Today it is recognized that the regulatory systems namely nervous, endocrine and immune systems, do not function independently but are
intimately linked, constituting a psychoneuroimmunoendocrine system. The communication between these physiological systems, is the basis
of the maintenance of homeostasis and therefore of health.
Each of these homeostatic systems is complex and more so, the interactions between them. Currently, there is abundant work that confirms
this bidirectional communication, which depends on the following facts: A) The cells of each of the three systems can express receptors for
the mediators of the others, namely cytokines, hormones and neurotransmitters; B) Immune, nervous and endocrine products coexist in lymphoid,
endocrine and neural tissue; C) Endocrine and neural mediators can affect the immune system; and D) Immune mediators can affect
endocrine and neural functions. These bidirectional communications may happen in long or short loops. With respect to the long loops, the
effect of mediators of nervous and endocrine systems on the immune cells was possibly the easiest aspect to understand, since both primary
and secondary immune organs, are innervated and irrigated. It was more difficult to accept that immune mediators, such as cytokines, can
arrive to the brain. In fact, mediators produced by peripheral immune cells reach the Central Nervous System (CNS), and the leukocytes even
being able, in specific situations, to pass through the blood-brain barrier. Nevertheless, the CNS can show an immune response using its resident
cells such as glial cells, ependymal cells or neurons. At the level of short-loop interactions, the capacity of production of typical neurotransmitters
and hormones by immune cells, as well as of cytokines by nervous and endocrine cells, was also difficult to accept, not only at
peripheral level, but also in the brain.
Currently, the improved knowledge of this communication between homeostatic systems constitutes the scientific basis, which allows us to
understand many facts of everyday life. Thus, it is well known that situations of emotional stress or anxiety are accompanied by a greater
vulnerability to conditions ranging from infectious processes to cancer or autoimmune diseases, agreeing with the concept that the immune
system is impaired. By contrast, pleasant emotions and a “positive outlook” on life help us to overcome immune system-related diseases and
enjoy better overall health. Conversely, it has been shown that immune system changes, such as those found in infectious processes, alter the
functions of the nervous system, which could lead, if those changes are not well controlled, to psychotic disorders and neural diseases. Thus,
we must take into consideration that health is the result of the appropriate functioning of homeostatic systems as well as the perfect balance of
mediators produced by them. When one of these mediators is overproduced or released in lower amounts than those necessary, the pathology
appears. Any process is good or bad for health depending on the context, the amount of mediators, the period of time in which it is developing,
etc. For example, inflammation is essential for survival since it serves to eliminate dangerous intrinsic and extrinsic factors and mediates
tissue repair. However, this process requires a tight control exerted by anti-inflammatory cytokines. When the inflammation is uncontrolled
many pathologies occur.
In the current issue 15 different aspects of this psychoneuroimmunoendocrine communication will be presented by experts in the field, bringing
together the most recent and novel studies available. Moreover, on reading several reviews in this issue some new physiological, pathological
and therapeutic ideas will be discussed opening our mind to new ways of understanding health and sickness.
It is possible that the response to stress situations, which are an integral part of daily life, is one of the best examples to understand the communication
between the homeostatic systems. The stress response is essential for survival and when this is not adequate, due to bad crosstalk
between the three regulatory systems, health can be compromised leading to the development of a pathology. In the article of Cruces et al.
 the effects of stress, and especially psychological stress, on the nervous, endocrine and immune systems are covered. Moreover, social
isolation, an important cause of psychological stress, provokes a deterioration of the psychoneuroimmunoendocrine system and thus may
increase morbidity and mortality. In fact, this increase has been commonly observed in individuals following the death of their partner. Nevertheless,
these deleterious effects depend on the individual’s reaction, for example whether the subject shows anxiety or not, in this stress
situation. Maternal deprivation, a model of isolation in the early stages of life, is another example of the effects of stress disrupting the communication
between the homeostatic systems.
As another concrete example of how a psychological stress situation affects the neuroimmunoendocrine communication the study of Palermo-
Neto and Alves  deals with the effects produced by cohabitation with a sick partner. Since this subject has not been sufficiently studied in
caregivers of sick persons, and the results obtained in rodent models appear to be similar to those in humans, the authors propose a rodent
model, which permits a deeper study of the mechanisms involved in the response to this psychological stress.
