Central Self - Tolerance by Thymic Presentation of Self - Antigens and Autoimmunity

Abstract

Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves inactivating mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T cells. During ontogeny, T cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes at the molecular level the dual role of the thymus in T cell negative and positive selection. Thymic precursors not only constitute a source of growth peptides for cryptocrine signaling between thymic stromal cells and pre-T cells, but are also processed in a way that leads to the presentation of self-antigens by thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases.

Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology

“…The integration of the thymus in endocrine physiology did not completely vanish, however, and the primary lymphoid organ is crucially located at the crossroad between the major systems of cell-to-cell communication, the neuroendocrine and immune systems. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation (reviewed in Geenen et al 1999Geenen et al , 2003. Glucocorticoids also are synthesised in thymic epithelium and are able to impact on thymocyte development (reviewed in Ashwell et al 2000).…”

“…Neuroendocrine selfantigens derive from the processing of precursors dominantly expressed in the thymus and usually correspond to peptide sequences highly conserved during evolution. According to the theory of clonal selection, thymic MHC presentation of neuroendocrine self-antigens would be responsible for the establishment of central immune selftolerance of neuroendocrine principles (Martens et al 1996b, Geenen et al 1999, 2003.…”