Word count: 2437 - Sportsci



Word count: 2437

The Cellular Immune System and Muscular Activity.

Bente Klarlund Pedersen

The Center of Muscle Research

Department of Infectious Diseases

M 7721

Tagensvej 20

DK-2200 Copenhagen N

Denmark

The cellular immune system is highly influenced by muscular exercise. In essence the immune response is enhanced during moderate and severe exercise, but suppressed only after exercise of high intensity and long duration. At rest the immune response is slightly elevated in trained compared to untrained. It is suggested that during the time of immunodepression microbacterial agents, especially virus, invade the host, whereby infections can be established. However, in those who perform regular moderate exercise the immune system is often temporarily enhanced and this will protect these from infections.

During the past few years knowledge has accumulated regarding the effect of physical exercise on different components of the immune system, however, it is still debated, whether physical exercise is beneficial to the immune system or not, and how exercise influences resistance to infectious diseases and tumor growth. The present review will discuss possible mechanisms behind exercise-induced alterations of the cellular immune system.

Acute Physical Exercise

Leucocyte Subpopulations.

There are several consistent patterns of changes in leukocyte numbers in relation to acute exercise. Exercise leads to a neutrophilia and lymphocytosis during exercise. Two hours after severe exercise (e.g. bicycle exercise, 1 hour, 75% of O2max) the neutrophil count is still elevated, whereas the lymphocyte concentration declines below prevalues. Subpopulations of blood mononuclear cells (BMNC) can be quantified by the technique of direct immunofluorescence using fluorescein conjugated monoclonal antibodies specific for any subpopulation. During exercise lasting a few minutes especially natural killer (NK) cells, but also B and T cells are recruited to the blood. Simultaneously the composition of T cells are altered, meaning that the CD4/CD8 ratio decreases. Following severe exercise a late monocytosis occur.

NK Cells

NK cells are thought to play an important role in the first line of defense against viral diseases, furthermore, NK cells are believed to play a role in resistance to cancer. It is well known that NK cells are highly influenced by physical exercise. During physical exercise the absolute concentration and the relative percentage of cells expressing characteristic NK cell markers as CD16 and CD56 are increased. Simultaneously the NK cell activity (the ability of NK cells to kill a tumor target cell) are increased. Two hours after maximal exercise (bicycle ergometer, 1 h, 75% of O2max) the NK cell activity has been shown to be suppressed. The post-exercise suppressed NK cell activity is probably not due to fluctuations among the NK cells since the proportion of CD16+ cells was normal. Strong evidence exists that the post-exercise down-regulation of NK cell activity is at least partly caused by prostaglandins released by the elevated number of monocytes.

Proliferation of Lymphocytes.

It is well known that although the numbers of lymphocytes in the blood are increased during exercise the ability of lymphocytes to proliferate in vitro following stimulation with phytohemaglutinin (PHA) decrease. The decreased PHA response during bicycle exercise is, however, not due to a changed proliferative response per CD4+ cell, but caused by a decline in the contribution of the CD4+ cell subgroup to proliferation.

B Cell Function.

Salivary sIgA was found to be suppressed in cross-country skiers and the levels of sIgA was suppressed after a race. This finding has later been confirmed in a study showing 70% decrease in sIgA for several hours after a hard 2 h bicycle ergometer session. In order to study the mechanism behind the suppression of immunoglobulins a plaque forming cell (PFC) assay was used, this assay allows to identify the individual immunoglobulin-secreting cells. Stimulation af cells with poke weed mitogen (PWM), interleukin-2 (IL-2) and Epstein-Barr virus (EBV) resulted in significant decreases in numbers of IgG, IgA and IgM-secreting blood cells during as well as 2 h after bicycle exercise, with reversal to preexercise levels 24 h later. The fraction of CD20+ B cells do not change in relation to exercise, suggesting that the suppression of immunoglobulin-secreting cells was not due to changes in numbers of B cells. Purified B cells produce plaques only after stimulation with EBV and in these cultures no exercise-induced suppression was found. It was concluded that the exercise-induced suppression of the PFC response was mediated by monocytes.

Cytokines.

Cytokines are polypeptide products of activated lymphocytes, monocytes and other cell types that participate in a variety of cellular immunoinflammatory responses. They act as molecular signals between immunocompetent cells. Cytokines can be detected in supernatants from stimulated BMNC or in plasma-samples. Supernatants from LPS-stimulated supernatants from BMNC isolated in relation to severe physical exercise showed increased production of IL-1a , IL-1b and IL-6 2 h after severe bicycle exercise lasting 1 h. This increase could at least partly be ascribed to increased fraction of monocytes among the stimulated BMNC suspension. Following a marathon increased IL-6 in plasma was found, others have

found increased plasma-TNF-a,IL-1 has been found in muscle tissue up to 5 days following eccentric muscle work.

Physical Exercise At Different Intensity.

The NK and LAK cell activities were enhanced during severe, moderate and light exercise (75%, 50% versus 25% of O2max, bicycle exercise). Two hours after severe exercise the NK and LAK cell activities and the IL-2 production of PHA-stimulated BMNC were suppressed. Following moderate and light exercise there are no immunosuppression. In essence it can be concluded that the immune system is enhanced during light, moderate and severe exercise, however, only severe exercise induces a post-exercise immune suppression. The intensity of exercise more than the duration seems to determine to which degree the immune system is enhanced during exercise. However, a combination of high intensity and long duration determines whether the immune system is suppressed following exercise.

Possible Mechanisms Of Action.

