Download Table 1. CELLULAR COMPONENTS OF THE IMMUNE SYSTEM

Immune and Endocrine Responses -1-
INTERRELATIONSHIPS BETWEEN ACUTE AND CHRONIC EXERCISE AND
THE IMMUNE AND ENDOCRINE SYSTEMS
Valéria M. Natale* and Roy J. Shephard**,
from
**Faculty of Physical Education and Health,
University of Toronto,
**Defence & Civil Institute of Environmental Medicine,
North York, ON.
*Hospital das Clínicas da Faculdade de Medicina da Universidade de São
Paulo, São Paulo, Brazil
and
**Health Studies Program, Brock University,
St. Catharines, ON., Canada
1. INTRODUCTION
Exercise places a wide spectrum of demands on the body, depending on the form,
intensity and duration of the required effort, as superimposed on a background of
physiological and psychological constraints peculiar to the host. Moreover, responses are
modified by repetition of the exercise stimulus, giving rise to the typical training response.
Since 1893, when the first publication on exercise-induced leukocytosis was written by
Schultz (129), inter-relationships between exercise and immune function have been widely
studied and discussed. Several monographs now provide detailed reference sources
(45,77,114). An acute bout of exercise stimulates immune responses during the activity, but
immune function is commonly sub-normal for 2 to 24 hours following a prolonged bout of
endurance exercise. The ability of exercise to alter circulatory hemodynamics and thus
homeostasis within the immune system is now well established (57, 82). Growing evidence
also indicates that moderate exercise training can enhance resting immune responses,
possibly decreasing susceptibility to viral infections of the respiratory tract (75,139). In
contrast, excessive training leads to immune suppression (64,73,126), with an increased risk
of illness.
Opinions vary as to the mechanisms whereby exercise influences immune function.
The current consensus is that exercise-induced immunomodulation is mediated by a complex
interplay between hormones, cytokines, and neural and hematological factors. Possible
underlying mechanisms include metabolic, physiological, and hormonal changes.
Among
potential metabolic and nutritional influences (133), we may note the role of glutamine. The
Immune and Endocrine Responses -2-
"glutamine hypothesis" (18) is grounded on two main facts: skeletal muscle provides an
important reservoir of glutamine production and lymphocytes depend on glutamine for optimal
growth. Thus, it has been hypothesized that plasma glutamine serves as a "metabolic link"
between skeletal muscle and the immune system (91). Plasma glutamine concentrations
show a modest (15-20%) decline following sustained exercise (58), particularly if it is pursued
to the point of muscle glycogen depletion. It has therefore been suggested that during intense
physical exercise, the demands on the muscle for glutamine exceed supply, so that the
lymphoid system is forced into glutamine debt, with a temporary deterioration of its functional
capacity (91).
Vigorous exercise induces many physiological changes, including an increase of
cardiac output and vascular shear forces and the secretion of stress hormones, but from the
viewpoint of the immune system the effects of the rise in core body temperature and local or
general hypoxia may be of particular importance. A rise in body temperature also induces
changes in circulating leukocyte counts that in many respects resemble those observed
during exercise (15,22,52,53,55,131,122). Acute hypoxia induces a recruitment of natural
killer (NK) cells from reservoir sites to the circulating blood stream (61), possibly by increasing
the secretion of catecholamines, and Kløkker et al. (62) have observed that the exerciseinduced increases in NK cell activity is more pronounced during hypoxia than under normoxic
conditions. Vigorous exercise does not induce a generalized decrease in arterial oxygen
saturation, except in top-level athletes (25) and patients with chronic chest disease, but local
hypoxia commonly arises from forceful contraction of muscles, obstructing local blood flow to
the active limbs (56).
Muscular exercise also increases the plasma concentrations of a number of stress
hormones.
Noradrenaline and adrenaline concentrations rise soon after the onset of
exercise, and if the activity is sustained there are increases in cortisol, growth hormone,
insulin, and beta-endorphins. Associated micro-trauma can increase plasma levels of
prostaglandins, and these substances can have a substantial inhibitory influence on immune
function.
The purpose of the present chapter is to discuss interrelationships between exercise,
physical training and the responses to these two stimuli observed in the neuroendocrine and
immune systems. After making a brief survey of the immune system, we thus consider its
responses to acute and chronic exercise, together with the contribution of hormonal factors to
the observed changes. A concluding section discusses possible clinical applications of our
current knowledge.
2. OVERVIEW OF THE IMMUNE SYSTEM
The immune system plays a major role in defending the integrity of the organism
against foreign proteins and micro-organisms, providing the essential basis of a discrimination
between self and non-self or altered self. The immune system also makes a major
contribution to homeostasis, and it provides important feedback loops running from the
working muscles to the secretory regions of the hypothalamus (67). In this section, we offer a
brief sketch of the immune system, its principal components and its main functions.
The immune system comprises an intricate network of cells, hormones, paracrine and
autocrine mediators (see Tables 1 and 2). All of the cellular elements in the immune system
arise initially from hematopoietic stem cells located in the bone marrow. These pluripotent
cells divide to produce two more specialized types of stem cell: lymphoid stem cells (lymphoid
progenitors, which give rise to T and B lymphocytes), and myeloid stem cells (myeloid
progenitors, which give rise to the remaining categories of leukocyte). The T and B
Immune and Endocrine Responses -3-
lymphocytes are distinguished by their site of differentiation; T cells mature in the thymus, and
