Neurohormonal immunoregulation

The immune system may be divided into primary lymphoid organs (bone marrow, bursa of Fabricius, and thymus), which produce mature leukocytes and secondary organs (spleen, lymph nodes, tonsils, Peyer's patches, etc.), which are concerned with specific immune responses. In the primary organs, stem cells proliferate and differentiate into various subsets of polymorphonuclear and mononuclear cells. Evidence is increasing that cell proliferation in the primary lymphoid organs is dependent on pituitary growth hormone (GH) and prolactin (PRL), which control the expression of growth regulatory genes (protooncogenes) such as c-myc and also induce essential growth factors (insulinlike growth factor, thymic and bursal hormones, etc.) and, possibly, their receptors. The adrenocorticotropic hormone-adrenal axis serves as an inhibitory pathway, antagonizing the action of PRL and GH on primary lymphoid tissue. The effect of glucocorticoids is especially forceful on thymocytes through the activation of the genetically programmed suicide pathway. Sex hormones also regulate the primary lymphoid organs, but their mechanism of action remains to be clarified. Thymus-derived feedback signals toward the pituitary gland have already been described. The pituitary gland exerts a similar regulatory influence on mature lymphocytes during their antigen-driven differentiation. PRL or GH is required for primary immune reactions; however, the secondary immune response may be less dependent on these hormones. Once the immune system is primed, antigen itself becomes a primary regulator. Exposure of memory cells to antigen leads to the production of growth factors (interleukins) and to the expression of their receptors. Therefore, antigen appears to fulfill, at this stage, a role that is originally played by GH or PRL in the primary lymphoid organs and, to some extent, also during antigen-driven differentiation. During immune reactions, interleukin-1 and tumor necrosis factor activate the adrenocorticotropic hormoneadrenal axis, which plays an important role in setting upper limits to and terminating responses. Lymphocytes have receptors for and react to numerous hormones, neurotransmitters, and mediators derived from a number of organs and tissues. Therefore, ultimately the reaction of a lymphocyte will be the vector of all positive and negative signals received. A hierarchy and sequential system of signals exists. Primary regulatory signals (competence signals) represent the most powerful regulators (e.g., PRL, GH or antigen) of lymphoid cells. The delivery of a competence signal is the prerequisite for subsequent lymphoproliferation, which is regulated by growth factors that are specific for a certain developmental stage of the lymphoid cell and act sequentially. Hormonal factors that promote growth and differentiation deliver the second regulatory signals. Competence factors and growth and differentiation hormones regulate gene expression in lymphocytes. The third class of signals modulate the function of mature effector cells (e.g., locomotion, secretion, phagocytosis, cytotoxicity). Neuro-transmitters appear to function as secondary signal modulators and tertiary functional regulators.