EVIDENCE OF THE EFFECT OF EXERCISE THERAPY ON IMMUNITY

The capability of the human body to resist almost all types of organisms or toxins that tend to damage the tissues and organs is called immunity. [1] The immune system is traditionally divided into two different branches - the adaptive immune system, the arm of the immune system that mounts a specific response to foreign antigens, and the innate immune system. [2] Acquired immunity does not develop until after the body is first attacked by a bacterium, virus, or toxin, often requiring weeks or months to develop the immunity. Innate immunity results from general processes, rather than from processes directed at specific disease organisms. [1] The immune system may be detailed as-: [3]

Table 1: Main elements of the immune system [3]Innate componentsAdaptive components

Cellular

Cellular

Natural killer cells (CD 16+, CD56+) Phagocytes (neutrophils, eosinophils, basophils, monocytes, macrophages)

T cells (CD3+, CD4+, CD8+) B cells (CD19+, CD20+, CD22+)

SolubleSoluble

Acute phase proteins Complement Lysozymes Cytokines (interleukins, interferons, colony-stimulating factor, tumour necrosis factors) Immunoglobulins IgG, IgA, IgD, IgE, IgM Memory

Over the past years, a variety of studies have demonstrated that exercise induces a considerable physiological change in the immune system. The interactions between exercise stress and the immune system provide a unique opportunity to link basic and clinical physiology. [4] In essence, a bout of exercise induces mobilization of immunocompetent cells to the circulation. [5]

Comparison of immune function in athletes and nonathletes reveals that the adaptive immune system is largely unaffected by athletic endeavour. It is the innate immune system which appears to respond differentially to the chronic stress of intensive exercise, with natural killer cell activity tending to be enhanced while neutrophil function is suppressed. [6]

Major findings of practical importance in terms of public health and athletic endeavour include: [7]

i. In response to acute exercise, natural killer (NK) cells, neutrophils, and macrophages (of the innate immune system) appear to be most responsive to the effects of acute exercise, both in terms of numbers and function. [7]

ii. In response to long-term exercise training, significant elevation in NK cell activity is seen but there is some indication that neutrophils function is suppressed during periods of heavy training. [7]

iii. Limited data suggest that unusually heavy acute or chronic exercise may increase the risk of upper respiratory tract infection (URTI), while regular moderate physical activity may reduce URTI symptomatology. [7]

iv. Work performance tends to diminish with most systemic infections, and clinical case studies and animal data suggest that infection severity, relapse, and myocarditis may result when patients exercise vigorously. [7]

v. Although regular exercise has many benefits for HIV-infected individuals, helper T cell counts and other immune measures are not enhanced significantly.[7]

vi. Data suggest that the incidence and mortality rates for certain types of cancer are lower among active subjects. The role of the immune system may be limited, however, depending on the sensitivity of the specific tumor to cytolysis, the stage of cancer, the type of exercise program, and many other complex factors. [7]

vii. As individuals age, they experience a decline in most cell- mediated and humoral immune responses. Two human studies suggest that immune function is superior in highly conditioned versus sedentary elderly subjects. [7]

Athletes who are undergoing heavy training regimens should realize that each of these factors has the potential to compound the effect that exercise stress is having on their immune systems. [7]

Thus, this essay covers these above mentioned points in details to understand the effect of exercise or exercise therapy on immunity in athletes along with some evidence in the non-athletic population in terms of the chronic illnesses.

Immune Functions in Sports

Exercise can have both positive and negative effects on immune function and susceptibility to minor illnesses. The relationship between exercise and susceptibility to infection has been modelled in the form of a J-shaped curve. This model suggests that, while engaging in moderate activity may enhance immune function above sedentary levels, excessive amounts of prolonged, high intensity exercise may impair immune function. [8] The adaptive immune system (resting state) in general seems to be largely unaffected by intensive and prolonged exercise training. The innate immune system appears to respond differentially to the chronic stress of intensive exercise.[6]

Figure 1: The J-Shaped Model [9]

However, one study gave an extended relationship of the J-shaped model; in the elite athletes suggesting the relationship is S-shaped postulating that previous infections, pathogen exposure, and other stressors than exercise may also influence the infection outcome. Observed infections in athletes can, therefore, be either the result of increased susceptibility to a novel pathogen, or more severe symptoms of an already established infection. [10

Figure 2: The S-Shaped Model [10]