B cells in the bone marrow. They are also distinguished by their antigen receptors.
Leukocytes that are derived from the myeloid stem cells include the monocytes, and
neutrophils, eosinophils and basophils. The last three cell types are termed collectively
polymorphonuclear leukocytes or granulocytes.
The monocytes differentiate into
macrophages; these are the main phagocytic cells of the immune system which are to be
found in muscle and other tissues. In contrast, neutrophils are the most important circulating
phagocytic cells; they have functions similar to those of macrophages, but they normally
remain within the bloodstream. The eosinophils are blood-borne cells that are involved mainly
in inflammation. Basophils are also found in the circulating blood; they are similar in some
respects to mast cells, although they arise from a separate cell lineage. Mast cells also arise
from precursor cells in bone marrow, but they complete their maturation within specific
tissues; they are important to allergic responses.
There are two main classes of immune response, innate or natural immunity and
adaptive immunity, respectively. Innate or natural immunity is present from birth and it
includes numerous nonspecific defense mechanisms. Body surfaces, especially the skin, form
the first line of defense against penetration by microorganisms. When these barriers are
broken, the invading organisms encounter other elements of the innate immune system,
cellular components (such as monocytes/macrophages, neutrophils, eosinophils, basophils,
mast cells, and natural killer cells), along with soluble components (such as lysozyme,
complement, acute-phase proteins, and alpha and beta interferons).
The natural killer (NK) and lymphokine-activated killer (LAK) cells comprise a
heterogeneous population of leukocytes that mediate the killing of a broad range of target
cells. They are thought to play an important role in the first line of defense against acute and
chronic virus infections and certain types of tumor cell, since they can exercise their functions
without the intervention of MHC class proteins. Nevertheless, their cytolytic activity is
enhanced if T cells are activated and plasma levels of interleukin 2 are increased.
If the innate immunity is overwhelmed, adaptive immune responses come into play,
with the development of an inflammatory response. Adaptive responses are distinguished by
a remarkable specificity against the offending agent and by a memory of previous responses
to the same antigen. Mediators include cellular components (T and B lymphocytes), and
soluble elements (antibodies and cytokines). Excessive inflammation can have serious
negative consequences for health, either in its own right, or because of a secondary
suppression of the immune system by counter-regulatory cytokines. Clinical manifestations of
excessive inflammation include bacterial penetration of the gut wall, sepsis, the respiratory
distress syndrome, and the multiple organ distress syndrome It is currently debated how far
such reactions can account for the negative immunologic effects of prolonged and intense
exercise (135).
During an adaptive type of immune response, the antigen is initially taken up and
processed by antigen processing cells, primarily macrophages and related cells. Fragments
of the ingested material become expressed as immunogenic epitopes, which are complexed
on the surface of the antigen-presenting macrophage along with class II MHC molecules.
The T-helper (TH) cells bind with the macrophage through the action of certain adhesion
molecules, recognizing characteristic features of both the epitope and the class II MHC
molecule.
Activated TH cells regulate the activities of other lymphocytes in a positive, cascadelike fashion through the secretion of soluble factors known collectively as lymphokines. One of
these substances, interleukin-2 (IL-2), enhances the function of natural killer cells, and it also
Immune and Endocrine Responses -4-
serves as an activating signal for a second class of T cell, the T-cytotoxic (TC) cell (which
recognizes antigens expressed in the context of class I MHC molecules on the surface of
target cells). Furthermore, the TH cells furnish important growth and differentiation signals to
B cells, accelerating their proliferation and differentiation into antibody-secreting plasma cells.
The basis for memory in the immune response is the generation of antigen-specific TH
and B cells following initial exposure to a given antigen. The memory cells have characteristic
surface proteins, and they are prepared to make a more rapid and amplified response if they
subsequently encounter the same antigen in a secondary, or anamnestic, response.
TC cells and antibodies use a variety of mechanisms to eliminate foreign antigens,
some of which are integrally linked to the processes of inflammation and sepsis.
3. THE IMMUNE SYSTEM AND ACUTE MUSCULAR EXERCISE
Exercise induces an immediate leucocytosis, the magnitude of which is related to the
intensity and duration of the activity which has been undertaken. The pattern of change in the
leukocyte count post-exercise is determined mainly by the time which has elapsed since the
beginning of exercise, rather than by the intensity of effort or the total amount of work which
has been performed.
The exercise-induced leukocytosis reflects increased numbers of circulating
neutrophils, monocytes and lymphocytes. The neutrophil count increases during exercise and
it continues to increase, sometimes for as long as several hours, following exercise (82).
During exercise natural killer, T and B cells are all recruited to the circulating blood stream,
and there is an increase in the total lymphocyte count. However, the NK cell count increases
more than the T cell count, so that the CD3 +T cell percentage declines during exercise. The
number of CD8+ cells increase more than the number of CD4+ cells, resulting in a decreased
+
+
CD4 /CD8 ratio (112). Following long-duration exercise, the lymphocyte count decreases
below its baseline level. The duration of this phase of immunosuppression depends on the
intensity and duration of the exercise that has been undertaken (113), but it generally seems
of rather short duration to have any substantial clinical effect on resistance to either viral
