Source: Rehabilitation Oncology, 2002
Author: Goodman, Catherine C., Et al.
The Effect of Exercise on the Immune System(FN1)
More than ever, the gap between science and clinical applications of therapeutic exercise has been narrowed. New diagnostic technology, the genome project, and an increasing understanding of the molecular basis for disease end injury are changing the approach for health care intervention in many areas including the musculoskeletal system. The ability to document the influence and effects of exercise at the molecular and cellular levels has resulted in early functional rehabilitation, prevention exercise programs, and the use of exercise as first-line intervention for many conditions.
Research centered on the effect of exercise on the immune system is in its early stages but already important information is being reported. Interactions between the immune system and nervous system have shed additional light on how mood, emotions, and immunocompetence are uniquely intertwined. These new findings will impact the role of the physical therapist significantly in the 21st century.
INTERACTIONS BETWEEN THE IMMUNE AND CENTRAL NERVOUS SYSTEMS
The role of the nervous and endocrine systems in homeostasis has now been shown to include interaction with the immune system.FN2 Two pathways link the brain and the immune system: the autonomic nervous system and neuroendocrine outflow via the pituitary. Immune responses alter neural and endocrine functions, and in turn, neural and endocrine activity modifies immunologic function.
Many regulatory peptides and their receptors previously thought to be limited to the brain or to the immune system are now known to be expressed by both. It has also been shown that communication between the CNS and the immune system is bidirectional,FN3 that endocrine factors can alter immune function, and that immune responses can alter both endocrine and CNS responses.2
Findings that link immune and neuroendocrine function may help explain how emotional state or response to stress can modify a person's capacity to cope with infection or cancer and influence the course of autoimmune disease. Whether emotional factors can influence the course of autoimmune disease, cancer, and infection in humans is a subject of intense research but studies so far have shown reduced lymphocyte sensitivity with chronic distress.1
The CNS can be involved in immune reactions arising from within the brain or in response to peripheral immune stimuli. Activated immunocompetent cells such as monocytes, lymphocytes, and macrophages can cross the blood-brain barrier and take up residence in the brain, where they secrete their full repertoire of cytokines and other inflammatory mediators such as leukotrienes and prostaglandins. All aspects of immune and complement cascades can occur in the brain because of these nerve-macrophage communications. The CNS modulates immune cells by direct synaptic-like contacts in the brain and at peripheral sites, such as the lymphoid organs.20
A number of cytokines called neurocytokines (eg, IL-1, -2, -4, -6, neuroleukin, and TNF-alpha) are formed by glia (the supporting structure of nervous tissue) The activation of cytokines in the CNS occurs in response to local tissue injury and can lead to profound changes in neural functions, ranging from mild behavioral disturbances to anorexia, drowsiness, sleep disturbances, coma, dementia, and the destruction of neurons. The activation of cytokines in neural tissue by injury or toxins has a positive benefit as well by stimulating the production of nerve growth factor.
Based on studies using animal models, researchers suggest the brain can regulate immunocompetence. Much of this neuroimmunomodulation takes place through the hypothalamic-pituitary system but also through the sympathetic nervous system, the latter by the release of catecholamines at autonomic nerve endings and from the adrenal medulla. The principal immunoregulatory organs (lymph nodes, thymus, spleen, and intestinal Peyer's patches) are abundantly supplied by autonomic nerve fibers. Sensory neurons contain a variety of neurotransmitters and neuropeptides that can influence lymphocyte function.
