As early as the 1970s, a bidirectional relationship between the neuroendocrine system or the brain and the immune system was being investigated. If immune function is controlled by the brain, then interrupting (lesioning; i.e., cutting or damaging) neuronal pathways should disrupt normal immune function. Experiments have proved this. For example, lesioning the preoptic anterior hypothalamus (the structure that controls body temperature, eating, sleeping, and other vegetative functions) reduces the number of leukocytes in the spleen and thymus, reduces natural killer-cell function, and suppresses antibody production. Lesions to the limbic system (which is involved in emotion and motivation) have the opposite effect on the spleen and thymus. Interestingly, lesions to the cerebral cortex exhibit lateralized influences: lesions on one side of the cortex increase T-cell number and function in the spleen and thymus, and lesions on the other side have the opposite effect.

Electron microscopy studies have confirmed that the secondary lymphoid tissues (thymus, spleen, and lymph nodes) are innervated by the autonomic nervous system. In addition, all the elements necessary for synaptic signal transmission have been identified at the interface between nerve terminals and leukocytes in these tissues. Several neurotransmitters have been identified in the neurons innervating lymphoid tissue. Corresponding receptors for these neurotransmitters have been found on leukocytes, and leukocyte function is altered in vitro in response to these substances. As with any synapse, a mechanism needs to be in place to break down the neurotransmitters and thus terminate the individual signal; leukocytes possess appropriate enzymes to
accomplish this. In addition, neurons have cytokine receptors (chemicals released by leukocytes) that make them susceptible to feedback control by leukocytes. And finally, leukocytes themselves make neuropeptides that can presynaptically influence neuronal function and signaling, further emphasizing the feedback loop. Examples of neurotransmitters that bind to immune tissue and their effects are included in Table 7-1.

Another critical linkage between the neuroendocrine and the immune systems involves cytokines, the chemical mediators of inflammation described in Chapter 4. Cytokines may also function as neurotransmitters. They have the capability of stimulating sensory neurons in the viscera or crossing the blood-brain barrier to impact brain and nervous system function. Neuroendocrine
signals can influence cytokine synthesis; conversely, cytokines can alter neuronal function and endocrine secretion. Since cytokines control the proliferative, cytotoxic, and synthetic activities of all the different leukocyte populations, neuroendocrine modification of cytokine synthesis or cytokine receptor expression can influence immune function more profoundly than can direct neuroendocrine action on individual leukocytes. Cytokines, in turn, modify neuroendocrine function (such as the hypothalamic-pituitary-adrenal axis) during times of infection or stress.