infections or tumor cells. The lymphocyte proliferative response per individual CD4 + cell does
not change substantially with exercise (150).
Both the absolute cell count and the relative fraction of blood mononuclear (BMNC)
cells which express characteristic NK cell surface markers (CD3-CD16+CD56+) are markedly
enhanced during physical exercise. The NK and LAK cell activities increase simultaneously,
although there is at most only a small increase in lytic activity per fixed number of
mononuclear cells. The intensity of exercise seems the prime determinant of the increase in
NK cell count and activity during exercise, whereas the duration as well as the intensity of
exercise determine if and to what extent a post-exercise immunosuppression may occur
(110). NK and LAK cell activities are normally suppressed during the first few hours that
follow a bout of intensive exercise which lasts for one hour or longer (110).
The leukocytes carry receptors for various hormones, including catecholamines and
cortisol. They are also capable of secreting hormones in their own right, as part of the
feedback regulatory system. Catecholamine concentrations rise early during a bout of acute
endurance exercise. Their secretion is associated with a mild leukocytosis, but a strong and
rapid lymphocytosis. The lymphocytes are probably supplied from several storage sites such
as the spleen and the liver, together with the walls of high-endothelial venules (20). The
infusion of physiological doses of catecholamines can induce similar changes in cell counts to
those seen during exercise (152).
Immune and Endocrine Responses -5-
Cortisol concentrations increase in response to either high-intensity or prolonged submaximal exercise, particularly if the subject perceives the activity in question as stressful (67).
Cortisol can induce a leukocytosis. It promotes the entry of neutrophils into the circulation
from bone marrow, while inhibiting the entry of lymphocytes and facilitating their egress to
peripheral tissues and lymph nodes (82,92,127). Thus, cortisol, which may remain elevated
for at least 1.5h following a prolonged period of endurance exercise (92), reduces circulating
lymphocyte numbers by encouraging their trafficking to peripheral tissues (23). Cortisol also
down-regulates the interleukin-1 and interleukin-2 receptors on the T cells. The immediate
consequence of these actions is a reduction in both natural killer cell activity and the rate of B
cell proliferation (9). In a more long-term perspective, a chronic elevation of cortisol levels
increases the rate of catabolism, thus modifying the reserves of amino acids available for
lymphocyte growth and proliferation (91).
The effects of catecholamines probably predominate during and immediately following
an acute bout of moderate exercise, explaining the large increase in number of circulating
lymphocytes, but it is possible that cortisol plays a major role in maintaining a neutrophilia and
lymphopenia following a prolonged period of intensive exercise.
Prostaglandin E2 is secreted by macrophages in response to exercise-induced tissue
injury. It depresses the proliferative response of peripheral blood mononuclear cells to
mitogens, and decreases their IL-2 production (132). The late suppression of NK cell activity
following a bout of strenuous exercise can be largely abolished by administration of nonsteroidal anti-inflammatory drugs such as indomethacin, which counter the effects of the
prostaglandin (54).
4. PHYSICAL TRAINING
4.1. INFLUENCE OF TRAINING ON IMMUNE AND ENDOCRINE SYSTEMS
There is a bilateral system of communication between the immune and neuroendocrine
systems (67). Hormones have significant effects on many aspects of immune function,
including T-lymphocyte selection, splenic lymphocyte release, and the expression and
secretion of intercellular mediators (see table 3). Leukocytes also have both receptors for
and the capacity to secrete a wide range of hormones (80). Until now, around 20 different
neuroendocrine peptides and/or their mRNAs, have been identified in cells of the immune
system. These peptides probably mediate autocrine and paracrine functions, and despite
their rapid breakdown in vivo, it is possible that they have endocrine roles, regulating function
elsewhere in both the immune and neuroendocrine systems. For example, T lymphocytes
can synthesize ACTH, endorphins, growth hormone and others hormones (10). Lymphocytes
also have neural synapses (2), and their function is modified by changes in sympathetic nerve
activity (4,81,120). Moreover, the various types of leukocyte all carry catecholamine
receptors. Receptor densities are greater for B and CD8 + cells than for CD4+ cells, and are
still greater on NK cells (20,66, 86). However, the ranking of response to plasma-borne
stimuli depends also on second messenger systems, which are poorly developed within the B
cells.
The immediate intercellular mediators between the various types of immune cell are
called cytokines. These substances promote the regulation of immune and inflammatory
responses, and they can exert a profound influence on neuroendocrine activity (see table 4).
Cytokine receptors have been identified in neuroendocrine tissues, and they have been
classified into three major families (32). The hematopoietic growth factor receptor family
includes receptors for interleukin-6 and related cytokines. The TNF receptor family includes
Immune and Endocrine Responses -6-
receptors for both TNF- and TNF-. Finally, the immunoglobulin supergene family includes
two identified interleukin-1 receptors, the 80-kDa type I receptor which is found mainly on T
cells and fibroblasts, and the smaller 68-kDa type II receptor which has been identified on B
cells and macrophages.
Interplay between the immune, endocrine and nervous systems is most commonly
associated with stressors that have a pronounced effect on the overall immune response.
Any type of stress, including not only psychological and environmental challenges, but also
vigorous physical activity, can initiate a hormonal stress response, with a potential for additive
effects if there is exposure to more than one type of stress (137).
In the context of exercise, training and immune responses, hormones that have
