ABSTRACT
I. INTRODUCTION In distant species and invertebrates, the foundations of the neuroendocrine system and innate immunity have coexisted until nowwithout any apparent problem. Some 300million years ago, a relatively short time period after jawless fishes (agnathans), adaptive immunity emerged in the first cartilaginous fishes. Somatic recombination machinery characterizes adaptive immunity and is responsible for the random generation of the huge diversity of immune receptors able to recognize nonself antigens. The emergence of this novel form of immune defense exerted so potent an evolutive pressure that structures and mechanisms developed along the paths of lymphocyte traffic to impose immunological self-tolerance, that is, the inability of the immune system to attack the host organism. Together with the generation of diversity and memory, self-tolerance constitutes a fundamental property of the immune system. The progressive rise in the level of immune diversity and complexity also explains why self-tolerance failures (i.e., autoimmune diseases) were increasingly detected during evolution, the maximum being currently observed in the human species´. The first thymus appeared in cartilaginous fishes, concomitantly with the emergence of rudimental forms of adaptive immunity [1]. Though some forms of tolerance induction take place in primary hematopoietic sites (fetal liver and bone marrow), antigen-dependent B-cell tolerance is predominantly due to an absence of T-cell help [2]. Among all lymphoid
structures, the thymus is the only organ specialized in the establishment of central selftolerance. As this chapter will illustrate, the thymus is a crucial meeting place between the neuroendocrine and immune systems. In this organ responsible for thymopoiesisT-cell generation-the neuroendocrine system regulates the process of T-cell differentiation from the very early stages. In addition, and more specifically, T lymphocytes inside the thymus undergo a complex process that establishes central T-cell self-tolerance of neuroendocrine principles. The thymus is a unique organ wherein occurs a permanent confrontation between ancient neuroendocrine principles and a recent system equipped with recombination machinery promoting the stochastic generation of immune diversity. Contrary to a previous, rather dogmatic view, the thymus functions throughout life and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy [3].