Retrospective and prospective longitudinal studies have identified that the majority of elite athletes experience symptoms of URTI at a rate similar to the general population, however, the episodes of URTI in elite athletes do not follow the usual seasonal patterns of URTI but rather occur during or around competitions. Symptoms occur more frequently during the high intensity training and taper period prior to competitions in some sports, such as swimming and kayaking, while in other endurance sports, such as long distance running, URTI symptoms appear more frequently in the athletes after a competition. [9]

Figure 3: The Comparison of the Swimmers and Sedentary Controls for the Neutrophil Function [6]Pyne and colleagues, for example, reported that elite swimmers undertaking intensive training had a significantly lower neutrophil oxidative activity at rest than age- and gender-matched sedentary individuals, and that function was further suppressed during the period of strenuous training prior to national-level competition. Nonetheless, upper respiratory tract infection rates did not differ between the swimmers and sedentary control individuals. [6]

Acute Immune Response to Exercise Training

After a period of brief strenuous exercise following changes are seen in the immune function. [4]

Figure 4: The Effect of Strenuous Exercise on Immune Function [4]

Figure 5: The Effect of Strenuous Exercise on Cytokines [14]

Several authors have suggested that prolonged cardio respiratory endurance exercise leads to transient but clinically significant changes in immune function. During this open window of altered immunity (which may last between 3 and 72 hours, depending on the immune parameter measured as well as the type, duration and intensity of exercise), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. [6]

The open window theory is characterised by short term suppression of the immune system following an acute bout of endurance exercise. This window of opportunity may allow for an increase in susceptibility to upper respiratory illness (URI). [11]

Ten male A grade cyclists exercised for two hours at 90% of their second ventilatory threshold. Blood samples were collected pre-, immediately post-, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-exercise. Immune variables examined included total leukocyte counts, neutrophil function , lymphocyte subset counts , natural killer cell activity (NKCA), and NK phenotypes . This is the first study to show changes in immunological variables up to 8 hours post-exercise, including significant NK cell suppression, NK cell phenotype changes, a significant increase in total lymphocyte counts, and a significant increase in eosinophil cell counts all at 8 hours post-exercise. Suppression of total lymphocyte counts, NK cell counts and neutrophil phagocytic function following exercise may be important in the increased rate of URI in response to regularintense endurance training [11].

Figure 6: Immune System after Heavy, Prolonged Exertion

The production of secretory immunoglobulin A (SIgA) is the major effector function of the mucosal immune system providing the first line of defence against pathogens. To date, the majority of exercise studies have assessed saliva SIgA as a marker of mucosal immunity but more recently the importance of other antimicrobial proteins in saliva (e.g. -amylase, lactoferrin and lysozyme) has gained greater recognition. Acute bouts of moderate exercise have little impact on mucosal immunity but prolonged exercise and intensified training can evoke decreases in saliva secretion of SIgA. [9]

A study conducted to determine the effects of high-intensity endurance exercise on skin immunity by estimating secretory immunoglobulin A (SIgA) and staphylococci on skin surface. Seven healthy adult men performed bicycle exercise at 75% HRmax for 60 minutes from 2030 to 2130 hours. Secretory immunoglobulin A was obtained from 1 ml extraction liquids stirred with the microtube homogenizer in the open end of a polypropylene tube for 60 seconds. Skin surface samples were collected from the chest and the forearm. Secretory immunoglobulin A concentration on the forearm was significantly lower than on the chest The number of staphylococci was significantly higher on the forearm. The study concluded that high-intensity endurance exercise might depress immune function and enhance infectious risk on skin surface. Coaches should encourage their athletes to take a shower and change into clean clothes immediately after sports activities and athletes should maintain a clean skin surface to decrease the infectious risk on skin surface. [12]

In the true resting state (i.e. more than 24 h after their last training session) circulating lymphocyte numbers and functions appear to be broadly similar in athletes compared with non-athletes. In contrast, T and B cell functions appear to be sensitive to increases in training load in well trained athletes undertaking a period of intensified training, with decreases in circulating numbers of Type 1 T cells, reduced T cell proliferative responses and falls in stimulated B cell Ig synthesis reported. The cause of this depression in acquired immunity appears to be related to elevated circulating stress hormones, particularly cortisol, and alterations in the pro/ anti-inflammatory cytokine balance in response to exercise. This appears to result in a temporary inhibition of Type 1 T cell cytokine production with a relative dampening of the Type 1 (cell-mediated) response. [9]