The effect of physical activity and exercise (aerobic, endurance, and resistance) on the immune system and neuroimmune system has been an area of research interest. A brief summary of the results is presented here but a more detailed accounting of exercise and the immune system and future direction for studies is available.13,15
Depending on the intensity, activity, or exercise can enhance or suppress immune function. In essence, the immune system is enhanced during moderate exercise. Moreover, regular, moderate physical activity can prevent the neuroendocrine and detrimental immunologic effects of stress.4
In contrast to the beneficial effects of moderate exercise on the immune system, strenuous/intense exercise, or long-duration exercise, like marathon running is followed by impairment of the immune system. Intense exercise can suppress the concentration of lymphocytes, suppress natural killer cell activity, and leave the host open to microbial agents, especially viruses that can invade during this open window of opportunity and may lead to infections. Extreme and long-duration strenuous exercise appears to lead to deleterious oxidation of cellular macromolecules. The oxidation of DNA is important because the oxidative modifications of DNA bases are mutagenic and have been implicated in a variety of diseases including aging and cancer.18
Effect on Neutrophils and Macrophages
Exercise triggers a rise in blood levels of neutrophils (PMNs) and stimulates phagocytic activity of neutrophils and macrophages. The exercise-evoked increase in the PMN count is greater if the exercise has an eccentric component, such as downhill running. If the exercise goes beyond 30 minutes, there tends to be a second, or delayed, rise in-PMNs over the next 2 to 4 hours, while the exerciser is at rest. This delayed rise in PMNs is probably the result of cortisol, which spurs release of PMNs from the bone marrow and hinders the exit of PMNs from the bloodstream.10
After brief, gentle exercise, the PMN count soon returns to baseline, but after prolonged, strenuous exercise, this return to normal may take 24 hours or longer.3 In many instances, exercise enhances macrophage function and can increase anti-tumor activity in mice but many questions still remain regarding the mechanism(s) by which acute or chronic exercise affect macrophage function.21
Effect on Natural Killer Cells
Most researchers agree that the number of NK cells and the function or activity of these cells in the blood increases during and immediately after exercise of various types, durations, and intensities.15 This phenomenon, referred to as NK enhancement, is temporary and seems to be the result of a surge in epinephrine levels as well as from cytokines released during exercise. NK enhancement by exercise occurs in everyone regardless of sex, age, or level of fitness training; however, once a person is accustomed to a given exercise level, the NK enhancement falls off, suggesting it is a response not to exercise per se but to physiologic stress.
After intense exercise of long duration the concentration of NK cells and NK cytolytic activity declines below pre-exercise values. Maximal reduction in NK cell concentrations and lower NK cell activity occurs 2 to 4 hours after exercise.15 Although this depression in NK cell count seems too brief to have major practical importance for health, there may be a cumulative adverse effect in athletes who induce these changes several times per week. Further study is warranted before specific exercise guidelines are determined.19
Effect on Lymphocytes
Brisk exercise (even brief, heavy exertion, such as maximal bicycle ergometry for 30 or 60 seconds) increases the WBC count in proportion to the effort.5,12 This exercise-induced increase in WBCs (including lymphocytes and NK cells) is largely the result of the mechanical effects of an increased cardiac output and the physiologic effects of a surge in serum epinephrine concentration. Lymphocytes may be recruited to the circulation from other tissue pools during exercise (eg, from the spleen, lymph nodes, gastrointestinal tract). The number of cells that enter the circulation is determined by the intensity of the stimulus.15
The number of lymphocytes in circulation increases during exercise but decreases below the normal levels for several hours after intense exercise. Decreased numbers of lymphocytes are associated with decreased lymphocyte responsiveness and antibody response to several antigens after intense exercise.9
The effects of intense exercise on secondary antibody response in older adults remain unknown. In one study with older mice there were no adverse effect(s) of multiple bouts of intense exercise on antibody levels.9 In contrast to intense exercise, moderate exercise training enhances secondary antibody response in young animals and is mediated in part by endogenous opioids.8,9 Primary antibody response is not influenced by exercise training.
Effect on Cytokines
It has been established that strenuous exericse(FN4) can suppress immune function and damage enough tissue to evoke the acute phase response in humans.14 This complex cascade of reactions can modulate immune defense by activating complement and spurring the release of TNF, interferons, interleukins, and other cytokines. More research is needed before we can understand the clinical applications of this exercise-induced acute phase response.
Strenuous exercise is accompanied by an increase in circulating proinflammatory and inflammation responsive cytokines similar to the response to infection and trauma.11 Eccentric exercise is associated with an increase in serum interleukin (IL-6) concentration whereas no changes are found after concentric exercise. The rise in IL-6 with eccentric exercise is accompanied by a corresponding increase in creatine kinase in the following days because of exercise-induced muscle damage.16
Exercise and Apoptosis
The role of apoptosis or programmed cell death in exercise is the focus of much research in the area of exercise science. Apoptotic cell death differs morphologically and biochemically from necrotic cell death, although both appear to occur after exercise. Accelerated apoptosis has been documented to occur in a variety of disease states, such as AIDS and Alzheimer's disease, as well as in the aging heart.
