ContentsDefinitionCentral tolerancePeripheral toleranceBack up mechanisms
What is Immunologic Tolerance?State in which the individual is incapable of developing an immune response to a specific antigen.Self tolerance: refers to the lack of individual’s antigens.Affects the ability to live in harmony with our own cells and tissues.
Classification Immunologic tolerance Central Peripheraltolerance tolerance
Central ToleranceRefers to death (deletion) of self-reactive T- and B-lymphocyte clones during their maturation in the central lymphoid organs (the thymus for T cells and the bone marrow for B cells).Experiments with transgenic mice provide abundant evidence that T lymphocytes that bear receptors for self antigens undergo apoptosis within the thymus during the process of T-cell maturation
T-cells that bear receptors for self antigen undergo apoptosis within the thymus during the process of T-cell maturation. Many autologous protein antigen are processed and presented by thymic antigen- presenting cells in association with self MHC (major histocompatibility complex) proteins. Developing T-cells having high affinity receptors for such antigens are negatively selected, or deleted, and therefore the peripheral T-cell pooling is lacking or deficient in self reactive cells. The developing thymocytes express high levels of Fas causing negative selection.
Clonal deletion of T-cells also affects B- cells.When developing B-cells encounter a membrane-bound antigen within the bone marrow, they undergo apoptosis.No self antigen present in the thymus: T- cells and B-cells slip into the periphery.B-cells bearing receptors for thyroglobulin, collagen and DNA can be found in the periphery.
PERIPHERAL TOLERANCET-cells that escape intrathymic negative selection can cause tissue injury unless they are deleted or muzzled in the peripheral tissues.3 “back up” mechanisms that silence such potentially autoreactive T-cells are:- 1.Clonal deletion by activation-induced cell death 2.Clonal anergy 3.Peripheral suppression by T-cells
1. Clonal deletion by activation- induced cell deathMechanism to prevent uncontrolled T-cell activation during normal immune response involves apoptotic death of activated T- cells by Fas-Fas ligand system.Expression of Fas (CD95) is upregulated in antigen activated T-cells.Engagement of Fas by Fas L, coexpressed on activated T-cells, dampens the immune response by inducing apoptosis of activated T-cells.
The self antigens that are abundant in the peripheral tissues cause repeated and persistent stimulation of self-antigen-specific T-cells leading eventually to their elimination via Fas mediated apoptotis.
2.Clonal anergyRefers to a prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions.
Activation of T-cells requires 2 signals:- a.Recognition of peptide antigen in association with self MHC molecules on the surface of antigen-presenting cells and set of costimulatory signals provided by antigen-presenting cells. b.To initiate second signals, certain T-cells associated molecules, such as CD28, must bind to their ligand, a negative signal is delivered, and the cell becomes anergic.
Such a cell then fails to be activated even if the relevant antigen is presented by component antigen presenting cells that can deliver costimulation.Since costimulatory molecules are not expressed or are weekly expressed on most normal tissues, the encounter between auto reactive T-cells and their specific antigen leads to clonal anergy.Also affects B-cells.
B-cells encounter antigen in the absence of specific helper T-cells, the antigen-receptor complex is down regulated, and such cells never re-express their immunoglobin receptors.Such cells are unable to respond to subsequent antigenic stimulation.
3.Peripheral stimulation of T-cellsFocus is on suppressor T-cells with the ability to downregulate the function of other autoreactive T-cells.Molecular mechanisms by which suppressor T-cells recognize antigens and exert their suppressive effects are little understood.Some evidence is that peripheral suppression of autoreactivity may be mediated, in part, by the regulated secretion of cytokinesis.
Tolerance of self-reactive T-cells is extremely important for prevention of autoimmune disease.