It has long been known that motor activity can have a significant impact on a person's overall mental and physical well-being (Glenister, 1996; Fox, 1999; Paluska, Schwenk, 2000; Salmon, 2001). Of particular interest recently has been how a person's mental state can, in turn, influence a wide range of physiological indicators that determine the ability to maintain homeostasis and overall body health. Despite the fact that the positive effect of motor activity on the physiological state of the organism has long been known, the influence of physical activity on the physiology of the organism in terms of its psychological state remains virtually unexplored. Exact mechanisms underlying this influence are not known, but it is commonly assumed that the psychological state of a person influences the functioning of the nervous and endocrine systems to a considerable degree. The fact that motor activity can influence components of the nervous and endocrine systems suggests that, at least in part, these effects can take place at the psychological level. In recent years, sufficient evidence has accumulated to support the existence of a functional relationship not only between the nervous and endocrine systems, but also between the nervous, endocrine, and immune systems (Conti et al., 2000; Ader et al., 2001).

The considerable body of evidence suggesting that the nervous and endocrine systems are capable of independently influencing a variety of immune system functions is a good enough reason to suggest that there is a close relationship between motor activity and immunity. As we will see below, there is indeed a relationship mediated by the neuroendocrine system between motor activity and immune system function. This relationship may play an important role in the emergence and development of diseases that are not amenable to the immune system (e.g., infectious diseases and cancer) or are caused by unwanted activation of the immune system (e.g., allergies, autoimmune diseases).

It should be noted that in writing this chapter we did not aim to create an exhaustive review of all the literature relevant to the study of the motor activity-immune system relationship. Such information on this line of research can be found in several recent reviews (Hoffman-Goetz, 1996; Nieman, Pedersen, 2000; Pedersen, Hoffman-Goetz, 2000; Shephard, Shek, 2000a; Hoffman-Goetz, Pedersen, 2001). This chapter is specifically designed to introduce the reader to the mechanisms of neuroendocrine regulation that underlie the relationship between motor activity and certain aspects of immune system function. In addition, we will review areas of research where understanding the relationship between exercise and immune system function will enhance our knowledge through recent advances in the study of immune system function and the use of modern experimental approaches that allow for the quantification of these functions. Finally, let us analyze the possible effects of motor activity on diseases whose prevention and causes are related to disturbances in one or more aspects of immune system function.

Neuroendocrine-immune interaction

The neuroendocrine system

Before starting a discussion of the diverse functional relationships between the neuroendocrine and immune systems and their influence on the immunocompetence of the human body, it is necessary to briefly review some basic principles of interaction between the nervous and endocrine systems and its possible modulation under the influence of motor activity. At the same time, it should be noted that a comprehensive consideration of the nervous and endocrine systems, as well as the physiology of motor activity, is beyond the scope of this chapter, and these issues are discussed in more detail in other works (Robergs, Kctcyian, 2003).

INTERACTION OF THE NERVOUS AND ENDOCRINE SYSTEMS

Since a certain point, it has become apparent that the nervous and endocrine systems function in the body as a unified whole. The functional relationship between these two systems and their role in the regulation of the various processes occurring in the human body is the main subject of study in neuroendocrinology. This relationship is two-way: the endocrine system influences the nervous system, and the nervous system influences the endocrine system. The main mediators of endocrine system influence on the nervous system are hormones, while the signal transmission from the nervous system to the endocrine system takes place at the point of their direct contact, at the neuroendocrine cell level.

Due to the fact that hormones are transported in the blood, they can influence virtually all tissues in our body. The functional interactions between hormones and their target tissues depend largely on the specific binding of hormones to receptors on the cells that are competent for their action. Depending on the chemical nature of the hormone, such receptors can be located on the cell membrane, in the cytoplasm, or in the nucleus. There are different mechanisms of hormonal action - it can be changes in membrane transport, stimulation of gene transcription, activation of intracellular secondary messengers, such as cyclic adenosine monophosphate (cAMP).

