define the open window hypothesis

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The open window of susceptibility to infection after acute exercise in healthy young male elite athletes

Affiliation.

1 Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia. [email protected]
PMID: 20839496

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). Many studies have indicated a decrease in immune function in response to exercise. However many studies do not indicate changes in immune function past 2 hours after the completion of exercise, consequently failing to determine whether these immune cells numbers, or importantly their function, return to resting levels before the start of another bout of exercise. Ten male 'A' grade cyclists (age 24.2 +/- 5.3 years; body mass 73.8 +/- 6.5 kg; VO2peak 65.9 +/- 7.1 mL x kg(-1) x min(-1)) 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 (oxidative burst and phagocytic function), lymphocyte subset counts (CD4+, CD8+, and CD16+/56+), natural killer cell activity (NKCA), and NK phenotypes (CD56dimCD16+, and CD56(bright)CD16-). There was a significant increase in total lymphocyte numbers from pre-, to immediately post-exercise (p < 0.01), followed by a significant decrease at 2 hours post-exercise (p < 0.001). CD4+ T-cell counts significantly increased from pre-exercise, to 4 hours post- (p < 0.05), and 6 hours post-exercise (p < 0.01). However NK (CD16+/56+) cell numbers decreased significantly from pre-exercise to 4 h post-exercise (p < 0.05), to 6 h post-exercise (p < 0.05), and to 8 h post-exercise (p < 0.01O). In contrast, CD56(bright)CD16- NK cell counts significantly increased from pre-exercise to immediately post-exercise (p < 0.01). Neutrophil oxidative burst activity did not significantly change in response to exercise, while neutrophil cell counts significantly increased from pre-exercise, to immediately postexercise (p < 0.05), and 2 hours post-exercise (p < 0.01), and remained significantly above pre-exercise levels to 8 hours post-exercise (p < 0.01). Neutrophil phagocytic function significantly decreased from 2 hours post-exercise, to 6 hours post- (p < 0.05), and 24 hours post-exercise (p < 0.05). Finally, eosinophil cell counts significantly increased from 2 hours post to 6 hours post- (p < 0.05), and 8 hours post-exercise (p < 0.05). 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 regular intense endurance training.

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Home > Books > Current Issues in Sports and Exercise Medicine

Exercise and Immunity

Submitted: 08 May 2012 Published: 15 May 2013

DOI: 10.5772/54681

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Current Issues in Sports and Exercise Medicine

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Author Information

Hilde grindvik nielsen *.

University College of Health Sciences – Campus Kristiania, Oslo, Norway

*Address all correspondence to: [email protected]

1. Introduction

Epidemiological evidence suggests a link between the intensity of the exercise and the occurrence of infections and diseases. The innate immune system appears to respond to chronic stress of intensive exercise by increased natural killer cell activity and suppressed neutrophil function. The measured effects of exercise on the innate immune system are complex and depend on several factors: the type of exercise, intensity and duration of exercise, the timing of measurement in relation to the exercise session, the dose and type of immune modulator used to stimulate the cell in vitro or in vivo , and the site of cellular origin. When comparing immune function in trained and non-active persons, the adaptive immune system is largely unaffected by exercise.

Physical activity in combination with infections is usually associated with certain medical risks, partly for the person who is infected and partly for the other athletes who may be infected. The risk of infection is greatest in team sports, but also in other sports where athletes have close physical contact before, during and after training and competitions.

This chapter starts with a short introduction of the immune system followed by a description of free radicals’ and antioxidants’ role in the immune system and how they are affected by physical activity. The chapter will also focus on need of antioxidant supplementation in combination with physical activity. The different theories regarding the effect of physical activity on the immune system will be discussed, along with advantages and disadvantages of being active, and finally effects of physical activity on the immune system are described.

2. The immune system

The immune system is large and complex and has a wide variety of functions. The main role of the immune system is to defend people against germs and microorganisms. Researchers are constantly making new discoveries by studying the immune system. There are several factors which influence or affect the daily functioning of the immune system: age, gender, eating habits, medical status, training and fitness level.

Bacteria and viruses can do harm to our body and make us sick. The immune system does a great job in keeping people healthy and preventing infections, but problems with the immune system can still lead to illness and infections. The immune system is separated in two functional divisions: the innate immunity, referred to as the first line of defense, and the acquired immunity, which, when activated, produces a specific reaction and immunological memory to each infectious agent.

2.1. The innate immune system

The innate immune system consists of anatomic and physiological barriers (skin, mucous membranes, body temperature, low pH and special chemical mediators such as complement and interferon) and specialized cells (natural killer cells and phagocytes, including neutrophils, monocytes and macrophages [ 1 ] ( Table 1) . When the innate immune system fails to effectively combat an invading pathogen, the body produces a learned immune response.


Physical barriers	Epithelial cell barriers Mucus	Humoral	Antibody Memory
Chemical barriers	Complement Lysozyme pH of body fluids Acute phase proteins	Cell-mediated	Lymphocytes T cells B cells
White blood cells	Monocytes/macrophages Granulocytes Natural killer cells

Innate and adaptive immunity (Source: Modified after Mackinnon, 1999).

Leukocytes (also known as white blood cells) form a component of the blood. They are mainly produced in the bone marrow and help to defend the body against infectious disease and foreign materials as part of the immune system. There are normally between 4x10 9 and 11x10 9 white blood cells in a liter of healthy adult blood [ 2 ] ( Table 2) . The leukocytes circulate through the body and seek out their targets. In this way, the immune system works in a coordinated manner to monitor the body for substances that might cause problems. There are two basic types of leukocytes; the phagocytes, which are cells that chew up invading organisms, and the lymphocytes, which allow the body to remember and recognize previous invaders [ 1 ].