A very interesting subject, which is not frequently considered in physiological studies, is the circadian system, which could be a relevant part
of the homeostatic complex that represents the neuroimmunoendocrine system. In fact, this system shows circadian as well as circannual or
seasonal variations in most of its variables. The aging process is another biological rhythm. With aging, an impairment of the homeostatic
systems occurs and an alteration in the control of circadian and circannual rhythms has been demonstrated. This regulation of the homeostatic
systems, especially that of the immune system, by biological rhythms as well as its age-related dysregulation, which compromise the quality
of life of individuals, is covered by Maté et al. . In this review it is shown how several immune function parameters, which are good markers
of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Thus, the immune
functions during the early afternoon show values more similar to those of older subjects than during the morning. In addition, in winter, especially
in the case of mature men and women, the immune cell function show the most significant impairment. The role of immunomodulatory
hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process is noteworthy. Furthermore,
the evidence of regulation of the circadian system by the immune system and its disturbance with aging, is also mentioned, highlighting the
importance of proinflammatory cytokines in this complex cross-talk. In addition to age, in some diseases the biological rhythms can be impaired.
This and the use of chronotherapy are other relevant aspects encompassed in this review.
To understand the mechanisms underlying the impairment of homeostatic systems it is necessary to know how oxidative stress and inflammatory
stress are involved. In the review by Vida et al.  this subject is covered, highlighting the oxidative-inflammatory stress in the regulatory
systems, which occurs with aging and anxiety, two very related situations. In fact, in a model of premature aging in mice, in which animals
show a poor response to stress and high levels of anxiety, an oxidative stress in their immune cells and tissues occurs, as well as a premature
immunosenescence and a shorter life expectancy. This model supports the hypothesis that anxiety can be a situation of chronic oxidative
stress and inflammation, especially in brain and immune cells, and this accelerates the rate of aging.
Nitric oxide (NO) is a significant molecule involved in oxidative stress. NO can be transformed into highly reactive and harmful molecules
producing an impairment of the bio-molecules (DNA, lipids or proteins), altering their function. Thus, NO shows an important role in many
pathological processes, but also in many physiological functions, including those of a mediator of blood vessel dilation, neurotransmitter,
neuromodulator and inductor of mitochondrial biogenesis. The dual action of NO and its role in homeostasis, especially in the nervous and
immune systems, is reviewed by Rocha et al. .
As mentioned above, an aspect of neuroimmunoendocrine communication, is the production by immune organs of molecules with hormonal
functions. In the review by Reggiani et al. , the physiological and therapeutic roles of thymulin, a thymic hormone, are covered. Moreover,
studies that show how the production and secretion of thymulin is strongly influenced by the neuroendocrine system are mentioned.
These represent examples of how mediators of the nervous and endocrine systems can affect immune organs.
The endocannabinoid system constitutes a relevant example of molecules produced by both brain and immune cells. This system has as its
main function the maintenance of body homeostasis. The role of this in the hypothalamic-pituitary axes in their responses to inflammation
and infection has been extensively reviewed by De Laurentiis et al. . These authors also covered the potential pharmacological therapies
based on the manipulation of the components of this endocannabinoid system, which could provide novel treatments for many disorders.
More information on the cannabinoid system as well as its role in inflammation as a neuro-protective system, is shown in the review by Hernangómez
et al., . These authors demonstrate the importance of innate immunity response within the CNS and the role that this response
plays, when it is uncontrolled (with macrophages and microglia as important participants), in the development and expansion of autoimmune
and neurodegenerative diseases. Primary examples of these are multiple sclerosis (MS) and Alzheimer's disease (AD). In the regulatory
mechanisms involved in the control of this CNS innate immunity, the neuroimmune regulatory proteins (NIReg) are relevant. Concretely, in
this review the role of CD200 and its receptor CD200R, in silencing and reshaping an adverse innate immune response, is emphasized. Thus,
CD200-CD200R as an anti-inflammatory and neuroprotective pair in MS, is highlighted. In addition, the role of CD200-CD200R in aging
brain and in Alzheimer´s disease (AD) is reviewed. Moreover, the possibility that endocannabinoids can be used as therapeutic targets for
promoting CD200-CD200R interaction is proposed for the above mentioned diseases.
