L01 - Clark T. Sawin Memorial History of Endocrinology Lecture - History of the Thymus: From a Vestigial Organ to the Unique Orchestrator of Central Immunological Self-Tolerance to Neuroendocrine Principles

This lecture will present the most important disruptions of concepts concerning the thymus since its discovery by Galenus (119-210 AC) in Antique Greece. At the beginning of the 20th century, this organ was still a complete enigma but the Swedish endocrinologist JA Hammar showed in 1921 important variations of thymic size in different endocrine diseases. Consequently, the thymus was considered as another component of the endocrine system. In 1946, the Hungarian investigator Hans Selye showed that stress, stimulating the hypothalalamic-pituitary-adrenal (HPA) axis, simultaneously caused thymic involution and adrenal hypertrophy.

In 1961, the Australian scientist JFAP Miller discovered that the thymus is the organ responsible for the development of immunocompetent cells, the thymus-dependent (T) lymphocytes. Miller then advanced the hypothesis of thymic hormone(s) that would be responsible for driving T-cell differentiation. However, it will be never possible to establish the reality of such thymus-specific growth factor(s) and to apply the endocrine model to the communication between epithelial cells and thymocytes (pre-T cells) in the thymus.

In the continuation of his revolutionary theory of clonal selection, the great Australian virologist and immunologist Frank Macfarlane Burnet coined the term ‘self-tolerance’ to characterize one of the cardinal properties of the adaptive immune system together with diversity, specificity and memory. He also prophesied that self-reactive T-cell clones are eliminated during T-cell differentiation in the thymus and that a failure in this process would be responsible for the initiation of autoimmune diseases. Such negative selection of 'forbidden clones' was independently demonstrated by different groups in 1988-1989, so that the thymus was definitively proved to play an essential and unique role in programming central immunological self-tolerance.

The basic mechanism implicated in this function is the transcription in the thymic epithelium of genes encoding neuroendocrine-related and tissue-restricted self-antigens that are presented to developing T-cells. Already during fetal life, this presentation promotes negative selection of self-reactive T cells. Mainly after birth, this presentation also drives the intrathymic generation of self-specific regulatory T cells. Confirming Burnet's prediction, numerous studies, including the identification of Aire and Fezf2 genes, have demonstrated that a thymus defect indeed plays a crucial role in the development of autoimmune disorders.

Endocrine autoimmunity is observed in type 1 diabetes (T1D), most of thyroid disorders, Addison’s disease, hypoparathyroidism, premature ovarian failure, some cases of hypophysitis and hypothalamitis (with ‘idiopathic’ diabetes insipidus). While most autoimmune endocrine diseases are quite effectively managed by non-expensive pharmaceutical treatment, T1D is a chronic devastating disease associated with severe complications affecting the cardiovascular system, kidney, retina, and peripheral nervous system. Blood glucose monitoring, insulin therapy and clinical care of diabetic complications constitute very heavy charges in terms of public health expenses.

The discovery of the central tolerogenic action of the thymus constitutes a scientific revolution according to the criteria formulated by the American philosopher Thomas Kuhn. This novel knowledge should pave the way for innovative tolerogenic therapies against autoimmunity, the heavy tribute paid by mankind mainly for the extreme diversity and efficiency of adaptive immunity.