The granulocytes (a type of phagocyte that has small granules visible in the cytoplasm) consist of polymorphonuclear cells (PMN) which are subdivided into three classes; neutrophils, basophils, and eosinophils ( Table 2) . The neutrophils are the most abundant white blood cells, they account for 65 to 70% of all leukocytes [ 2 ]. When activated, the neutrophils marginate and undergo selectin-dependent capture followed by integrin-dependent adhesion, before migrating into tissues. Leukocytes migrate toward the sites of infection or inflammation, and undergo a process called chemotaxis. Chemotaxis is the cells’ movement towards certain chemicals in their environment.

Granulocytes along with monocytes protect us against bacteria and other invading organisms, a process that is called phagocytosis (ingestion). Only cells participating in the phagocytosis are called phagocytes. The granulocytes are short lived. After they are released from the bone marrow they can circulate in the blood for 4 to 8 hours. Then they leave the blood and enter into the tissues and can live there for 3 to 4 days. If the body is exposed for serious infections, they live even shorter. The numbers of granulocytes in the blood depends on the release of mature granulocytes from the bone marrow and the body’s need for an increased number of granulocytes (i.e. during infection). The neutrophil granulocytes are very important in the fight against infections. If a bacterial infection occurs, the neutrophils travel to the infected area and neutralize the invading bacteria. In those cases, the total number of neutrophil granulocytes is high. The eosinophil granulocytes do not phagocytize and are more important in allergic reactions. The same is the case with the basophil granulocytes; they contain histamine and heparin and are also involved in allergic reactions.

Monocytes (another type of white blood cell) are produced by the bone marrow from hematopoietic stem cell precursors called monoblasts. Monocytes make up between 3 and 8% of the leukocytes in the blood [ 2 ], and circulate in the blood for about 1 to 3 days before moving into tissues throughout the body. Monocytes are, like the neutrophil granulocytes, effective phagocytes, and are responsible for phagocytosis of foreign substances in the body. When the monocytes leave the blood barrier, they differentiate in the tissues and their size and characteristics change. These cells are named macrophages. Macrophages are responsible for protecting tissues from foreign substances but are also known to be the predominant cells involved in triggering atherosclerosis. Macrophages are cells that possess a large smooth nucleus, a large area of cytoplasm and many internal vesicles for processing foreign material.


Leukocytes	4 500 – 11 000
-Neutrophils	4 000 – 7 000
-Lymphocytes	2 500 – 5 000
-Monocytes	100 – 1 000
-Eosinophils	0 – 500
-Basophils	0 - 100

Normal values of circulating blood cell levels. Rhoades, 2003.

2.2. The acquired immune system

The second kind of protection is called adaptive (or active) immunity [ 2 ]. This type of immunity develops throughout our lives. Adaptive immunity involves the lymphocytes and develops from early childhood. Adults are exposed to diseases or are immunized against diseases through vaccination. The main cells involved in acquired immunity are the lymphocytes, and there are two kinds of them: B lymphocytes and T lymphocytes; both are capable of secreting a large variety of specialized molecules (antibodies and cytokines) to regulate the immune response. T lymphocytes can also be engaged in direct cell-on-cell warfare ( Table 1) . Lymphocytes start out in the bone marrow where they reside and mature into B cells. Lymphocytes can also leave and travel to the thymus gland and mature into T cells. B lymphocytes and T lymphocytes have separate functions: B lymphocytes are like the body's military intelligence system, seeking out their targets and organizing defenses, while T cells are like the soldiers, destroying the invaders that the intelligence system has identified [ 1 ].

3. C-Reactive Protein (CRP)

C-reactive protein (CRP) is an acute phase protein presented in the blood and rises in response to inflammation. Its physiological role is to bind to phosphocholine expressed on the surface of dead or dying cells to activate the complement system. The complement system is the name of a group of plasma proteins, which are produced by the liver, and is an important part of the innate immune system. The complement system has an important role in the fight against bacteria and virus infections.

A blood test is commonly used in the diagnosis of infections. The level of CRP rises when an inflammatory reaction starts in the body. Blood for analysis may be taken by a finger prick and can be analyzed quickly. The level of CRP increases in many types of inflammatory reactions, both infections, autoimmune diseases and after cellular damage. After an infection, it takes almost half a day before the CRP increase becomes measurable. During the healing process the level of CRP decreases in a relatively short time (½h ~ 12-24 hours in the blood).

The levels of CRP increase more during bacterial infections than viral and can thus be used to distinguish between these two types of infections. Bacterial infection can increase CRP to over 100 mg/L, while during viral infections the values are usually below 50 mg/L. This distinction between bacteria and viruses are often useful because antibiotics (such as penicillin) have no effect on viral infections, but can often be very useful in bacterial infections.

Recent investigations suggest that physical activity reduce CRP levels. Higher levels of physical activity and cardiorespiratory fitness are consistently associated with 6 to 35% lower CRP levels [ 3 ]. Longitudinal training studies have demonstrated reductions in CRP concentration from 16 to 41%, an effect that may be independent of baseline levels of CRP, body composition, and weight loss [ 3 ].