attracted particular attention include components of the neurohormonal stress response and
metabolic regulators (136), particularly catecholamines, cortisol, corticotropin-releasing,
adrenocorticotropic hormones, growth hormone, endorphins and enkephalins, insulin, thyroid
hormones, prolactin and prostaglandins. Unfortunately, the various studies which have
examined the influence of physical training on the immune response differ widely from each
other with respect to the type of subject recruited, the volume of training undertaken, and the
immunological methodology employed. Moreover, when studies have involved athletes, it
has been difficult to ensure adequate recovery from the effects of recent sessions of
strenuous training. It is thus difficult to make reliable comparisons between studies.
The hypothalamic-pituitary-adrenal (HPA) axis is the key player in the stress response.
The principal cell type involved within the HPA axis is the corticotroph. This cell produces,
processes and stores peptides derived from a 31kDa protein called propiomelanocortin
(POMC). Adrenocorticotrophic hormone (ACTH, corticotropin) and -endorphin are products
derived from POMC. During a typical stress response, cognitive recognition of stress by the
higher centers of the central nervous system (CNS) causes the release of corticotropinreleasing hormone (CRH) from the hypothalamus. The CRH acts on the pituitary
corticotrophs, causing a release of ACTH into the circulation. ACTH then acts on the adrenal
gland, causing it in its turn to produce glucocorticoid hormone. Many of the physiological
effects of stress are mediated by the glucocorticoids, which can modify both metabolism and
immune function. These same substances also inhibit the synthesis and release of CRH and
ACTH by a form of negative feedback.
Beta-endorphin is another substance released from the anterior pituitary in response to
sustained and vigorous exercise. It elevates mood, and accounts for the occasional individual
who becomes chemically dependent on regular bouts of prolonged exercise. The endorphin tends to suppress the formation of ACTH and cortisol, possibly by a feedback
inhibition of CRH (146). Although leukocytes carry receptors for the endorphins, the extent of
their contribution to the immune response has yet to be clarified.
Activation of the sympathetic nervous system stimulates the release of catecholamines
from the adrenal medulla and the sympathetic nerve terminals (60). The response of the
sympatheticoadrenomedullary system to exercise is more swift and more powerful than that
of the HPA axis (26). Sympathetic activation occurs within a few seconds of initiating physical
activity, but the HPA response and secretion of glucocorticoids often do not begin until 20 to
30 minutes after commencing exercise (121).
A period of physical training alters the response of most of the above hormones to
exercise at any given power output, largely because the specified effort now represents a
substantially smaller fraction of the individual’s peak aerobic power. However, there is less
evidence of a change in response at a fixed fraction of peak aerobic power. Training also
modulates the immediate resting concentrations of several stress hormones, particularly the
Immune and Endocrine Responses -7-
catecholamines. Aerobic training decreases resting sympathetic (-adrenergic) activity, while
increasing parasympathetic (vagal) tone (33,84).
Hack et al. (40) studied long-distance
runners before and up to 24 h after they had performed a graded exercise test to exhaustion;
the responses observed during periods of moderate and intensive training were compared
with the responses seen in untrained (control) subjects. Probably because of incomplete
recovery from previous training sessions, resting plasma adrenaline and noradrenaline levels
were increased in subjects who were undertaking intensive training relative to controls or
subjects who were performing only moderate training. However, the plasma catecholamine
response at a given sub-maximal work rate was decreased following endurance training
(36,158).
Training programs may lead to a modification in the sensitivity and/or density of
adrenergic receptors. Prolonged or habitual physical exercise tends to cause a downregulation of -receptor density (104), probably because of repeated exposure to high
catecholamine levels. Butler et al. (16) observed an almost 60 percent decrease in the
density of -receptors on lymphocytes over two months of intensive aerobic training.
Because exercise training is so efficient in down-regulating the sensitivity of the sympathetic
nervous system (SNS), it has even been used as relaxation technique (85). In support of the
view that the mechanism of downregulation is the high catecholamine levels reached during
training, Krawietz et al. (63) noted an inverse association between receptor density and
circadian variations in catecholamine levels. However, Dorner et al. (27) found a higher receptor density on the granulocytes of subjects with a high level of aerobic fitness.
The magnitude of the neurohormonal response to any given physical task is
augmented by associated emotional stress (12) and by any increase in core body
temperature (83,128). On the other hand, the secretion of endogenous opioids such as endorphin (3) and habituation to a given situation each reduce catecholamine secretion and
the resultant physiologic and immunologic responses to exercise (68).
When subjects have been compared at the same sub-maximal work-rate, trained
persons have generally had smaller increases in plasma cortisol levels than untrained
persons (37,82).
Serum concentrations of several endogenous opiates or neuropeptides including lipotropin, -endorphin, and met-enkephalin increase in response to exercise (41). Aerobic
exercise was also found to augment -endorphin release in seven women who participated in
a rigorous 8-week protocol consisting of conditioning exercises, cycling and running (17).
These results suggest that aerobically fit individuals who continue to exercise and maintain
their aerobic fitness may release more endogenous opioids than their non-exercising, less-fit
counterparts during exercise. This in turn would explain why they derive a sustained
