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Immunological tolerance
Immunological tolerance
Definition:
Unresponsiveness to a given antigen induced by the interaction of that antigen with the lymphocytes;
Antigen specific!!! Unlike immunosuppresion.
Why is this important?
-All individuals are tolerant to their own antigens(self tolerance).
-Failure of self tolerance results in autoimmunity.
-Terapeutic potential:
Treat autoimmune diseases, allrgic reaction or even tissue rejection.
Central and peripheral tolerance to self antigens.
Elimination of self-reactive clones
BUT!!! Some T-cell clones escape,
Elimination of „fugitive” or altered
clones important role for regulatory Tcells.
Central T cell tolerance
The structure of the thymus
Only a small fraction of T cells mature into functional T cells
Positive selection:
Occurs in the cortex, requires thymic epithelial
cells (MHCI/MHCII positive)
-Az αβ double-positive Thymocytes must
recognize self-MHC.
- First step, (Ca 2% of thymocytes survive!!)
- Selection occurs in 3-4 days!!
Positive selection --- results in
clones that are reactive to self
MHC. Basis of MHC restriction
Peptides are recognized in the
context of self MHC
Cortical epithelium
Interaction of a double-positive T cell with a selfpeptide:self-MHC complex
during positive selection determines whether the T cell will become
a CD4 or a CD8 T cell
Negative selection:
Elimination of potentially autoreactive clones.
Requires several cell types besides epithelial cells:
For example DC or macrophages
Negative selection of T cells in the Thymus
Autoimmun regulator (AIRE)
AIRE is responsible for the expression of tissue antigens in the thymus
Mutations in AIRE cause an autoimmune polyendocrine syndrome
Lack of proper negative selection allows too many self reactive T-cell clones to
leave the thymus
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
Peripheral T-cell tolerance
T- cell Anergy
Anergy: long-term functional unresponsiveness which occurs when lymphocytes are exposed
to the antigen in the absence of proper co-stimulation.
In the absence of co-stimulation inhibitory signals dominate.
Development and function of regulatory T cells.
FoxP3+
CD25+
CTLA4+
GITR+
PD1
TGFβ
IL10
Inhibitory receptor expression,
inhibitory cytokines
IL2 dependence
Therapeutic posiibilities:
Treatment of
Autoimmun diseases
GVH
Cancer
Infectious diseases?
FOXP3- mutations
IPEX: immune dysregulation, polyendocrinopathy, enteropathy, Xlinked
Central B-cell tolerance
Immature B cells with specificity for multivalent self antigens are retained
in the bone marrow
Many self-reactive B cells are rescued by receptor editing, which changes
their antigen specificity
Immature B cells specific for monovalent self antigens develop a state of anergy
The general route of B-cell circulation through a lymphoid tissue
Immature B cells must pass through a primary follicle in a secondary
lymphoid tissue to become mature B cells