Chronic Exercise and Immune Response

The immune function (resting levels) in athletes compared with non-athletes has more similarities than disparities, as reviewed.Natural immunity may be slightly increased, whereas neutrophil function has been reported to be slightly suppressed. The adaptive immune system (resting state) in general seems to be largely unaffected by intensive and prolonged exercise training. The innate immune system appears to respond differentially to the chronic stress of intensive exercise, with NK cell activity tending to be enhanced while neutrophil function is suppressed. [14]

Moderate Exercise and Immune Response

Nieman et al. examined the effect of 15 weeks of moderate-intensity exercise training on symptoms of URTI. Exercising subjects demonstrated shorter infectious episodes compared to their sedentary controls as measured by number of symptom-days per infectious episode. In addition, URTI symptom-days were negatively-correlated with increases in fitness. [13]

It is the Th1 response which is essential in combating the viral infection. Of particular importance is IL-12 which bridges the gap between innate and adaptive immunity by driving the differentiation of nave T helper cells (Th0) toward a Th1 phenotype characterized by the production of pro-inflammatory cytokines IL-2 and IFN-. Th1 secreted IL-2 promotes the maturation of antigen specific cytotoxic T-lymphocytes (CD8+ T cells) which recognize viral antigens on infected cells through the association of major histocompatibilty complex (MHC) I interactions with T cell receptors (TCR). Prolonged Th1 activity, however, may lead to respiratory tissue pathology, through increased cell damage and necrosis. Immune counter-regulatory mechanisms attempt to prevent Th1 induced pathology by shifting the Th cell phenotype towards Th2, characterized by the secretion of anti-inflammatory proteins IL-4 and IL-10. [13]

Effect of Exercise Therapy on Immunodeficiency Disorders or Inflammatory Conditions or Aging

It is generally believed that immune function undergoes degenerative changes with aging. This immune senescence potentially engenders an increased susceptibility to infectious diseases, malignancy, and autoimmune disorders in elderly people. By this immunosenescence, as the thymus involutes, T cells, which play a central role in cellular immune function, show the largest age-related alterations in distribution and function. [15]

Twenty-four elderly subjects were assigned to an exercise training group or a non-exercise control group. Subjects in EXC participated in exercise sessions 2 d_wk for 12 weeks. Subjects in CON maintained their normal physical activity levels during the study period. The study concluded that exercise training in elderly people is associated with increased CD28-expressing Tc cells and CD80-expressing monocytes. Therefore, exercise training might upregulate monocyte and T-cell-mediated immunity in elderly people. [15]

Chronic diseases are the largest cause of death in the world, led by cardiovascular disease followed by cancer, chronic lung diseases, and diabetes mellitus. Regular exercise offers protection against all-cause mortality, primarily by protection against atherosclerosis, Type 2 diabetes, colon cancer, and breast cancer. In addition, physical training is effective in the treatment of patients with ischemic heart disease, heart failure, Type 2 diabetes, and chronic obstructive pulmonary disease. [16]

The initial cytokines in the cytokine cascade are (named in order) TNF-, IL-1, IL-6, IL-1 receptor antagonist (IL-1ra), and soluble TNF-_ receptors (sTNFR). Chronic low-grade inflammation accompanies aging as well as some chronic medical disorders. During aging, increased plasma levels of TNF-, IL-6, IL-1ra, sTNF-R, and CRP have been demonstrated. Given that low-grade systemic inflammation is found in patients with obesity, insulin resistance, Type 2 diabetes, and atherosclerosis The first two cytokines in the cytokine cascade are TNF- and IL-1, which are produced locally. These cytokines are usually referred to as pro-inflammatory cytokines. TNF- and IL-1 stimulate the production of IL-6, which has been classified as both a pro- and an anti-inflammatory cytokine. The cytokine response to exercise differs from that elicited by severe infections. The fact that the classic pro-inflammatory cytokines, TNF- and IL-1, in general do not increase with exercise indicates that the cytokine cascade induced by exercise markedly differs from the cytokine cascade induced by infections. Typically, IL-6 is the first cytokine present in the circulation during exercise. The level of circulating IL-6 increases in an exponential fashion (up to 100-fold) in response to exercise and declines in the post-exercise period. [16]

Figure 7: In sepsis (A), the cytokine cascade within the first few hours consistsof TNF-, IL-1, IL-6, IL-1ra, TNF-R, and IL-10. The cytokine response toexercise (B) does not include TNF-_ and IL-1 but does show a marked increasein IL-6, which is followed by IL-1ra, TNF-R, and IL-10. Increased CRP levelsdo not appear until 812 h later.