elevation of mood and perceived health from their exercise habit. It also seems reasonable to
postulate that exercise training modifies psychological stress reactivity, and there is some
empirical evidence of a reduced reaction to psychological stressors among those who are
well-trained. LaPerriere has proposed a model in which exercise training reduces negative
affective states, increasing the release of endogenous opiates, reducing HPAC activation,
and enhancing immunity (67).
4.2. CELLULAR RESPONSES TO TRAINING
Less information is available about the effects of training on the immune system than
about acute exercise and immune responses (136). Several studies have made crosssectional comparisons of the immune system between athletes and non-athletes (14, 21, 38,
Immune and Endocrine Responses -8-
65, 70, 79, 93, 96, 108, 111, 151). Others have followed sedentary individuals as they have
initiated exercise programs, comparing pre- and post-exercise training immune parameters
relative to control groups (11, 89, 94, 95, 100, 143, 156). The majority of these studies have
not demonstrated any important effects of regular exercise training on the circulating numbers
of total leukocytes, lymphocytes or their various sub-populations. However, several
investigations of both humans and animal populations have shown significant increases in
natural killer cell cytotoxic activity (NKCA) with exercise training (21, 65, 78, 94, 95, 111, 140,
151). As yet, researchers disagree whether the higher NKCA is due to greater numbers of
circulating NK cells, or to an enhanced cytotoxic capacity per individual NK cell (95,111,151).
With regard to lymphocyte proliferation, the data are conflicting; cross-sectional and
prospective studies on both animals and humans have reported positive (87, 95, 115, 147,
156), neutral (38, 51,79, 95, 150) or negative (31,72, 87, 107, 108) effects of exercise
training.
We will now give brief consideration to some studies on the cellular component of
immune responses to physical training.
4.2.1. Neutrophils - Numbers and function
4.2.1.1. Resting cell counts
Analyzing studies which have compared sedentary and trained subjects, we found that
resting neutrophil counts were higher in the trained group (13, 106, 124, 130) when the
intensity of training was moderate, but the opposite was true when training was intensive (71,
95, 99, 119, 151). Longitudinal studies have shown a similar picture (8, 40, 71, 88, 125).
Thus, it is possible to conclude that moderate training is associated with a positive
modulation of the resting neutrophil count, whereas intensive training seems to depress the
numbers of circulating neutrophils, possibly because of a migration of these cells to injured
muscles.
4.2.1.2. Exercise cell counts
During the first few minutes following an acute bout of exercise there is a biphasic
change in the neutrophil count (82). Studies comparing trained and untrained individuals
have suggested that exercise produces a similar increase of neutrophil count in trained and
untrained subjects (13, 39, 70), or that the neutrophilia post-exercise is substantially larger in
trained subjects (7, 27, 40). In contrast, Oshida (106) found a smaller granulocytosis in
trained than in untrained individuals. Longitudinal data, at this moment, are inconclusive.
4.2.1.3. Functional activity
Some authors (7, 8, 105) have reported that neutrophils have a greater functional
activity in trained individuals than in sedentary subjects. In contrast, Prasad et al. (118)
suggested that heavy training causes a dysfunction of neutrophils.
Much of the available data suggest that conditioning programs induce little change of
neutrophil function. In contrast, severe training may have a suppressant effect .
4.2.2. Eosinophils and Basophils
Few studies have studied the influences of exercise and training on these cell
categories. Nieman et al. (101) found higher resting eosinophil and lower resting basophil
counts in marathoners than in control subjects. In contrast, Janssen et al. (50) observed no
increase of resting eosinophil count and an increase of basophil count in subjects weho had
trained in preparation for a 15-kilometer run.
Immune and Endocrine Responses -9-
4.2.3. Monocytes/macrophage counts
Comparison between sedentary and trained subjects showed lower resting monocyte
counts in the trained group (6, 24, 34, 70, 101).
Several authors have found little change in peripheral blood resting monocyte counts in
response to training (50, 88, 117). On the other hand, Ferry et al. (30) observed large
increases in both resting and exercise counts after a period of vigorous training, and Ndon et
al. (88) also noted a larger exercise-induced monocytosis in trained than untrained
individuals.
4.2.4. T cell counts
Sedentary and trained subjects commonly show little difference of resting CD4 + counts
(6, 43, 95). However, some authors have noted substantially higher resting CD8 + counts in
active than in sedentary individuals (30, 59). Data on the CD4 +/CD8+ ratio have been more
consistent, athletes showing low ratios in comparison with sedentary individuals (6, 30, 95,
151).
The majority of longitudinal data have shown decreases in resting CD4 + and CD8+ (5,
43, 90, 117, 151) counts with training, but the influence of conditioning programs on
CD4+/CD8+ ratio has varied from one study to another.
Cross-sectional data show a little difference in exercise-induced changes of CD4+
count between fit and unfit subjects (30, 59, 106). However, exercise induced a larger
increase of CD8+ count in trained than in untrained individuals (30, 59). The exercise-induced
changes in CD4+ and CD8+ counts and the CD4+/CD8+ ratio have been inconsistent in
longitudinal training programs (43, 90, 154).
4.2.5. B cell counts
Cross-sectional comparisons of resting B cell counts between trained and untrained
subjects offer inconsistent results (13, 71, 95).
Studies of moderate training have shown a substantial increase (95), no change (71),
or a decrease (125) in B cell counts.
4.2.6. Lymphocyte proliferation
Cross-sectional and prospective studies of animals and humans have reported positive
(87, 95, 115, 147, 156), neutral (38, 51, 79, 95, 150) or negative (31, 72, 87, 107, 108) effects
of exercise training on lymphocyte proliferation.