Alzheimer´s disease (AD) is widely considered in the review by Gimenez-Llort et al. . This disease can be better understood in the context
of the aging of the neuroimmunoendocrine system. These authors show evidence of the relevance of the disruption of the cross-talk between
the cells of the homeostatic systems and their mediators from the prodromal stages of AD, when cognitive function still seems apparently
normal. This disruption contributes to the onset of disease, and to know this, may help us to understand its biological mechanisms and to find
behavioral and immunological biomarkers for the prodromic phases. Moreover, the use of lifestyle strategies such as physical exercise, environmental
enrichment and nutrition to improve the nervous and immune functions in animal models for this disease is highlighted in the review.
As previously stated, all the homeostatic system mediators have to be present in the appropriate amount and their production and release must
take place with a perfectly controlled spatial and temporal pattern. As an example of this Besedovsky and Del Rey  show what happens
with IL-1, the pro-inflammatory cytokine most studied in the context of nervous-immune communication. Among the different physiological
effects of this cytokine, its role in re-setting glucose homeostasis, in the peripheral and brain levels, is emphasized in this review. The authors
mention the capacity of IL-1 to deviate glucose to immune cells during inflammatory and infectious diseases as one of the bases of metabolic
control produced by the immune system. Several mechanisms are involved in the deviation of the physiological functions of IL-1 to pathology.
Thus, depending on the amount of this cytokine, physiological or diabetogenic effects are produced.
The role of bacterial infections and the possible aberrant activation of the inflammatory response and the consequent disease are covered in
the following reviews. Burdet et al.  review the case of pregnant women, and how maternal infections and inflammation can produce
premature labor. How bacteria invade the uterine capacity, which is normally a sterile environment, is a very interesting subject. This, and the
reasons why different species of bacteria vary in their capacity to induce inflammation and preterm birth, are covered in this review as well as
possible therapeutic interventions.
The review by Rettori et al.  shows periodontitis as another chronic inflammatory complex problem caused by microorganisms. This
disease, characterized by the progressive destruction of the tooth and its support leading to tooth loss, has a possible impact on general health,
and the balance of the host neuro-immuno-endocrine responses is altered. The possible link between periodontitis and diabetes, cardiovascular
diseases, strokes and metabolic syndromes, all sharing a common denominator that is inflammation and oxidative stress, is covered. In
addition, the negative effects of stress on this disease, the effects of oxytocin in modulating the individual response to stress, and the participation
of components and functions of the endocannabinoid system with anti-inflammatory actions on gingiva, are also mentioned.
As another concrete example of the involvement of the reciprocal interactions between the neuroendocrine and immune systems in a pathological
situation, Hauk et al.  review an inflammatory disorder, the Sjögren syndrome (SS), in which a progressive loss of salivary and
lacrimal gland secretions occurs. The effects of the neurotransmitter vaso intestinal peptide (VIP) and its receptor (VPAC) using a model of
SS, non obese diabetic (NOD) mice, showing the physiopathological mechanisms of this disease, are mentioned in this review.
The microbiota present in the gut and the gut-brain-immune system axis are extensively dealt with by Martín-Villa . In this context, the
author explains the etiology of two major inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. Recent data suggest
that these diseases are an exaggerated mucosal immune response to microbiota present in the gut, in which T lymphocytes play a crucial role
in the pathogenic events leading to tissue damage. These diseases are the result of psychological trauma, stress or depression, acting on genetically
predisposed individuals. Thus, these diseases are an example of how emotional stress could increase epithelial permeability, modify
the gut microbiota composition and activate pre-sensitized T lymphocytes, showing the link between emotions, microbiota and immune functions.
Following the relevant role of micro-organisms, especially those in gut, the last review of this issue by Montiel-Castro et al.  deals with a
very novel and interesting subject such as the effect of the microbiota-gut-brain axis on social interactions. The first part of the article describes
concepts of behavior and nervous system function. This is followed by how different neurological processes are the base of socialdecision
making and how the regulation of different aspects of animal behavior is carried out. Finally, the authors suggest the involvement of
microbiota in the social interactions of each individual. The idea that microbiota are our closet partners interacting with gut immune and
nervous systems, and these with the central nervous system, and how these microbiota can modify our behavior is a new field in psychoneuroimmunoendocrinology.
The collection of articles in this issue of CPD allows the reader to bring their knowledge of psychoneuroimmunoendocrinology up to date.
This is a novel field of research not frequently found in scientific publications. Moreover, it should be stated that any pharmaceutical intervention
designed to improve health will affect the three regulatory systems and their communication. Thus, the contributions to this issue
highlighting original aspects of this field could lead to a better understanding of our prospects of health.