In conclusion, regular exercise protects against diseases associated with chronic low-grade systemic inflammation. This long-term effect of exercise may be ascribed to the anti-inflammatory response elicited by an acute bout of exercise. [16]

Also, epidemiological evidence exists that supports the anecdotal impression1 that regular exercise increases resistance to infections such as the common cold, whereas hard training is associated with increased upper respiratory tract infections. Also, there is accumulating evidence that exercise is a lifestyle that offers some protection against malignancy. It has become clear that moderate exercise stimulates the immune system and may be somewhat responsible for exercise related reduction in illness. However, strenuous exercise induces immunosuppression in the recovery period and may explain the increased risk of infection in athletes. [14]

References:

1. Guyton, Arthur C, John E, Resistance of the Body to Infection: II. Immunity and Allergy In. Guyton, Arthur C, John E, (eds.) Textbook of Medical Physiology, 11th ed. Pennsylvania, Elsevier Saunders, 2006 p 439-450.

2. David J Lynn, Calvin Chan, Misbah Naseer, Melissa Yau, Raymond Lo, Anastasia Sribnaia, Giselle Ring,Jaimmie Que, Kathleen Wee, Geoffrey L Winsor, Matthew R Laird, Karin Breuer, Amir K Foroushani, Fiona SL Brinkman, Robert EW Hancock, Curating The Innate Immunity Interactome, BMC Systems Biology 2010, 4:117:1-14.

3. Roy J. Shephard,Pang N. Shek, Potential Impact Of Physical Activity And Sport On The Immune System A Brief Review, Br J Sp Med 1994; 28(4): 247-255.

4. Bente Klarlund Pedersen,Laurie Hoffman-Goetz, Exercise and the Immune System: Regulation, Integration, and Adaptation, Physiological Reviews, Vol. 80, No. 3, July 2000, 1055-1081.

5. Pedersen, B. K., Bruunsgaard, H., Jensen, M., Toft, A. D., Hansen, H., & Ostrowski, K. (1999). Exercise and the immune system - Influence of Nutrition and Ageing. Journal of Science and Medicine in Sport 2(3): 234-252.

6. David C. Nieman,Bente K. Pedersen, Exercise and Immune Function: Recent Developments, Sports Med 1999 Feb; 27 (2): 73-80.

7. D.C.Nieman, Exercise Immunology: Practical Applications, Int J Sports Med 1997; 18:91-1008. Michael Gleeson, Immune Function in Sport and Exercise, J Appl Physiol 103: 693699, 2007.

9. Elena Papacosta, Michael Gleeson, Effects of Intensified Training and Taper on Immune Function, Rev Bras Educ Fs Esporte,2013;27(1):159-76.

10. C. Malm, Susceptibility to Infections in Elite Athletes: The S-Curve, Scand J Med Sci Sports 2006: 16: 46.

11. Kakanis MW,Peake J,Brenu EW,Simmonds M,Gray B,Hooper SL,Marshall-Gradisnik SM, The Open Window Of Susceptibility To Infection After Acute Exercise In Healthy Young Male Elite Athletes. Exercise Immunology Review, 2010; 16:119-37.

12. Nobuhiko Eda, Kazuhiro Shimizu, Satomi Suzuki, Yoko Tanabe, Eunjae Lee,Takao Akama Altered Secretory Immunoglobulin A On Skin Surface After Intensive Exercise, J Strength Cond Res 27(9): 25812587,2013.

13. Stephen A. Martin, Brandt D. Pence, Jeffrey A. Woods, Exercise and Respiratory Tract Viral Infections, Exerc Sport Sci Rev. 2009 October ; 37(4): 157164.

14. Bente Klarlund Pedersen, Anders Dyhr Toft, Effects of Exercise On Lymphocytes And Cytokines, Br J Sports Med 2000; 34:246251.

15. Kazuhiro Shimizu,Natsumi Suzuki,Tomoko Imai, Katsuji Aizawa,Hideyuki Nanba,Yukichi Hanaoka,Shinya Kuno,Noboru Mesaki, Ichiro Kono,Takao Akama, Monocyte And T-Cell Responses To Exercise Training In Elderly Subjects, J Strength Cond Res 25(9): 25652572, 2011.

16. Anne Marie W. Petersen, Bente Klarlund Pedersen, The Anti-Inflammatory Effect Of Exercise, J Appl Physiol 98: 11541162, 2005.

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