Central tolerance Totally Explained

Everything about Central Tolerance totally explained

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery, while peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self-reactive T cells in the thymus during T cell differentiation, but they exert their immune suppression in the periphery on other self-reactive T cells.

Requirement for central tolerance

Central tolerance is required due to the random nature of somatic recombination of germ-line DNA for the primary antigen receptors of T cells (the T cell receptor) and B cells (the B cell receptor, also known as antibody). The T cell receptor and B cell receptor genes contain multiple gene fragments which need to be physically recombined together to make a functional gene, with billions of alternative possibilities for the order of rearrangement and the deliberate introduction of mutation during the rearrangement. This random Generation of Diversity allows the creation of T cell receptors and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defence against rapidly evolving pathogens. Conversely, the random nature of the Generation of Diversity creates, by chance, a population of T cells and B cells that are self-reactive (ie, recognise an antigen which is a constituent component of the host).
In mammals the process occurs in the thymus (T cells) and bone marrow (B cells). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells the cells are sensitive to antigen-recognition. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to stimulation with antigen by undergoing a rewiring of the cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), altering its antigen receptor (receptor editing) or entering a regulatory lineage.
As this tolerance is dependent on encountering the self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells in the bone marrow, this is limited to ubiquitous and bone-marrow specific antigens present in the bone-marrow and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through the action of the transcription factor AIRE, which allows the expression of organ-specific antigens such as insulin in the thymus.

Mechanisms of central tolerance

After exposure to self antigens, T cells and B cells become immunologically tolerant (non-reactive) in a number of ways :

Negative selection - the active induction of cell-dependent suicide (apoptosis)
Anergy - the induction of a non-responsive state, whereby the cell won't become activated if it encounters antigen in the peripery
Receptor editing - recombination of the antigen receptor to change the specificity of the autoreactive cell into a more benign state
Division to a regulatory lineage - such as the expression of Foxp3 in Regulatory T cells. Regulatory T cells that encounter their antigen in the periphery become activated, but after activation they silence the immune response to prevent autoimmunity.

Genetic diseases caused by defects in central tolerance

Genetic defects in central tolerance can lead to autoimmunity.

Autoimmune Polyendocrinopathy Syndrome Type I is caused by mutations in the human gene AIRE. This leads to a lack of expression of peripheral antigens in the thymus, and hence a lack of negative selection towards key peripheral proteins such as insulin. Multiple autoimmune symptoms result.

immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is caused by mutations in the human gene Foxp3. In the absence of Foxp3, autoreactive T cells are unable to become regulatory T cells, and therefore instead of inhibiting disease in the periphery they aid disease progression. As Foxp3 is on the X-chromosome and the disease is fatal early on in life, only males can develop IPEX.Further Information

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