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 T- cells.

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

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. T- cell Anergy

Development and function of regulatory T cells. FoxP3+ CD25+ CTLA4+ GITR+ PD1 TGFβ IL10 FOXP3- mutations IPEX: immune dysregulation, polyendocrinopathy, enteropathy, Xlinked Inhibitory receptor expression, inhibitory cytokines IL2 dependence Therapeutic posiibilities: Treatment of Autoimmun diseases GVH Cancer Infectious diseases?

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