The mechanisms behind the role physical activity plays in reducing inflammation and suppressing CRP levels are not well defined [ 4 ]. Chronic physical activity is associated with reduced resting CRP levels due to multiple mechanisms including: decreased cytokine production by adipose tissue, skeletal muscles, endothelial and blood mononuclear cells, improved endothelial function and insulin sensitivity, and possibly an antioxidant effect [ 4 ]. A short-term increase in serum CRP has been observed after strenuous exercise [ 4 ]. This is due to an exercise-induced acute phase response, facilitated by the cytokine system, mainly through interleukin- 6 (IL-6). Exercise training may influence this response, whereas there is also a homeostatic, anti-inflammatory counter-acute phase response after strenuous exercise.

The most common infections in sports medicine are caused by bacteria or viruses. Infections are very common, particularly infections in the upper respiratory tract [ 5 ]. Asthma/airway hyper-responsiveness (AHR) is the most common chronic medical condition in endurance trained athletes (prevalence of about 8% in both summer and winter athletes) [ 6 ]. Inspiring polluted or cold air is considered a significant aetiological factor in some but not all sports people [ 6 ]. The symptoms of infections are healthy, which means that the body is reacting normally. The common cold is generally caused by virus infections and is self-healing and most of the times free of problems, but sometimes bacteria will follow and cause complications (e.g. ear infections). Mononucleosis (“kissing disease”) and throat infections are usually caused by various viruses. Infections in the heart muscle (myocarditis) can be due to both virus and bacteria and represent a problematic area within the field of sports medicine [ 7 ].

4. Cytokines

Cytokines are substances secreted by certain immune system cells that carry signals locally between cells, and thus have an effect on other cells. Cytokines are the signaling molecules used extensively in cellular communication. The term cytokine encompasses a large and diverse family of polypeptide regulators that are produced widely throughout the body by cells of diverse embryological origin.

A pro-inflammatory cytokine is a cytokine which promotes systemic inflammation, while an anti-inflammatory cytokine refers to the property of a substance or treatment that reduces inflammation. TNF-α, IL-1β and IL-8 are some examples of pro-inflammatory cytokines. IL-6 and IL-10 belong to the anti-inflammatory category. IL-6 can be both pro-inflammatory and anti-inflammatory.

Heavy physical activity produces a rapid transient increase in cytokine production and entails increases in both pro-inflammatory (IL-2, IL-5, IL-6, IL-8, TNFα) and anti-inflammatory (IL-1ra, IL-10) cytokines. Interleukin-6 (IL-6) is the most studied cytokine associated with physical exercise [ 8 ]. Many studies have investigated the effects of different forms and intensities of exercise on its plasma concentration and tissue expression [ 9 - 11 ]. The effects of physical exercise seem to be mediated by intensity [ 10 ] as well as the duration of effort, the muscle mass involved and the individual’s physical fitness level [ 12 ].

Increases in IL-6 over 100 times above resting values have been found after exhaustive exercise such as marathon races, moderate exercise (60–65% VO 2max ) and after resistance exercise, and may last for up to 72 h after the end of the exercise [ 13 ]. One explanation for the increase in IL-6 after exhaustive exercise is that IL-6 is produced by the contracting muscle and is released in large quantities into the circulation. Studies have shown that prolonged exercise may increase circulating neutrophils’ ability to produce reactive oxygen metabolites, but the release of IL-6 after exercise has been associated with neutrophil mobilization and priming of the oxidative activity [ 14 ]. Free radical damaging effects on cellular functions are for IL-6 seen as a key mediator of the exercise-induced immune changes [ 13 ].

5. Free radicals

Free radicals are any atom with an unpaired electron. Reactive oxygen species (ROS) are all free radicals that involve oxygen. ROS formation is a natural ongoing process that takes place in the body, while the antioxidant defense is on duty for collecting and neutralizing the excess production of oxygen radicals. Many sources of heat, stress, irradiation, inflammation, and any increase in metabolism including exercise, injury, and repair processes lead to increased production of ROS [ 15 ]. ROS have an important function in the signal network of cellular processes, including growth and apoptosis, and as killing tools of phagocytising cells [ 15 ]. The granulocytes and the monocytes produce ROS like superoxide anion (O 2 - ), hydrogen peroxide (H 2 O 2 ), peroxynitrite (ONOO - ), and hydroxyl radical (OH ).

Superoxide anion (O 2 - ), an unstable free radical that kills bacteria directly, is produced through the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated oxidative burst reaction [ 16 ]. The superoxide anion also participates in the generation of secondary free radical reactions to generate other potent antimicrobial agents, e.g. , hydrogen peroxide [ 16 ]. Superoxide anion is generated in both intra- and extracellular compartments and when nitric oxide (NO) and O 2 - react with each other, peroxynitrite (ONOO - ) can form very rapidly [ 17 ]. Peroxynitrite is a strong oxidation which damages DNA, proteins and other cellular elements. The stability of ONOO - allows it to diffuse through cells and hit a distant target. Intracellular ONOO - formation will usually minimize by increased intracellular superoxide dismutase (SOD) activity [ 17 ] ( Figure 1) .

A simplified overview of the generation of ROS.