There are a variety of mechanisms for the reflation of hormone release. Endogenous circadian or diurnal rhythms provide a cyclic periodicity of secretion independent of the nature of physiological processes. These endogenous rhythms are superimposed on the effect of extremely complex circuits of positive and negative feedback, the functioning of which contributes to the maintenance of endocrine-related homeostasis.

ACTION AND SIGNIFICANCE OF NEUROENDOCRINE INTERACTION

Neuroendocrine interactions are important because they allow our body to maintain a state of homeostasis. For example, neuroendocrine interactions play a crucial role in preventing moisture loss and maintaining osmotic pressure, blood volume and pressure, maintaining growth and development, metabolism, electrolyte balance, ovulation and childbirth, and behavioral responses. Disruption of hormone formation and secretion, as well as hormonal regulation, can lead to a variety of pathological conditions, including non-sugar diabetes, osteoporosis, and acromegaly.

The neuroendocrine system also provides adaptive physiological responses that allow the body to respond and adapt to changes in the environment. The ability to adapt to such changes is central to maintaining a number of physiological indicators within normal limits, which provides an opportunity for the body to survive. Thus, the activation of the hypothalamic-pituitary-adrenal system is one of the first components of the physiological response to external stress influences. Although different types of stress can be distinguished, namely psychological, physical, or their combination, in any case the body's response will include activation of the hypothalamic-pituitary-adrenal system (Chrousos, Gold, 1992; Dhabhar, McEwen, 2001).

Well-coordinated interaction between the cells and tissues that form the hypothalamic-pituitary-adrenal system is of particular importance for the maintenance of homeostasis under stress. Signals from the limbic system of the brain initiate corticoliberin (corticotropin-releasing hormone) secretion by cells in the paraventricular nucleus of the hypothalamus, which in turn induces adrenocorticotropic hormone (ACTH) release in the adenohypophysis. ACTH enters the bloodstream, where it interacts with the adrenal cortex cells, stimulating cortisol formation in humans (corticosterone in rats and mice). It is important to understand, however, that the ability of each of these compounds to have a regulatory effect on the organs that secrete them is the basis for clear control of their synthesis.

NEUROENDOCRINE ADAPTATIONS TO PHYSICAL ACTIVITY

The body's ability to tolerate physical activity is regulated by a complex interaction between the autonomic nervous and endocrine systems. During motor activity, the body responds to nervous system stimulation as well as to specific chemical and mechanical influences that, through a complex of hormones, contribute to the regulation of a number of physiological functions. These functions include the processes of energy metabolism, mobilization of energy substrates, maintenance of water balance, hemodynamic parameters of blood vessels, and protein synthesis. The nature of each organism's response to motor activity is different and depends on the intensity of exercise and the gender of the individual.

Exercise-induced hormonal regulation of physiological processes involves a number of hormones, including cortisol, somatotropic hormone, vasopressin (antidiuretic hormone), repin, aldosterone, thyroxin, insulin, glucagon, and the catecholamines adrenaline and noradrenaline. Adrenaline and noradrenaline, which are secreted by the adrenal glands, control changes in metabolism in muscle tissue, the magnitude of cardiac output, and the resistance of the blood vessels. In addition, there can be changes in the levels of other hormones (estrogen, follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, a- and b-endorphins and enkephalins) that are not necessarily related to the maintenance of homeostasis. During motor activity, there are changes in the levels of peptide hormones such as somatotropic hormone, insulin, and prolactin as a component of the metabolic response. Many, if not all, of these hormones are able to bind to immune cells and initiate a variety of cellular processes.

The body's neuroendocrine responses to exercise have recently been established. In addition, studies unrelated to the effects of motor activity have found that many of the hormones whose levels change as a result of these reactions affect various aspects of immune system function in vitro and in vivo. However, it further became clear that exercise itself can have real effects on the immune system through the effects of neuroendocrine hormones.

