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History of Tolerance

 Burnet postulated that antigens encountered while

the immune system was immature can tolerize the
relevant lymphocytes.
 Medewar subsequently investigated the effects of
transferring hemopoietic cells from
histoincompatible mice at different times after
birth. He found that if the cells were transferred in
the first few days of life (but not later) the recipient
mouse acquired lifelong tolerance to the antigens
of the donor.
Note: Recent experiments have shown that adults
can also be tolerated under certain circumstances
and that neonates can make effective immune
responses if the antigen is presented in sufficiently
immunogenic form.
Immunological tolerance refers to the specific
immunological non-reactivity (unresponsiveness)
to an antigen due to a previous exposure to the same

While the most important form of tolerance is non-

reactivity to self antigens, it is possible to induce
tolerance to non-self antigens. When an antigen
induces tolerance, it is termed as Tolerogens.

Tolerance is different from non-specific

immunosuppression and immunodeficiency. It is an
active antigen-dependent process in response to the
Like immune response, tolerance is specific and like
immunological memory, it can exist in T-cells, B cells
or both and like immunological memory, tolerance at
the T cell level is longer lasting than tolerance at the B
cell level.

Tolerance to tissue and cell antigens can be induced by

injection of hemopoietic (stem) cells in neonatal or
severely immunocompromised animals.

Grafting of allogeneic bone marrow or thymus in early

life results in tolerance to the donor type cells and
tissues. Such animals are known as chimeras.
Induction of tolerance in T cells is easier and requires
relatively smaller amounts of tolerogen than
tolerance in B cells.

Maintenance of immunological tolerance requires

persistence of antigen.

Tolerance can be broken naturally (as in

autoimmune diseases) or artificially (by x-
irradiation, certain drug treatments and by exposure
to cross reactive antigens).

Low-dose cyclophosphamide or gemcitabine therapy

can selectively deplete T regulatory cells (Treg).
Immunogenic antigen vs Tolerogenic antigen
 It can be shown that there are T cells and B cells specific
for auto-antigens present in circulation.

 These cells are quite capable of making a response but are

unaware of the presence of their auto-antigen. This arises
for 2 reasons.

 The first is that the antigen may simply be present in too

low concentration. Since all lymphocytes have a
threshold for receptor occupancy which is required to
trigger a response then very low concentrations of
antigen (in the case of T cells these are very low) will not
be sensed.
 The second possibility is a more interesting one.
Some antigens are sequestered from the immune
system in locations which are not freely exposed to

 These are termed immunologically privileged

sites. Examples of such sites are the eye, CNS and

 Pathologically mediated disruption of these

privileged sites may expose the sequestered
antigens leading to an autoimmune response.
Central Tolerance
(this occurs during lymphocyte development. )
Peripheral Tolerance
(occurs after lymphocytes leave the primary lymphoid organs. )
Mechanisms of tolerance induction
1. Clonal deletion:
 Functionally immature cells of a clone encountering
antigen undergo a programmed cell death, as auto-
reactive T-cells are eliminated in the thymus following
interaction with self antigen during their differentiation
(negative selection).

 Likewise, differentiating early B cells become tolerant

when they encounter cell-associated or soluble self

 Clonal deletion has been shown to occur also in the

Clonal deletion:
reactive Dies

Immature Not Survives
no membrane Ig B-cell self-
membrane Ig reactive Mature
random receptor B-cell
2. Clonal anergy:
 Auto-reactive T cells, when exposed to antigenic peptides
which do not possess co-stimulatory molecules, become
anergic to the antigen.

 B cells when exposed to large amounts of soluble antigen

down regulate their surface IgM and become anergic.

 B cells also up-regulate the Fas molecules on their surface.

An interaction of these B cells with Fas-ligand-bearing
cells results in their death via apoptosis.
3. Receptor editing:
 B cells which encounter large amounts of soluble antigen, and
bind to this antigen with very low affinity become activated to re-
express their RAG-1 and RAG-2 genes. These genes cause them to
undergo DNA recombination and change their antigen specificity.

 The BCRs of self reactive B cells are given an opportunity to

rearrange their conformation via the continued expression of the
Recombination Activation Gene (RAG). Through the help of RAG,
receptor editing involves light chain gene rearrangement of the B
cell receptor.

 If receptor editing fails to produce a BCR that is less autoreactive,

apoptosis will occur. Note that defects in the RAG-1 and RAG-2
genes are implicated in Severe Combined Immunodeficiency
(SCID). The inability to recombine and generate new receptors
lead to failure of maturity for both B cells and T cells.
1. Kindt TJ, Goldsby RA, Osborne BA, Kuby
Immunology, sixth edition, WH Freeman and
Company, New York.

2. Romagnani S, “Immunological tolerance and

autoimmunity”, Department of Internal Medicine,
Excellence Centre Denothe, University of Florence,
Florence, Italy.