Regular physical activity and exercise at moderate levels are important factors for disease prevention [ 18 ]. Strenuous exercise leads to the activation of several cell lines within the immune system, such as neutrophils, monocytes, and macrophages, which all are capable of producing ROS [ 19 ]. During resting conditions, the human body produces ROS to a level which is within the body’s capacity to produce antioxidants. During endurance exercise, there is a 15- to 20-fold increase in whole body oxygen consumption, and the oxygen uptake in the active muscles increases 100- to 200-fold [ 20 ]. This elevation in oxygen consumption is thought to result in the production of ROS at rates that exceed the body’s capacity to detoxify them. Oxidative stress is a result of an imbalance between the production of ROS and the body’s ability to detoxify the reactions (producing antioxidants). In the literature, there is disagreement whether or not oxidative stress and subsequent damage associated with exercise is harmful or not. This ambiguity may partly be explained by the methods chosen for the different investigations [ 18 ]. Experimental and clinical evidence have linked enhanced production of ROS to certain diseases of the cardiovascular system including hypertension, diabetes and atherosclerosis [ 21 ]. Oxidized LDL inhibits endothelial ability to produce nitric oxide (NO). This is unfortunate since NO increases blood flow, allows monocytes to adhere to the endothelium, decreases blood clots and prevents oxidation of LDL. High amount of free radicals promotes the atherosclerosis process by oxidation of LDL. Free radicals react with substances in the cell membrane and damage the cells that line the blood vessels. This means that the fat in the blood can more easily cling to a damaged vessel wall. If there are sufficient antioxidants present, it is believed that the harmful processes in the blood vessels can be slowed down. On the other hand, free radicals are not always harmful, but can serve a useful purpose in the human body. The oxygen radicals are necessary compounds in the maturation process of the cellular structure. Complete elimination of the radicals would not only be impossible, but also harmful [ 22 ].

6. Antioxidants

An antioxidant is a chemical compound or a substance such as vitamin E, vitamin C, or beta carotene, thought to defend body cells from the destructive effects of oxidation. Antioxidants are important in the context of organic chemistry and biology: all living cells contains a complex systems of antioxidant compounds and enzymes, which prevent the cells by chemical damages due to oxidation. There are many examples of antioxidants: e.g. the intracellular enzymes like superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, catalase, the endogenous molecules like glutathione (GSH), sulfhydryl groups, alpha lipoic acid, Q 10, thioredoxin, the essential nutrients: vitamin C, vitamin E, selenium, N-acetyl cysteine, and the dietary compounds: bioflavonoids, pro-anthocyanin.

The task of antioxidants is to protect the cell against the harmful effects of high production of free radicals. We can influence our own antioxidant defenses by eating food that contains satisfactory amounts of antioxidants ( Table 3) . A diet containing polyphenol antioxidants from plants is necessary for the health of most mammals [ 23 ]. Antioxidants are widely used as ingredients in dietary supplements that are used for health purposes, such as preventing cancer and heart diseases [ 23 ]. However, while many laboratory experiments have suggested benefits of antioxidant supplements, several large clinical trials have failed to clearly express an advantage of dietary supplements. Moreover, excess antioxidant supplementation may be harmful [ 22 ].


Vitamin C	Fruit and vegetables
Vitamin E	Oils
Polyphenols/flavonoids	Tea, coffee, soya, fruit, chocolates, red wine and nuts
Carotenoids	Fruit and vegetables

Examples of food with a high content of antioxidants.

Neutrophils are protected against ROS by SOD, catalase, glutathione peroxidase, and glutathione reductase. The exogenous antioxidants include among others vitamin E (∝-tocopherol), vitamin C and coenzyme Q. The lipid-soluble α-tocopherol is considered the most efficient among the dietary antioxidants, because it contributes to membrane stability and fluidity by preventing lipid peroxidation. Coenzyme Q or ubiquinon is also lipid-soluble, and has the same membrane stabilization effect as vitamin E. Ascorbic acid or vitamin C (water-soluble) is, however, the predominant dietary antioxidant in plasma. The apprehension of increased rates of ROS production during exercise is part of the rationale why many athletes could theoretically profit by increasing their intake of antioxidant supplements beyond recommended doses. Table 4 shows an overview of the localization and function to the enzymatic antioxidants which protects the cell against oxidative stress.


Superoxid oxidase	Mitochondria, cytosol	Superoxid anion
Glutathion peroxidase	Mitochondria, cytosol, cell membrane	Reduces H O
Catalase	Perisosomes	Reduces H O
Glutaredoksine	Cytolsol	Protects and repair proteins and no-proteins thioles

An overview of enzymatic antioxidants and associated free radicals.

Non-enzymatic antioxidant reserve is the first line of defense against free radicals ( Table 5) . Three non-enzymatic antioxidants are of particular importance. 1) Vitamin E, the major lipid-soluble antioxidant which plays a vital role in protecting membranes from oxidative damage, 2) Vitamin C or ascorbic acid which is a water-soluble antioxidant and can reduce radicals from a variety of sources. It also appears to participate in recycling vitamin E radicals. Interestingly, vitamin C can also function as a pro-oxidant under certain circumstances. 3) Glutathione, which is seen as one of the most important intracellular defense against damage by reactive oxygen species.

In addition to these "big three", there are numerous small molecules that function as antioxidants. Examples include bilrubin, uric acid, flavonoids, and carotenoids.


Vitamin C	Aqueous	Scavenger free radicals
Vitamin E	Cell membrane	Reduces free radicals to less active substances
Carotenes	Cell membrane	Scavenger free radicals
Glutathione	Non- proteins thiols	Scavenger free radicals
Flavenoids/polyphenoles	Cell membrane	Scavenger free radicals
Ubuquinon	Cell membrane	Scavenger free radicals

An overview of non-enzymatic antioxidants and associated free radicals.

The optimal aim is an equal production of free radicals together with equal production of antioxidants ( Figure 2) . There is broad evidence suggesting that physical exercise affects the generation of ROS in leukocytes [ 3 , 15 ] which may induce muscle damage [ 12 , 23 ] and may explain phenomena like decreased physical performance, muscular fatigue, and overtraining [ 16 ]. Detrimental influences of free radicals are due to their oxidizing effects on lipids, proteins, nucleic acids, and the extracellular matrix. However, the available data to support the role of ROS in relation to physical exercise are highly inconsistent and partly controversial. These controversies are probably due to the different methodologies used to assess ROS, generally including time-demanding and laborious cell isolation procedures and subsequent cell culturing that most certainly affects the ROS status of these cells in an uncontrolled and unpredictable manner. The type of physical activity studied also varied considerably and probably influenced the results presented.