Exercise and immunity

"Exercise helps get rid of increased fatigue and other disease symptoms," is the headline to a recent article that provides data on how exercise helps people cope with diseases such as multiple sclerosis and cancer. It also provides tips for designing a program of self-exercise, such as how to control your own heart rate and respiratory rate and how to calculate movement speed or intensity and duration of exercise so that exercise is appropriate for the individual body. Such articles linking physical activity to health and immunity can often be found in popular magazines, exercise books and newspapers. Although it is commonly believed that all physical activity is better than none at all, and that exercise is "good for you," exactly what effect physical activity has on the immune system is unclear. Although one of the researchers investigating the relationship between motor activity and immune system function stated rather skeptically, "...numerous attempts to link motor activity and even meaningful changes in immune system function have mostly proved inconclusive" (Moseley, 2000, p. 128). Nevertheless, the potential effects of exercise on the immune system should not be ignored, much less research in this area discontinued. This requirement is particularly true given the constant expansion of the boundaries of our understanding of immunity and the emergence of increasingly sensitive methods to quantify the function of the immune system.

There are several reasons stimulating the elucidation of the relationship between motor activity and health (Mackinnon, 2000a). If exercise can be used to treat various diseases, perhaps it can prevent them? However, can susceptibility to disease actually increase with excessive amounts of motor activity? For example, some athletes who train at high intensity and for long periods of time have an increased incidence of upper respiratory disease. Does this indicate that physical activity may suppress immune system function and therefore increase the risk of infection in the body? Can motor activity protect against autoimmune diseases or, on the contrary, lead to their exacerbation? What changes in the activity of the immune system occur in bed-ridden patients with a predominantly sedentary lifestyle or in astronauts in spaceflight? Does moderate-intensity exercise modulate immune system activity? Questions about the relationship between motor activity and health have been raised for centuries, but a serious systematic study of the mechanisms linking motor activity and immunity began only about 30 years ago.

In addition to the coDetermining the effects of physical activity on the human immune system

When interpreting data characterizing the effects of physical exercise on the immune system, it is very important to consider which methodological approaches have been used to assess immune function. Two approaches are most commonly used in human studies: counting cells belonging to different subpopulations of blood leukocytes (phenotyping) and ex vivo stimulation of lymphocytes in cell culture (lymphocyte activation). For ethical and technical reasons, most studies use peripheral blood as the source of lymphocytes for analysis. However, blood contains only 1 to 2% of the body's immune cells, many of which are in constant migration throughout the body, moving toward and away from sites of pathogenic infection. Flow cytometry is usually used to count different subpopulations of blood cells based on the use of fluorescent dye-labeled monoclonal antibodies that bind to specific cellular proteins - CD markers (cluster of differentiation markers). These surface proteins are used to differentiate and quantify immune cell types, e.g. CD3+/CD4+ are T-helper cells and CD3+/CD8+ are cytotoxic T cells. However, changes in the ratio and number of these cells in the blood do not necessarily indicate a change in cell function or reflect an immune response in any particular part of the body.

Several approaches are used to study immune cell function. One of the most commonly used methods is to culture lymphocytes ex vivo in the presence of substances such as concanavalin A or phytohemagglutinin, which are polyclonal T-cell mitogens and stimulate lymphocytes to produce various cytokines, express receptors and divide. Despite the apparent simplicity of this method, the results obtained this way are subject to a variety of experimental manipulations and may also depend on the ratio of immune cells in the blood sample being analyzed. To analyze changes in the number of cells after vigorous motor activity, the functional data obtained are often normalized in relation to the number of T cells in the sample, but the presence of other cell types in the blood after exercise can also influence the degree of T-lymphocyte activation.

The information that can be obtained using the methods described will in any case be limited by the source of the lymphocyte sample and by the fact that determining the number of lymphocytes and their ability to be activated in vitro is too generalized an estimate that does not necessarily reflect with sufficient accuracy the events occurring in vivo. Newer techniques that allow quantification of markers of cell activation and cellular cytokine synthesis directly ex vivo provide an opportunity to elucidate the mechanisms underlying exercise-induced changes in immune system activity.