated T-cells.
11. ďThe self antigens that are abundant
in the peripheral tissues cause
repeated and persistent stimulation
of self-antigen-specific T-cells
leading eventually to their
elimination via Fas mediated
apoptotis.
12.
13. 2.Clonal anergy
ďRefers to a prolonged or irreversible
functional inactivation of
lymphocytes, induced by encounter with
antigens under certain conditions.
14. ďActivation of T-cells requires 2
signals:-
a.Recognition of peptide antigen in
association with self MHC molecules on
the surface of antigen-presenting cells
and set of costimulatory signals
provided by antigen-presenting cells.
b.To initiate second signals, certain T-cells
associated molecules, such as CD28,
must bind to their ligand, a negative
signal is delivered, and the cell
becomes anergic.
15. ďSuch a cell then fails to be activated
even if the relevant antigen is presented
by component antigen presenting cells
that can deliver costimulation.
ďSince costimulatory molecules are not
expressed or are weekly expressed on
most normal tissues, the encounter
between auto reactive T-cells and their
specific antigen leads to clonal anergy.
ďAlso affects B-cells.
16. ďB-cells encounter antigen in the
absence of specific helper T-cells,
the antigen-receptor complex is
down regulated, and such cells
never re-express their
immunoglobin receptors.
ďSuch cells are unable to respond to
subsequent antigenic stimulation.
17.
18. 3.Peripheral stimulation of
T-cells
ďFocus is on suppressor T-cells with the
ability to downregulate the function of
other autoreactive T-cells.
ďMolecular mechanisms by which
suppressor T-cells recognize antigens and
exert their suppressive effects are little
understood.
ďSome evidence is that peripheral
suppression of autoreactivity may be
mediated, in part, by the regulated
secretion of cytokinesis.