The balance between antioxidants and the amount of free radicals.

7. Physical activity and antioxidant supplementation

A very important question in this context is whether exercise-induced oxidative stress is associated with an increased risk of diseases. The great disparities as to whether ROS production increases or decreases after physical exercise should be considered when comparing different studies of antioxidant supplementation and exercise-induced oxidative stress; likewise the differences in antioxidant dosages used, the biological potency of different forms of the same antioxidant and the different manufacturers’ products. The main explanations for the inconsistencies of the effect of antioxidant supplementation on oxidative stress seems to be due to the different assay techniques used to measure in vitro neutrophil ROS production, the exercise mode [ 22 ], and the fitness levels of participants.

The human body has an elaborate antioxidant system that depends on the endogenous production of antioxidant compounds like enzymes, as well as the dietary intake of antioxidant vitamins and minerals. Still, there is not enough knowledge at present as to whether the body’s natural antioxidant defense system is sufficient to counteract the induced increase of free radicals during physical exercise or if additional supplements are needed [ 27 ].

Until now, the majority of investigations address the effects of exercise on markers of oxidative stress, and not the occurrence of disease. However, most research points to a beneficial effect of regular moderate-to-vigorous physical activity on disease prevention [ 22 ] [ 27 ].

8. Different methods for detection of free radicals and antioxidants

The work of getting reliable and validated measures of both free radicals and anti-oxidants is still ongoing. The most common methods for detecting free radicals are: 1) Electron spin resonance (ESR) and “spin trapping”, which quantify and generate free radicals. This technique makes it possible to identify the cells in their own milieu. 2) Flow cytometry, which is a technique for counting, examining and sorting microscopic particles suspended in a stream of fluid, and 3) Chemiluminiscence Luminol, which is a method used to detect free radicals with chemical reactions ( Table 6) .


Electron spin resonance	Free radicals; O , OH - intra cellular
Flow cytometry	Free radicals; O , H O , ONOO - intra cellular
Cheluminiscence	Free radicals - extra cellular

An overview of some of the methods used for detection of free radicals.

Part of the problem with measuring free radicals is that cells are very reactive and short-lived. Most methods used today are not sensitive enough and it is not unusual to find false signals and interference from other substances. It is therefore difficult to compare various studies involving the use of different methods, because it is difficult to know if the different laboratories have measured the same substances ( Figure 3) .

No “perfect” methods.

Several methods have been introduced to measure the plasma total antioxidant capacity (TAC) [ 24 ], and there are several techniques for quantifying TAC. The most widely used methods for TAC measurements are 1) the colorimetric method (a method for determining concentrations of colored compounds in a solution), 2) the fluorescence method (a method for detecting particular components with exquisite sensitivity and selectivity) and 3) the chemiluminescence method (a method for observation of a light (luminescence) as a result of a chemical reaction) [ 24 - 26 ].

9. Effect of exercise on immunity

9.1. the j- curve.

Although the consensus is lacking in some areas, there is sufficient agreement to make some conclusions about the effects of exercise on the immune system. Numerous publications before 1994 resulted in assumption that a J-shaped relationship [ 27 ] best described the relationship between infection sensitivity and exercise intensity. The hypothesis is based on cross-section analysis of a mixed cohort of marathon runners, sedentary men and women as well as longitudinal studies on athletes and non-athletes [ 28 - 30 ] that showed increased immunity with increased exercise training. However, one study [ 31 ] observed a lower risk for upper respiratory tract infections (URTI) in over-trained compared with well-trained athletes. Previous infections, pathogen exposure, and other stressors apart from exercise may also influence immune response and therefore interpretations of the results of such studies need to be made with care. According to the J-shaped curve, moderate amounts of exercise may enhance immune function above sedentary levels, while excessive amounts of prolonged high intensity exercise may impair immune function [ 13 ] ( Figure 4) .

The risk of infection in relation to physical activity. Nieman et al.,1994.

9.2. The S-curve

With regard to induced infections in animals, the influence of any exercise intervention appears to be pathogen specific, and dependent on the species, age, and sex of the animals selected for study, and the type of exercise paradigm. Individuals exercising moderately may lower their risk of upper respiratory tract infections (URTI) while those undergoing heavy exercise regimens may have higher than normal risk. When including elite athletes in the J-curve model, the curve is suggested to be S-shaped [ 30 ] ( Figure 5) . This hypothesis states that low and very high exercise loads increases the infection odds ratio, while moderate and high exercise loads decreases the infection odds ratio, but this needs to be verified by compiling data from a larger number of subjects [ 30 ].

S-shaped relationship between training load and infection rate. Malm et al., 2006.

10. The open window theory

The J-curve relationship has been established among scientists, coaches, and athletes. However, the immunological mechanism behind the proposed increased vulnerability to upper respiratory tract infections (URTI) after strenuous physical exercise is not yet described [ 32 ]. The phenomenon is commonly referred to as the ‘‘open window’’ for pathogen entrance [ 33 ] ( Figure 6) . The “open window” theory means that there is an 'open window' of altered immunity (which may last between 3 and 72 hours), in which the risk of clinical infection after exercise is excessive [ 34 , 35 ]. This means that running a marathon or simply engaging in a prolonged bout of running, increases your risk of contracting an upper-respiratory system infection. Fitch [ 6 ] reported that Summer Games athletes who undertake endurance training have a much higher prevalence of asthma compared to their counterparts that have little or no endurance training. Years of endurance training seems to incite airway injury and inflammation [ 6 ]. Such inflammation varies across sports and the mechanical changes and dehydration within the airways, in combination with levels of noxious agents like airborne pollutions, irritants or allergens may all have an effect [ 6 ].