4.2.7. Natural killer cell number and function
Several studies have compared active and inactive groups. Cross-sectional data
involving moderate training have sometimes shown substantially larger NK counts in trained
individuals (6, 106, 111, 124, 151), but other studies have observed only small differences of
resting NK cell count between active and trained groups (59, 95). Liesen et al. (71) found very
low resting NK counts in athletes who were undergoing rigorous training.
Different authors have found the resting NK cell count to increase (30, 67, 117, 125) or
to decrease (5, 71, 151) over the course of a training program. One explanation for a
decrease in NK count may be incomplete recovery from recent training sessions.
Several investigations of both humans and animals have shown significant increases in
natural killer cell cytotoxic activity (NKCA) with exercise training (21, 65, 78, 94, 95, 111, 140,
Immune and Endocrine Responses -10-
151). Nevertheless, researchers still disagree whether the higher NKCA is due to a greater
number of circulating NK cells, or to an enhanced cytotoxic capacity per individual NK cell
(95, 111, 151).
4.3 Cytokines
Cytokines and adhesion molecules comprise the main regulatory elements in the
immune system. They govern the growth, differentiation and functional activation of all cells
in the immune system, and they are also responsible for the interaction of this system with
somatic cellular systems.
Plasma levels of cytokines are often difficult to measure accurately, but they appear to
change only slightly during exercise. However, an increased urinary excretion of several
cytokines has been noted after intensive prolonged exercise such as distance running or
cross-country skiing (reviewed by 103).
IL-6 is one of the easier substances to detect in the plasma. Sprenger et al. (144)
noted an increased plasma IL-6 concentration and increases in the urinary excretion of IL-1,
soluble IL-2 receptor (sIL-2r), IL-6, interferon (IFN) and TNF when male distance runners had
covered a distance of 20 km. In general, moderate exercise causes little change in plasma or
urinary excretion of cytokines. In contrast, strenuous exercise is associated with large
increases in urinary excretion of most of the cytokines which have been measured to date (IL1, sIL-2r, IL-6, IFN, TNF); the one possible exception is IL-2. There is also a decreased in
vitro production of cytokines by cells isolated after exercise, with the exception of IFN (which
appears to be produced in increased quantities, 103).
As yet, few studies have explored training-induced changes in cytokine secretion.
Training may cause no change (157) in the level of IL-2, the cytokine responsible for initiating
cell-mediated immune reactions. Rhind et al. (125) observed a small decrease in the plasma
IL-2 level following 12 weeks of moderate training. However, training has little influence on
IL-1, IL-6 IFN, and TNF, the pro-inflammatory cytokines, unless the conditioning program is
pushed to cause tissue injury and inflammation.
4.4. Other soluble factors
Moderate training tends to enhance both salivary and plasma levels of
immunoglobulins. On the other hand, very heavy training can lead to a decrease in the
concentrations of both secretory and circulating immunoglobulins (71, 76).
There are few reports on complement levels. Concentrations may be lower in trained
than in untrained individuals if the conditioning program is sufficiently intense to induce a
chronic inflammatory reaction (28, 93, 141, 148).
5. Clinical applications
5.1. Exercise and Upper Respiratory Tract Infections (URTI)
Many athletes develop upper respiratory infections, either following a single bout of
prolonged exercise such as a marathon run (94), or in response to a period of heavy training
as a major competition is approached (71). Some authors have also reported that heavy
training is associated with a reduction of immunoglobulin levels in serum, saliva and nasal
washings (71, 74). This has led to formulation of the so-called j-shaped hypothesis (102),
whereby moderate exercise exerts a protective effect, but heavy, stressful exercise
suppresses immune function with negative consequences for defense mechanisms.
If immunoglobulin levels are reduced by a period of heavy training, then there would
Immune and Endocrine Responses -11-
seem good grounds for suggesting an impairment of immune defenses. However, the
evidence that a single bout of prolonged physical activity can cause a clinically significant
depression of immune function is less convincing, since it is hard to envisage how the usual
brief depression of immune response (2-24 hours in duration) could have sufficient impact on
immune defenses to lower the resistance to infections for several weeks. The precise
mechanism of any exercise-induced immuno-suppression also continues a topic of
discussion. Either the increase in total energy expenditure or the repair of tissue microinjuries could conceivably increase the formation of reactive species, with negative
consequences for immune function. Given such a scenario, the athlete might be helped by
administration of megadoses of antioxidant vitamins. However, the practical benefit from
such therapy has been very limited among participants in the Comrades' marathon (116).
Alternatively, negative consequences might stem from microtraumata and an associated
release of prostaglandin-E2; if this were the modus operandi, it might be helpful to administer
non-steroidal anti-inflammatory drugs such as indomethacin. Other hypotheses include
hormone-induced changes in the trafficking of immune cells, the adverse influence of stress
hormones (particularly cortisol) on lymphocyte function, and a depletion of the reserves of
branch-chained amino-acids needed for lymphocyte proliferation. Plainly, further research is
needed to clarify which mechanisms underly any changes in immune responses that develop
with prolonged and intensive bouts of endurance exercise.
Several practical precautions may help athletes that are undergoing intensive training
to reduce their risk of URTI. Guidelines include the adoption of a well-balanced diet (19),
ensuring adequate sleep (47), spacing vigorous workouts and race events (98), where