In striking contrast, failure to activate this genetically regulated cell death may result in cancer and certain viral infections. It is surmised that exercise-induced apoptosis is a normal regulatory process that serves to remove certain damaged cells without a pronounced inflammatory response, thereby insuring optimal body function.17
Exercise and Infection7
From experimental studies it is clear that effects of exercise stress on disease lethality varies with the type and time the exercise is performed. In general, exercise or training before infection has either no effect or decreases morbidity and mortality. Exercise during the incubation period of the infection appears to have either no effect or increase the severity of infection.
Several epidemiological studies on exercise and upper respiratory tract infection (URTI) report an increased number of URTI symptoms (based on self-report rather than clinical verification) in the days after strenuous exercise (eg, a marathon race), whereas moderate training has been claimed to reduce the number of symptoms. However, in neither strenuous nor moderate exercise have these symptoms been causally linked to exercise-induced changes in immune function.15
SPECIAL IMPLICATIONS FOR THE THERAPIST
Physical therapists employ exercise in treatment of all ages with a variety of clinical problems thereby influencing immune function. Exercise as a means of preventing illness and attaining a healthy lifestyle and as an intervention tool in immunodeficiency states is becoming a larger part of preventive services. Research in the area of exercise immunology is in its infancy with many results based on studies in animals. Keeping abreast of research results is the first step to examining the clinical implications in this area.
Aged adults constitute a growing and important consumer group of therapy services. Since Immune function declines with advancing age, it is important that we understand the effects of exercise on immune function. Very few absolute guidelines have been developed but it seems that intense or strenuous exercise may be detrimental to the immune system whereas a lifetime of moderate exercise and physical activity enhances immune function. Further research is needed to clarify or modify this guideline.
It takes 6 to 24 hours for the immune system to recover from the acute effects of severe exercise. Each individual client must be evaluated after exercise to determine the perceived intensity of the exercise or intervention session. For example, in the deconditioned older adult with compromised cardiopulmonary function, reduced oxygen transport, and impaired mobility, ambulating from the bed to the bathroom may be perceived by their body as strenuous exercise.6
Intense exercise during an infectious episode should be avoided. For anyone (especially competitive athletes) wondering whether or not to exercise in the presence of an acute viral or bacterial infection (eg, when manifesting constitutional symptoms), do a neck check. If the symptoms are located above the neck, such as a stuffy or runny nose, sneezing, or a scratchy throat, exercise should be performed cautiously through the scheduled workout at half speed. If, after 10 minutes, the symptoms are alleviated, the workout can be finished with the usual amount of frequency, intensity, and duration. If, instead, the symptoms are worse and the head is pounding or throbbing with every footstep, the exercise program should be stopped and the person should rest. If there is a fever or there are symptoms below the neck, such as aching muscles, a hacking cough, diarrhea, or vomiting, exercise should not be initiated.
FN1 This article is taken from materials published in Goodman CC, Boissonnault WG, Fuller K. Pathology: Implications for the Physical Therapist, 2nd ed. Philadelphia, Pa: W.B. Saunders; 2003 (in press).
FN2 The study of immune responses involving the central nervous system (CNS) has been called neuroimmunology. Newer terms include neuroimmunomodulation, psychoneuroimmunology, and neuroimmunoendocrinology (see further discussion, chapter 1).
FN3 The immune system has the capacity not only to sense the presence of foreign molecules but also to communicate this to the brain and neuroendocrine system. This interaction is termed bidirectional communication between the immune and neuroendocrine systems.
FN4 Intense or strenuous exercise has been defined as exercising at a minimum of 80% of maximum oxygen consumption (VO^sub 2^ max).
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Catherine C. Goodman, PT, MBA
Department of Physical Therapy
University of Montana
Medical Multimedia Group, Medical Writer
Zoher F. Kapasi, PhD, PT
Division of Physical Therapy
Department of Rehabilitation Medicine