It is well known that exhausting exercise can result in excessive inflammatory reactions and immune suppression, leading to clinical consequences that slow healing and recovery from injury and/or increase your risk of disease and/or infection [ 18 ]. Comparing the immune responses to surgical trauma and stressful bouts of physical activity, there are several parallels; activation of neutrophils and macrophages, which accumulate free radicals [ 18 ] [ 33 ], local release of proinflammatory cytokines [ 34 ], and activation of the complement, coagulation and fibrinolytic cascades [ 35 ]. Both physical and psychological stress have been regarded as potent suppressors of the immune system [ 36 ], which leaves us with many unanswered questions about whether or not physical exercise is beneficial or harmful for the immune system [ 37 ].

One of the most studied aspects of exercise and the immune system is the changes in leukocyte numbers in circulating blood [ 36 - 39 ]. The largest changes occur in the number of granulocytes (mainly neutrophils). The mechanisms that cause leukocytosis can be several: an increased release of leukocytes from bone marrow storage pools, a decreased margination of leukocytes onto vessel walls, a decreased extravasation of leukocytes from the vessels into tissues, or an increase in number of precursor cells in the marrow [ 2 ]. During exercise, the main source of circulatory neutrophils are primary (bone marrow) and secondary (spleen, lymph nodes, gut) lymphoid tissues, as well as marginated neutrophils from the endothelial wall of peripheral veins [ 40 , 41 ]. Fry et al., [ 38 ] observed that neutrophil number increases proportionally with exercise intensity following interval running over a range of intensities. Exercise intensity, duration and/or the fitness level of the individual may all play a role in regards to the degree of leukocytosis occurring [ 42 - 44 ]. One way to cure physical stress for the immune system is to increase the total number of leukocytes for fighting the infection and for normalizing the homeostasis. The argument that exercise induces an inflammation like response is also supported by the fact that the raised level of cytokines result in the increased secretion of adrenocorticotrophic hormone (ACTH), which induces the enhancement of systemic cortisol level. Monocytes and thrombocytes are responsible for the initiation of exercise induced acute phase reaction [ 41 ].

The open window theory. Pedersen & Ullum, 1994.

11. Physical activity – A stimulator and an inhibitor to the immune system

Primarily physical activity stimulates the immune system and strengthens the infection defense. There are indications that untrained people who start exercising regularly get a progressively stronger immune system and become less susceptible to infections [ 45 ]. Intensive endurance training or competition which last for at least one hour stimulates the immune system sharply in the beginning, but a few hours after exercise/competition, a weakened immune system results [ 46 ]. This means that the immune system in the hours after hard exercise/competition has a weakened ability to fight against bacteria and viruses and the susceptibility to infection is temporarily increased [ 47 ]. This effect is seen in both untrained and trained individuals. How long this period lasts for is partly dependent of the intensity and duration of the exercise, and is very individual. The “open period” can last from a few hours up to a day. If such a long-term activity session happens too frequently, it can cause prolonged susceptibility to infections and increased risk of complications if an infection is acquired. Planning of training/activity/competition and rest periods is therefore very important and should be done on an individual basis.

12. Summary

The body's immune system fights all that it perceives as a foreign body. The immune system is separated in two functional divisions: the innate immunity, referred to as the first line of defense, and acquired immunity, which produces a specific reaction and immunological memory to each infectious agent.

A very important question in this context is whether exercise-induced oxidative stress is associated with an increased risk of disease. The great disparities as to whether ROS production increases or decreases after physical exercise should be considered when comparing different studies of antioxidant supplementation and exercise-induced oxidative stress; likewise the differences in antioxidant dosages used, the biological potency of different forms of the same antioxidant and the different manufacturers products. The main explanations for the inconsistencies as to the effect of antioxidant supplementation on oxidative stress seems to be due to the different assay techniques used to measure the ROS production, the exercise mode, and the fitness levels of participants.

The J-curve theory describes that moderate exercise loads enhance immune function above sedentary levels, while excessive amounts of prolonged high intensity exercise may impair immune function. However, the immunological mechanism behind the proposed increased vulnerability to upper respiratory tract infections (URTI) after strenuous physical exercise is not yet described. This phenomenon is referred to as the ‘‘open window’’. The “open window” theory means that there is an 'open window' of altered immunity (which may last between 3 and 72 hours) in which the risk of clinical infection after exercise is excessive. When including elite athletes in the J-curve model, the curve is suggested to be S-shaped. This hypothesis states that low and very high exercise load increases the infection odds ratio, while moderate and high exercise loads decreases the infection odds ratio, but this needs to be verified by compiling data from a larger number of subjects.

Exercise has anti-inflammatory effects, which means that moderate amounts of exercise may enhance immune function above sedentary levels.

Physical activity is associated with reduced resting C-reactive protein (CRP) levels.

Heavy physical activity produces a rapid, transient increases in cytokine production and entails increases in both pro-inflammatory and anti-inflammatory cytokines.

Physical exercise affects the generation of reactive oxygen species (ROS) in leukocytes, which may induce muscle damage, decreased physical performance, muscular fatigue, and overtraining.