possible avoiding contact with people who have viral infections (48), keeping other life
stresses to a minimum (44), and having inoculations against influenza and other prevalent
viruses. If immunoglobulin levels are low, it may also be helpful to administer immunoglobulin
preparations.
5.2. Exercise and Cancer
In keeping with the discussion of interactions between exercise and susceptibility to
acute viral infections, there is now a substantial volume of literature suggesting that regular
moderate exercise has a helpful effect in reducing all-site cancer rates, together with
susceptibility to cancers at specific sites, particularly the descending colon, but possibly also
the lungs, the female reproductive tract and breast, and the prostate gland in men (136). At
some of these sites (for example, the female reproductive tract) benefit seems to arise from
either a suppression of estrogen synthesis or an alteration of the pathway of estrogen
metabolism in thinner individuals. There is also evidence that susceptibility varies with NK
cell activity, so that the increases in NK function associated with moderate training may play
some protective role. However, there is also animal and anecdotal human evidence that in a
few instances excessive physical activity has predisposed to either the development of or the
recurrence of a neoplasm (134).
5.3. Exercise and the Chronic Fatigue Syndrome
Excessive stress, whether induced through emotional shock alone, over-vigorous
training, or a combination of these two factors can produce symptoms that merge with usual
descriptions of the chronic fatigue syndrome. It is important to monitor the condition of
athletes closely to ensure that they do not reach such a level of stress, since treatment of
chronic fatigue is prolonged and unsatisfactory. Unfortunately, there are few good markers of
Immune and Endocrine Responses -12-
excessive training. Warning is provided by a deterioration in performance, despite rigorous
training.
Perhaps the simplest, and often the most effective objective measure of
overtraining, is use of a simple psychological questionnaire, the Profile of Mood States
(POMS) (153); this usually shows a substantial deterioration of mood state in athletes who
are training too hard.
5.4. Exercise and Aging
Human immune responses decline significantly with advancing age and there is an
associated increase in susceptibility to infectious diseases, inflammatory response-based
disorders, and cancer, all of which are major health problems in older people. Aging leads to
substantial changes in both the functional and phenotypic profiles of T lymphocytes.
Changes include a shift toward greater proportions of CD4 +T cells of memory
+
+
(CD44hiCD45RO ) phenotype and fewer cells of naive (CD44 loCD45RA ) phenotype (69,35).
In parallel with these modifications of phenotype, functional changes include a decreased
proliferative response of T cells to mitogens (142) and alterations in the profiles of cytokines
which are produced with T cell activation (42).
Few investigators have studied the influence of physical training on immune responses
in the elderly. Xusheng et. al (159) found that the percentage of rosette forming (T) cells was
lower in 24 elderly devotees of Taichiquan than in 24 age-matched controls. Nieman et al.
(95) made both cross-sectional and 12-week longitudinal assessments of the effects of
training in women aged 67-85 years. They found that the highly conditioned elderly women
had greater NK and T cell function than their sedentary counterparts, but that twelve weeks of
moderate exercise did not improve immune function in previously sedentary elderly women.
Shinkai et al. (138) had similar findings in a cross-sectional study of trained and untrained
elderly subjects. Rall et al. (123) compared the response of young and elderly individuals (6580 years) to high-intensity progressive resistance strength training; they concluded that 12
weeks of training did not alter immune function in either group.
Although the number of reports is small, there seems some support for the view that
moderate exercise performed regularly throughout life may decrease the age-related decline
in immune function, particularly if it is coupled with other positive lifestyle habits.
5.5. Exercise and Sepsis
Perhaps the most interesting aspect of the immune response to heavy exercise is the
potential window it gives into human reactions to excessive inflammation and sepsis. For
ethical reasons, it is not possible to induce septic lesions by the deliberate infliction of injury
on experimental subjects, but the study of cellular, hormonal and cytokine responses in
athletes who have produced tissue injury through excessive training can serve many of these
same objectives (136).
6. Conclusions
Physical training results in a variety of important biological changes. Particular interest
attaches to interactions between the central nervous, endocrine, and immune systems, which
result in modifications of the immune response. Moderate regular exercise appears to
improve immune function, but in contrast, heavy physical training can suppress several
immune parameters of the immune response. The exact mechanisms involved in both
Immune and Endocrine Responses -13-
positive and negative reactions are not completely understood as yet. We may conclude that
moderate physical training could be helpful in the prevention or treatment of diseases and
conditions caused by or associated with a decline in immune function. However, further
studies are needed to find the best way of attenuating those adverse immune changes that
follow a period of very heavy exercise.
Immune and Endocrine Responses -14-
Acknowledgments:
Dr. V.M.Natale is grateful to the FAPESP (Fundação de Amparo à Pesquisa do Estado de
São Paulo - São Paulo, SP, Brazil) for support during her stay at the Defence and Civil
Institute of Environmental Medicine, Toronto, Ontario, Canada.
Dr. Shephard’s research is supported by grants from the Defence & Civil Institute of
Environmental Medicine and Canadian Tire Acceptance Limited.
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Immune and Endocrine Responses -23-
Table 1. CELLULAR COMPONENTS OF THE IMMUNE SYSTEM
CELLS
FUNCTION
INNATE
-
+
+
1. NK cell (CD3 16 56 )