In relation to exercise the concentration in the blood of a number of stress hormones, including adrenaline, noradrenaline, growth hormone, beta-endorphins and cortisol are increased. When healthy, young male students were given intravenous injection of adrenaline to obtain plasma concentrations identical with those observed during bicycle exercise (75% of O2max, 1 hour) it was shown that the modulation of BMNC subsets, NK activity and lymphocyte function was closely mimicked by administration of adrenaline. However, adrenaline caused minor increase in neutrophil concentration as compared with that induced by exercise. In vivo injection of growth hormone in humans had no effect on BMNC subset, NK activity, cytokine production or lymphocyte function, but induced a highly significant increase in neutrophil count. When naloxone was administered in vivo to young women who underwent a maximal bicycle ergometer test, the rise in NK cell activity was no longer significant. In another study it was shown that when healthy young men were given an epidural analgesia that blocked the afferent impulses and inhibited increase in beta-endorphins and ACTH during exercise, this did not inhibit the exercise-induced increase in NK cell function or NK cell concentration. During bicycle exercise (75% of O2max, 1h) only a minor increase in cortisol concentration is found. This minor increase in cortisol concentration can not account for the exercise-induced immunomodulation, but cortisol may play a role in exercise training of longer duration. In conclusion adrenaline can account for the effect of physical exercise on NK activity, BMNC subsets and proliferative responses, while adrenaline together with growth hormone may be responsible for the increase in neutrophil concentration following exercise.

Another possible mechanism responsible for post-exercise immunodepression involves the glutamine. It is now accepted that there are at least 2 major sources for the provision of energy for lymphocytes and monocytes, these are glucose and glutamine. High rates of glutamine utilization occur even in resting or quiescent lymphocytes and glutamine is required for in vitro mitogen-stimulated proliferation of lymphocytes. It was proposed that, in vivo, the glutamine pathway in lymphocytes may be under external regulation and that this may be with respect to the supply of glutamine itself. Muscle tissue contains a high concentration of glutamine, it has the enzymatic capacity to synthesize glutamine and it is known to release glutamine into the bloodstream at a high rate. Muscle, therefore plays a vital role in maintenance of the rate of the key process of glutamine utilization in the immune cells and, consequently, skeletal muscle can be considered as part of the immune system. Athletes who perform very hard training are more susceptible to minor infections, this could hypothetically at least in part be due to the fact that under physical exercise the demands on muscle and other organs for glutamine are such that the lymphocytes are not sufficiently supplied with this energy source and that its function is therefore temporarily impaired. To further understand the relationship between working muscles and immune competent cells.

Training Degree

The influence of training degree on the immune system has not been as extensively studied as the effect of acute exercise. The main problem while examining if the immune system is dependent on training status is to eliminate the effect of acute physical exercise. However, most studies show that the effect of physical exercise lasting 1 h on the immune system, is undetectable 20 hours after. In studies on the immune system in trained versus untrained it is important that the test-persons are allowed only to perform minimal physical activity 20 hours before blood sampling. The NK cell activity were found to be elevated in 29 top-trained elite cyclists compared to sex- and age-matched controls, but no differences in T and B cell subsets or proliferative responses to mitogens and antigens were found.

TRAINING AND DISEASE.

Training During Acute Illness.

Exercising during the polio incubation period was shown to worsen the disease. This has later been confirmed in experimental animal studies. In mice infected with Coxsackie B virus enforced swimming raised mortality and virus replication in the heart markedly increased. There are, however, also studies showing that the clinical severity of viral hepatitis is not dependent on if the patient have performed physical activity at any time of the disease.

Training During Chronic Illness.

For many years patients with rheumatoid arthritis (RA) have been excluded from exercise training fearing that it would be harmful to their joints. In a recent controlled study patients with RA performed eight weeks bicycle training. The O2max increased in the training group, but there was no significant changes on the immune system. Studies in USA have shown that training of HIV-positive patients induced significant increase in the concentration of CD4+ cells.

Overtraining And Immune Function.

Chronic overtraining or staleness is characterized by a decreased performance at competition, severe fatigue and depression. It generally occurs when there is extensively heavy training over a long period of time with many competitive events and little time for recovery between the events. It has been proposed that overtraining is associated with immunodepression caused by decreased plasma-glutamine in trained persons. There are, however, no controlled studies on immune function in relation to overtraining, but anecdotal reports about increased frequency of respiratory infections. Furthermore there are no internationally accepted criteria for "overtraining" and it is therefore impossible to compare studies on this item.

Training and Infections.

Increased frequency of URTI has been reported in a study including 1550 runners who took part in a 56 kilometer race compared to matched controls. Those who ran faster race times reported more symptoms, indicating a dose-response relationship. Other showed that the marathon runners who actually ran the marathon reported more symptoms of URTI during the weeks following the race than similarly experienced runners who applied but did not participate in the race for reasons other than sickness. However, moderate exercise reduced the frequency of self-reported URTI symptom days in mildly obese women.

Training and Cancer.

Acute physical exercise influences especially the NK cells and as said these cells are thought to play an important role in the defense of malignant cells. It would therefore be of interest to know whether a relationship exist between training and development of cancer. The prevalence rate of cancers of the reproductive system (uterus, ovary, cervix and vagina) and breast cancer was determined for 5398 living alumnae, 2622 of whom were former college athletes. The relative risk non-athletes/athletes for cancers of the reproductive system was 2.53 and for breast cancer 1.83. It was concluded that long term athletic training may lower the risk of these cancer forms. The association between physical job activity and colon cancer was examined in a 19-year-follow-up study of 1.1 million Swedish men. The relative risk of colon cancer in men employed in sedentary occupations was estimated at 1.3.

Conclusion

Future studies will show whether the undesired effects of training on the immune system can be avoided by careful monitoring of the immune system. This could warn the athletes when they are more susceptible so they can modify their training and reduce risk of serious infections.

References

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