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 toleranceoccurs in the thymus where T cells are edited before they enter the circulation as naïve cells

Clonal selection theory also applies to B lymphocytesthat are “edited” in the bone marrow and lymph nodes

B cells need T cell “help” to make high affinity antibody

T CELLTOLERANCE IS ESSENTIAL TO CONTROL POTENTIAL B CELL AUTOREACTIVITY

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 exchangeddetermines 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”

Therefore antigens encountered in the absence of infection or injury are NOT dangerous and induce tolerance

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

Tolerance or immunity can also be influenced by the tissue microenvironment

Immuno-suppressive mediators are secreted by the foetus and placenta (eg TGFand prevent “rejection”

Can we manipulate the immune system to avoid rejection of liver or kidney grafts?

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

SUMMARY

• 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 re-induce tolerance in autoimmunity or

to prevent graft rejection?