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central tolerance
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.〔(Lecture 12. Tolerance )〕 The concept of central tolerance was proposed in 1959 by Joshua Lederberg, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane Burnet. Lederberg hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. Lederberg's theory that self-tolerance is 'learned' during lymphocyte development was a major conceptual contribution to immunology, and it was experimentally substantiated in the late 1980s when tools to analyze lymphocyte development became available. Central tolerance is distinct from peripheral tolerance in that it occurs while developing immune cells are still present in the primary lymphoid organs (the thymus and bone-marrow), prior to export into the periphery. Such peripheral tolerance is generated after the cells reach the periphery by regulatory T cells. Such regulatory T cells can be considered both central tolerance ''and'' peripheral tolerance mechanisms, as they can be generated from self(or foreign)-reactive T cells in the thymus (during T cell differentiation), but can also exert immune suppression in the periphery on other self(or foreign)-reactive T cells.
==Requirement for central tolerance==
At first, all T and B cell precursors have an identical genome, but then receptor variety is generated by a combination of 3 mechanisms. The first mechanism is the combination of the alpha- and beta-chain for the T cell receptor (TCR), or of the heavy and light chain for the B cell receptor (BCR), each encoded by 2 different gene copies - the unused copy gets inactivated. T cell and B cell receptor genes contain multiple gene segments (the V, D, and J segments) which need to be physically rearranged by somatic gene rearrangement - called V(D)J-recombination - to make a functional gene. At the site of segment recombination, additional bases will be inserted, which results in additional diversity - called junctional diversity - and gives rise to the complementarity determining regions (CDR). These random combinations and base insertions allow 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 defense against rapidly evolving pathogens. Conversely, the random nature of junctional diversity creates, by chance, a population of T cells and B cells that are self-reactive (i.e., recognize an antigen which is a constituent component of the host).
In mammals, central tolerance is established 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 self-antigens. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to antigen stimulation by undergoing a rewiring of 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 self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells, this is limited to ubiquitous and bone-marrow specific antigens 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.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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