Download TOLERANCE

TOLERANCE
Deletion, anergy or ignorance?
Normal thyroid
Diseased thyroid
If the immune system fails to “delete” or anergise
tissue reactive lymphocytes, AUTOIMMUNITY occurs
If the immune system fails to “ignore”
harmless environmental antigens,
ALLERGY results
TO COMBAT THE DIVERSITY OF PATHOGENIC
ANTIGENS THAT MIGHT BE ENCOUNTERED BY THE
HOST, THE IMMUNE SYSTEM MUST PRODUCE
POPULATIONS OF LYMPHOCYTES WITH
RECEPTORS OF EQUAL DIVERSITY
To achieve this, the antigen receptors of T
lymphocytes and B lymphocytes are generated
randomly.
This repertoire will inevitably contain lymphocytes
specific for self antigen.
The body must therefore distinguish between self and
non-self determinants to avoid autoimmunity,
and between dangerous and non-dangerous antigen
to avoid allergy.
HOW IS THIS ACHIEVED?
• “Central tolerance” edits lymphocytes BEFORE they
enter the circulation as naïve cells
• “Peripheral tolerance” acts as a back up to eliminate
potentially autoreactive lymphocytes AFTER they
enter the circulation.
• Some cells are DELETED, some cells are
ANERGISED.
• ANERGIC cells can be re-activated if a “DANGER”
signal is encountered
Central tolerance
occurs in the
thymus where T
cells are edited
before they enter
the circulation as
naïve cells
Clonal selection
theory also applies
to B lymphocytes
that are “edited” in
the bone marrow
and lymph nodes
T CELLTOLERANCE IS ESSENTIAL TO CONTROL
POTENTIAL B CELL AUTOREACTIVITY
B cells need T cell “help” to make high affinity
antibody
Dendritic cells control T cell immuno-reactivity
and help decide the fate of the T cell
Vital messages are exchanged at the immunological synapse
The QUALITY and QUANTITY of the signals exchanged
determines whether the T cell is
ACTIVATED, ANERGISED OR DELETED
Quantity of antigen is also important:
lymphocytes specific for abundant self-antigen
are deleted, low level self-antigen is “ignored”
Dendritic cells have a sentinel function in the
periphery:
They can induce immunity or anergy depending on
signals exchanged and the microenvironment
The “DANGER HYPOTHESIS”
Dendritic cells have
receptors that recognise
pathogens and inflammatory
mediators released by other
cells. These “danger signals
help the DC activate T cells
and stimulate protective
immunity
Therefore antigens encountered in the absence
of infection or injury are NOT dangerous and induce
tolerance
Tolerance or immunity can also be influenced
by the tissue microenvironment
Immuno-suppressive
mediators are secreted
by the foetus and
placenta (eg TGF-b)
and prevent “rejection”
Can we manipulate the
immune system to
avoid rejection of liver
or kidney grafts?
SUMMARY
To combat the diversity of pathogenic antigens that
might be encountered by the host, the immune system
must produce populations of lymphocytes with
receptors of equal diversity
• To achieve this, the antigen receptors of T
lymphocytes and B lymphocytes are generated
randomly.
• This repertoire will inevitably contain lymphocytes
specific for self antigen.
• The body must therefore distinguish between self and
non-self determinants to avoid AUTOIMMUNITY,
• and between dangerous and non-dangerous antigen
to avoid ALLERGY.
• “Central tolerance” edits lymphocytes BEFORE they
enter the circulation as naïve cells
• “Peripheral tolerance” acts as a back up to eliminate
potentially autoreactive lymphocytes AFTER they
enter the circulation.
• Some cells are DELETED, some cells are
ANERGISED.
• ANERGIC cells can be re-activated if a “DANGER”
signal is encountered
Dendritic cells are vital in the process
and decide whether tolerance or
immunity to an antigen will occur
Can the immune response and
dendritic cells be manipulated to reinduce tolerance in autoimmunity or
to prevent graft rejection?