lysis of virus-infected cells, tumor cells; antibody dependent cellular
cytotoxicity
2. monocytes/macrophages

phagocytosis; antigen presenting; cytokine secretion
3. neutrophils

phagocytosis; activation of bactericidal mechanisms
4. eosinophils

killing of antibody-coated parasites; inflammatory response
5. basophils

inflammatory response
6. mast cells

allergic response; inflammatory response

antigen recognition; stimuli for B cell growth and differentiation;
ADAPTIVE
+
7. T cells ( CD3 )
 T-helper ( CD4 )
+
macrophage and T cytolytic activation by secreted cytokines;
development of inflammation


TH1
macrophage activation; pro-inflammatory action; Il-1; IL-2, IFN-,
and

TH2
TNF- secretion

B-cell activation; anti-inflammatory action; IL-4, IL-5, IL-10 secretion

antibody-dependent cytotoxicity

down-regulate the immune system

antibody production
 T-cytotoxic ( CD8 )
+
 T-suppressor ( CD8 )
+
+
8. B cells ( CD19 )
1.
Cluster of differentiation (CD) markers are molecules of monoclonal antibodies that identity a given
cell-surface molecule
2.
Sources: references 1,136,145
Immune and Endocrine Responses -24-
Table 2. SOLUBLE COMPONENTS OF THE IMMUNE SYSTEM
COMPONENTS
FUNCTION
INNATE
Major histocompatibility complex

T-cells only recognize an antigen if bound to MHC
 MHC class I

present peptides to CD4 cells
 MHC class II

present peptides to CD8 cells
complement

opsonization, phagocytosis, cell lysis, and the removal of
+
+
antibody/antigen complex
lysozyme

mechanism of defense against unencapsulated bacteria
acute phase proteins

inflammatory response; complement activation; opsonization
adhesion molecules

role in margination of immune cells; facilitate interactions
between cells and penetration of vascular endothelium
ADAPTIVE
antibodies

inflammatory response; immune memory
cytokines(1)

mediate
natural immunity; regulate lymphocyte activation;
regulate immune-mediated inflammation; stimulate the growth
and differentiation of immature leukocytes
1.
Cytokines: interleukins, interferons, TNF, chemokines, hematopoietic growth factors
2.
Sources: references 1,136,145
Immune and Endocrine Responses -25-
Table 3. NEUROPEPTIDES AND HORMONES THAT INFLUENCE IMMUNE FUNCTION
NEUROPEPTIDE OR
EFFECTS ON THE IMMUNE SYSTEM
HORMONE
CATECHOLAMINES
via  -adrenoreceptors: induce leukocytosis
may reduce endothelial adhesion of leukocytes to vessel walls
enhance the proliferation of CD3 , CD4 , and CD8 cells (by -adrenergic
+
+
+
stimulation)
inhibit the proliferation of CD4 and CD8 cells (by -adrenergic stimulation)
+
+
inhibit the degranulation of mast cells and basophilic granulocytes
CORTISOL
enhance leukocyte liberation from bone marrow
mediate lymphocyte distribution
inhibit T-cell proliferation
inhibit IL-1, IL-2 production
enhance IL-4 production
reduce phytohemagglutinin proliferation
BETA-ENDORPHIN
promote natural killer cell activity
inhibit lymphocyte chemotactic factor
may itself be a lymphocyte chemotactic factor
GROWTH HORMONE
promote T-cell generation
Sources: Madden(80), Shephard(136), Weicker(157)
Immune and Endocrine Responses -26Table 4. EFFECTS OF CYTOKINE ADMINISTRATION ON THE CONCENTRATIONS OF SOME
NEUROENDOCRINE HORMONES IN BLOOD
HORMONE
CYTOKINE
BLOOD
AUTHOR
ACTH
IL-1, IL-2, IL-6,TNF-
 concentration
Imura(46), Turnbull(149)
Corticosteroids
IL-1, IL-6,TNF-, CNTF
 concentration
Turnbull(149), Fantuizzi(29)
Growth hormone
IL-1
 and  concentration
Payne(109), Wada(155)
T3 and T4
IL-1, IL-6,TNF-
 concentration
Imura(46)

 = increased
 = decreased