It is currently not known whether the body’s natural antioxidant defense system is sufficient to counteract the induced increase of ROS during physical exercise or if additional supplements are needed.

There are three main theories describing the effects of exercise on immunity: 1) the J-curve theory, 2) the “open window” theory and 3) the S-curve theory.

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Exercise and Immunity: Beliefs and Facts

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Patricia López 4 , 5 ,
Carolina Chamorro-Viña 6 ,
Mariana Gómez-García 7 &
Maria Fernandez-del-Valle 4 , 8

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Exercise immunology is the field that studies the effects of exercise on the immune system. In the 1990s, Dr. Nieman formulated the controversial “J-shaped hypothesis” to describe the relationship between acute exercise intensity and the risk of acquiring infections, such as upper respiratory tract infections. This hypothesis suggested that moderate exercise has the ability to improve immune function above sedentary levels, while high intensity exercise depresses the immune system. Since then, current knowledge has exposed some methodological limitations, challenging the idea that any form of exercise can be considered “immunosuppressive”. Overall, acute bouts of moderate exercise have shown to enhance immune-surveillance, while frequent exercise has been associated with an increased immunological competency. Actually, contemporary research interests are focused in understand how immune changes induced by exercise are able to reduce risk for common chronic diseases. To this end, the introduction of -omics approaches (metabolomics, proteomics, lipidomics, and metagenomics) is providing new insights on the interactions between exercise and immunity. In this chapter, we deep into the previous literature addressing the “immunity-exercise axis” in order to critically review the basis of the J-shaped curve and open window hypothesis. In addition, an overview of the components of the immune system and how are affected by exercise considering the gender dimension will help us to unravel the key role of regular physical activity in the prevention and treatment of disease.

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Excessive Exercise and Immunity: The J-Shaped Curve

Human Immune System and Exercise Medicine: Current Process and Future Directions

Immune System and Its Adaptation to Exercise

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Carolina Chamorro-Viña

Department of Health, Instituto Superior de Educación Física, Universidad de la República, Montevideo, Uruguay

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Chapter Review Questions

Diverse studies comparing self-reported URTI with laboratory methods have concluded that the incidence of URTI is ______ in athletes compared to general population

none of the above

The J curve was first proposed based on

Studies with moderate exercise intensity

Studies in nonathletic population

Studies in athletic population that performed high-intensity exercise

Studies in rats

After moderate exercises, studies have showed to _______ immune responses to vaccination, low-grade inflammation and various markers in diseases (i.e., HIV, cancer, diabetes or obesity)

Randomly change

During prolonged aerobic exercise

Only a sharp increase of leukocyte is observed

A biphasic increase in leukocyte is observed

A decrease in leukocyte is observed

No changes in leukocytes are observed

Which is the most responsive cell to exercise stimulus?

Neutrophils

Lymphocyte T

Lymphocyte B

What causes NK cells increase their cell number immediately after exercise?

Increased catecholamine production

Decreased plasma volume

Increased Th2 lymphocyte numbers

Increased T lymphocytes

A transient reduction in the frequency of immune cells after exercise is due to

negative changes in cell count

negative changes in cell function

preferential mobilization of cells to tissues and organs

preferential mobilization of cells to the bloodstream

Which supplementation reduces URTI incidence following intensive exercise?

Females with normal menstrual cycles show ______ in immune cell counts and function as well as cytokine alterations in response to exercise compared to males.

During URTI episodes, the guidelines for exercise recommend do not exercise if we have

Sore throat

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López, P., Chamorro-Viña, C., Gómez-García, M., Fernandez-del-Valle, M. (2023). Exercise and Immunity: Beliefs and Facts. In: Robert-McComb, J.J., Zumwalt, M., Fernandez-del-Valle, M. (eds) The Active Female. Springer, Cham. https://doi.org/10.1007/978-3-031-15485-0_28

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open window hypothesis

The proposition that for a period (typically 3–72 h) after a bout of intense exercise (e.g. a marathon run) the immune system is suppressed, making the exerciser more susceptible to ... ...

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5.5 Introduction to Hypothesis Tests

Dalmation puppy near man sitting on the floor.

One job of a statistician is to make statistical inferences about populations based on samples taken from the population. Confidence intervals are one way to estimate a population parameter.

Another way to make a statistical inference is to make a decision about a parameter. For instance, a car dealership advertises that its new small truck gets 35 miles per gallon on average. A tutoring service claims that its method of tutoring helps 90% of its students get an A or a B. A company says that female managers in their company earn an average of $60,000 per year. A statistician may want to make a decision about or evaluate these claims. A hypothesis test can be used to do this.

A hypothesis test involves collecting data from a sample and evaluating the data. Then the statistician makes a decision as to whether or not there is sufficient evidence to reject the null hypothesis based upon analyses of the data.

In this section, you will conduct hypothesis tests on single means when the population standard deviation is known.

Hypothesis testing consists of two contradictory hypotheses or statements, a decision based on the data, and a conclusion. To perform a hypothesis test, a statistician will perform some variation of these steps:

Define hypotheses.
Collect and/or use the sample data to determine the correct distribution to use.
Calculate test statistic.
Make a decision.
Write a conclusion.

Defining your hypotheses

The actual test begins by considering two hypotheses: the null hypothesis and the alternative hypothesis. These hypotheses contain opposing viewpoints.

The null hypothesis ( H 0 ) is often a statement of the accepted historical value or norm. This is your starting point that you must assume from the beginning in order to show an effect exists.

The alternative hypothesis ( H a ) is a claim about the population that is contradictory to H 0 and what we conclude when we reject H 0 .

