Optimal host defense against pathogens requires cross-talk between the nervous and immune systems. This paper reviews sympathetic-immune interaction, one major communication pathway, and its importance for health and disease. Sympathetic innervation of primary and secondary immune organs is described, as well as evidence for neurotransmission with cells of the immune system as targets. Most research thus far as focused on neural-immune modulation in secondary lymphoid organs, and have revealed complex sympathetic modulation resulting in both potentiation and inhibition of immune functions. SNS-immune interaction may enhance immune readiness during disease-or injury-induced 'fight' responses. Research also indicate that dysregulation of the SNS can significantly affect the progression of immune-mediated diseases. However, a better understanding of neural-immune interactions is needed to develop strategies for treatment of immune-mediated diseases that are designed to return homeostasis and restore normal functioning neural-immune networks.

The roles of hypothalamic norepinephrine (NE) and dopamine (DA) in the regulation of LH and PRL are controversial. In the present studies, we used HPLC and push-pull perfusion to measure NE and DA releases in the medial preoptic area (MPA) of conscious, freely moving rats. Serum LH and PRL were determined in separate groups of rats with indwelling venous cannulas. In young (4- to 5-month-old) rats, concomitant with proestrous surges of serum LH and PRL, NE release in the MPA increased gradually to reach a peak at 1800 h, whereas DA release decreased gradually to its lowest level at 2000 h. Compared to the young animals, in middle-aged (8- to 10-month-old) animals, the proestrous surge of PRL was unaltered, but the LH surge was delayed and attenuated. The pattern of DA release in the middle-aged animals was also unaltered, but the peak in NE release was markedly attenuated, although the average NE release was increased compared to that in the young proestrous animals. In young diestrous rats and old (22- to 24-month-old), persistently diestrous rats, in which serum LH and PRL are known to be stable, both NE and DA releases were devoid of fluctuations. However, in the young diestrous animals, the average NE and DA releases were significantly increased compared to those in the young proestrous animals, whereas in the old, persistently diestrous animals, NE and DA releases were markedly reduced compared to those in the young diestrous animals. These data lead us to conclude that NE, through its stimulatory action, may be the primary regulator of LH release, and that it is the pattern, rather than the level, of NE release that appears to be critical in determining the pattern of LH release. DA, through its inhibitory action, appears to control PRL only and probably has no association with LH release. By tracing NE and DA activities from adulthood through middle-age to senescence, these studies revealed that the marked reductions in catecholamines in old age are preceded by a transitory increase in NE activity in middle-age, and that the cyclic increase in NE activity associated with the LH surge begins to diminish in middle age and disappears completely in old age.

In the past century, physiological, molecular, and cellular-based studies have proved that the functions of the nervous system, endocrine system, and immune system are dependent upon each other and that this interaction among these systems determines the maintenance of health or susceptibility to infections. The release of neurotransmitters and neuropeptides from the brain is a response to external environmental stimuli that influences the release of hormones from the pituitary in order to regulate the functions such as metabolism and growth, reproduction, etc. In addition, there are direct sympathetic noradrenergic and peptidergic innervations of primary (bone marrow and thymus) and secondary (spleen, lymph nodes, and lymphoid tissues) lymphoid organs. The neurotransmitters and neuropeptides released in these lymphoid organs then bind to specific receptors on the cells of the immune system to modulate their functions. Another circuit in this bidirectional communication involves the products of the immune system, for e.g., cytokines that can cross the blood-brain barrier to alter the activities of the neuronal function in the central nervous system especially during fever and inflammation in infectious diseases and cancer. Dysregulation of the interactions between the neuroendocrine and immune system due to alterations in the neural activity, secretion of hormones and cytokines, and synthesis of growth factors has been demonstrated to promote the pathogenesis and progression of infectious and autoimmune diseases, cancer, and neurodegenerative diseases. It is imperative that further research is carried out to understand the mechanisms of neuroendocrine-immune interactions to facilitate development of better treatment strategies for neurodegenerative diseases.

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Normal aging processes, as well as, psychological stress affect the immune system; each can act alone, or interact with each other, to cause dysregulation of immune function substantially altering physical and mental health. The sympathetic nervous system (SNS), a major mediator of stress effects on immune function, is significantly affected by normal aging process, and stress can affect aging of the SNS. Previously, we have shown age-associated changes in sympathetic noradrenergic (NA) innervation of lymphoid organs in male rodents that affect immune regulation. The purpose of this study was to investigate sympathetic innervation of lymphoid organs and associated alterations in immune responses in young and aging female Fischer 344 (F344) rats. Histofluorescence and immunocytochemistry for NA innervation, and neurochemistry for norepinephrine (NE) levels were performed in the thymus, spleen, and mesenteric lymph nodes (MLN) isolated from 3-month-old young (normal estrous cycle), 8-to 9-month-old (onset of irregular estrous cycling), and 24-25 month, and 30-31 month female F344 rats (acyclic) at diestrus based on vaginal smears. Age-related alterations in natural killer (NK) cell activity, interleukin-2 (IL-2) and interferon-γ (IFN-γ) production, T and B lymphocyte proliferation were examined in splenocytes. Sympathetic NA innervation and NE levels increased with aging in the thymus, declined in spleen and MLN, and was accompanied by significant reductions in NK cell activity, IL-2 and IFN-γ production, and T and B cell proliferation in old female rats. In 8-9 mo rats, NE levels in the hilar region of the spleen and IFN-γ production were unaltered, while NE levels in the end region of the spleen and IL-2 production were reduced. Collectively, these results suggest that aging is characterized by significant alterations in sympathetic NA innervation in the thymus, spleen, and MLN associated with immunosuppression, and that there is a marked shift in NA activity and immune reactivity occurring during middle-aged female rats.

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