LECTURE 7 :
autoimmunity
IMMUNITY TO SELF ANTIGENS
IMMUNOGICAL TOLERANCE
This is the state of immunological unresponsiveness, whereby T
cell and B cell receptors do not respond to antigens.
Immunological tolerance to self antigens is important to prevent
the immune system from recognizing self as foreign .
The process of inducing self tolerance occurs during embryonic
development whereby immature T cells and B cells are “tolerized”
to self antigens.
A breakdown in the mechanisms of self tolerance therefore leads
to immunity against self i.e. autoimmunity
B cells and T cells develop in the central/primary lymphoid organs
i.e. B cells develop in the bone marrow and T cells in the thymus.
During development, T cells and B cells acquire cell receptors to
antigens i.e. B cell receptors and T cell receptors (BCRs and
TCRs).
The diversity of BCRs and TCRs enables them to respond to
different epitopes they may encounter.
However, about 50% of BCRs and 20% of TCRs will have an
affinity to self antigens – may bind self antigens.
These BCRs and TCRs with affinity to self are eliminated to avoid
immunity to self.
MECHANISMS OF SELF TOLERANCE
There are two principal mechanisms by which self-reactive B cells
and T cells are eliminated in the body:
A. Central tolerance
B. Peripheral tolerance
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, A.Mechanisms of Central tolerance
In this mechanism, clones of self-reactive B cells and T
cells are removed from the bone marrow and thymus
respectively through programmed cell death (apoptosis).
This process is also referred to as clonal deletion
because it leads to the deletion of clones of self-reactive
B cells and T cells.
A. Central tolerance
Other than clonal deletion, self reactive B cells may undergo other
mechanisms to reduce reactivity to self.
Receptor editing is another mechanism of central tolerance,
whereby, the BCRs and TCRs undergo editing to reduce their
affinity to self antigens
Receptor editing may occur through recombination and
hypermutation of the BCR and TCR genes.
Other mechanisms of central tolerance include intrinsic and
extrinsic downregulation of the self-reactive BCRs and TCRs.
B. Peripheral tolerance
Some self reactive B cells and T cells may escape central tolerance
mechanisms and may be released from the bone marrow and the thymus
respectively into secondary or peripheral lymphoid organs.
These will be eliminated by mechanisms of peripheral tolerance:
i.Clonal Anergy: Whereby reactive T cells are rendered unresponsive to
self antigens due to lack of co-stimulatory signals during antigen
presentation e.g. lack of CD40 and CD28 co-stimulation.
ii.Active suppression: Whereby, self-reactive T cells are suppressed by
regulatory T cells that secrete Th2 cytokines e.g. TGF-β, IL10. This inhibits
immune response to self-antigen.
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autoimmunity
IMMUNITY TO SELF ANTIGENS
IMMUNOGICAL TOLERANCE
This is the state of immunological unresponsiveness, whereby T
cell and B cell receptors do not respond to antigens.
Immunological tolerance to self antigens is important to prevent
the immune system from recognizing self as foreign .
The process of inducing self tolerance occurs during embryonic
development whereby immature T cells and B cells are “tolerized”
to self antigens.
A breakdown in the mechanisms of self tolerance therefore leads
to immunity against self i.e. autoimmunity
B cells and T cells develop in the central/primary lymphoid organs
i.e. B cells develop in the bone marrow and T cells in the thymus.
During development, T cells and B cells acquire cell receptors to
antigens i.e. B cell receptors and T cell receptors (BCRs and
TCRs).
The diversity of BCRs and TCRs enables them to respond to
different epitopes they may encounter.
However, about 50% of BCRs and 20% of TCRs will have an
affinity to self antigens – may bind self antigens.
These BCRs and TCRs with affinity to self are eliminated to avoid
immunity to self.
MECHANISMS OF SELF TOLERANCE
There are two principal mechanisms by which self-reactive B cells
and T cells are eliminated in the body:
A. Central tolerance
B. Peripheral tolerance
111
, A.Mechanisms of Central tolerance
In this mechanism, clones of self-reactive B cells and T
cells are removed from the bone marrow and thymus
respectively through programmed cell death (apoptosis).
This process is also referred to as clonal deletion
because it leads to the deletion of clones of self-reactive
B cells and T cells.
A. Central tolerance
Other than clonal deletion, self reactive B cells may undergo other
mechanisms to reduce reactivity to self.
Receptor editing is another mechanism of central tolerance,
whereby, the BCRs and TCRs undergo editing to reduce their
affinity to self antigens
Receptor editing may occur through recombination and
hypermutation of the BCR and TCR genes.
Other mechanisms of central tolerance include intrinsic and
extrinsic downregulation of the self-reactive BCRs and TCRs.
B. Peripheral tolerance
Some self reactive B cells and T cells may escape central tolerance
mechanisms and may be released from the bone marrow and the thymus
respectively into secondary or peripheral lymphoid organs.
These will be eliminated by mechanisms of peripheral tolerance:
i.Clonal Anergy: Whereby reactive T cells are rendered unresponsive to
self antigens due to lack of co-stimulatory signals during antigen
presentation e.g. lack of CD40 and CD28 co-stimulation.
ii.Active suppression: Whereby, self-reactive T cells are suppressed by
regulatory T cells that secrete Th2 cytokines e.g. TGF-β, IL10. This inhibits
immune response to self-antigen.
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