The predominant stress pathways that were investigated were the hypothalamic-pituitary-adrenal (HPA) axis, the activation of which results in the release of cortisol or corticosterone (depending on the species), and the sympathetic nervous system, the activation of which results in the release of epinephrine and norepinephrine. Once it became possible to assess immune functions in a routine manner using techniques borrowed from clinical immunology, these influences were ascribed to modulation of immune responses by activation of the stress pathways. Not surprisingly, retrospectively, but at the time difficult for hardcore pathologists to admit, biobehavioral factors, in the form of exposure to well-defined stressors, were found to influence the initiation and progression of various infectious and noninfectious diseases in animal models of pathology. What was initially of interest to only a few practitioners in psychosomatic medicine-the influence of personality factors and emotional states on sensitivity to disease, or more generally the interrelationships among mind, body, and environment in health and disease-became an object of scientific investigation in the 1950s, when it was brought into the laboratory to be subjected to a reductionist approach ( 139). This is well reflected in the history of the research efforts in neural–immune interactions ( TABLE 1) ( 1). However, this situation is still relatively new, and the transition to it has been very progressive. Blurring of the boundaries between disciplines is probably the main outcome of this wave of research. This is the case, for instance, for purinergic signaling, which is investigated by immunologists for its role in macrophage function and plasticity ( 57) and by neurobiologists for its regulatory activity on synaptic plasticity ( 203). Communication signals and signaling pathways are commonly studied in different physiological systems using the same tools. What used to be a rarity a few decades ago, studying the expression and function of a given molecule within a different physiological system from the one in which it was first identified, has now become the norm. Our understanding of physiology has benefited greatly from the advances in molecular biology that have been at the origin of the explosive development of genetics and -omic techniques. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies. The necessary complementarity of these two modes of communication will then be discussed. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. This applies in particular to psychiatric disorders and several immune-mediated diseases. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction.
At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood.
Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. These associations are present at different levels of organization. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. This has particularly been the case for the immune system. Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other.
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