Since the null and alternative hypotheses are contradictory, you must examine evidence to decide if you have enough evidence to reject the null hypothesis or not. The evidence is in the form of sample data.

After you have determined which hypothesis the sample supports, you make a decision . There are two options for a decision. They are “reject H 0 ” if the sample information favors the alternative hypothesis or “do not reject H 0 ” or “decline to reject H 0 ” if the sample information is insufficient to reject the null hypothesis.

The following table shows mathematical symbols used in H 0 and H a :

Figure 5.12: Null and alternative hypotheses

equal (=)	not equal (≠) greater than (>) less than (<)
equal (=)	less than (<)
equal (=)	more than (>)

NOTE: H 0 always has a symbol with an equal in it. H a never has a symbol with an equal in it. The choice of symbol in the alternative hypothesis depends on the wording of the hypothesis test. Despite this, many researchers may use =, ≤, or ≥ in the null hypothesis. This practice is acceptable because our only decision is to reject or not reject the null hypothesis.

We want to test whether the mean GPA of students in American colleges is 2.0 (out of 4.0). The null hypothesis is: H 0 : μ = 2.0. What is the alternative hypothesis?

A medical trial is conducted to test whether or not a new medicine reduces cholesterol by 25%. State the null and alternative hypotheses.

Using the Sample to Test the Null Hypothesis

Once you have defined your hypotheses, the next step in the process is to collect sample data. In a classroom context, the data or summary statistics will usually be given to you.

Then you will have to determine the correct distribution to perform the hypothesis test, given the assumptions you are able to make about the situation. Right now, we are demonstrating these ideas in a test for a mean when the population standard deviation is known using the z distribution. We will see other scenarios in the future.

Calculating a Test Statistic

Next you will start evaluating the data. This begins with calculating your test statistic , which is a measure of the distance between what you observed and what you are assuming to be true. In this context, your test statistic, z ο , quantifies the number of standard deviations between the sample mean, x, and the population mean, µ . Calculating the test statistic is analogous to the previously discussed process of standardizing observations with z -scores:

$z=\frac{\overline{x}-{\mu }_{o}}{\left(\frac{\sigma }{\sqrt{n}}\right)}$

where µ o is the value assumed to be true in the null hypothesis.

Making a Decision

Once you have your test statistic, there are two methods to use it to make your decision:

Critical value method (discussed further in later chapters)
p -value method (our current focus)

p -Value Method

To find a p -value , we use the test statistic to calculate the actual probability of getting the test result. Formally, the p -value is the probability that, if the null hypothesis is true, the results from another randomly selected sample will be as extreme or more extreme as the results obtained from the given sample.

A large p -value calculated from the data indicates that we should not reject the null hypothesis. The smaller the p -value, the more unlikely the outcome and the stronger the evidence is against the null hypothesis. We would reject the null hypothesis if the evidence is strongly against it.

Draw a graph that shows the p -value. The hypothesis test is easier to perform if you use a graph because you see the problem more clearly.

Suppose a baker claims that his bread height is more than 15 cm on average. Several of his customers do not believe him. To persuade his customers that he is right, the baker decides to do a hypothesis test. He bakes ten loaves of bread. The mean height of the sample loaves is 17 cm. The baker knows from baking hundreds of loaves of bread that the standard deviation for the height is 0.5 cm and the distribution of heights is normal.

The null hypothesis could be H 0 : μ ≤ 15.

The alternate hypothesis is H a : μ > 15.

The words “is more than” calls for the use of the > symbol, so “ μ > 15″ goes into the alternate hypothesis. The null hypothesis must contradict the alternate hypothesis.

$\frac{\sigma }{\sqrt{n}}$

Suppose the null hypothesis is true (the mean height of the loaves is no more than 15 cm). Then, is the mean height (17 cm) calculated from the sample unexpectedly large? The hypothesis test works by asking how unlikely the sample mean would be if the null hypothesis were true. The graph shows how far out the sample mean is on the normal curve. The p -value is the probability that, if we were to take other samples, any other sample mean would fall at least as far out as 17 cm.

This means that the p -value is the probability that a sample mean is the same or greater than 17 cm when the population mean is, in fact, 15 cm. We can calculate this probability using the normal distribution for means.

Normal distribution curve on average bread heights with values 15, as the population mean, and 17, as the point to determine the p-value, on the x-axis.

A p -value of approximately zero tells us that it is highly unlikely that a loaf of bread rises no more than 15 cm on average. That is, almost 0% of all loaves of bread would be at least as high as 17 cm purely by CHANCE had the population mean height really been 15 cm. Because the outcome of 17 cm is so unlikely (meaning it is happening NOT by chance alone), we conclude that the evidence is strongly against the null hypothesis that the mean height would be at most 15 cm. There is sufficient evidence that the true mean height for the population of the baker’s loaves of bread is greater than 15 cm.

A normal distribution has a standard deviation of one. We want to verify a claim that the mean is greater than 12. A sample of 36 is taken with a sample mean of 12.5.

Find the p -value.

Decision and Conclusion

A systematic way to decide whether to reject or not reject the null hypothesis is to compare the p -value and a preset or preconceived α (also called a significance level ). A preset α is the probability of a type I error (rejecting the null hypothesis when the null hypothesis is true). It may or may not be given to you at the beginning of the problem. If there is no given preconceived α , then use α = 0.05.

When you make a decision to reject or not reject H 0 , do as follows:

If α > p -value, reject H 0 . The results of the sample data are statistically significant . You can say there is sufficient evidence to conclude that H 0 is an incorrect belief and that the alternative hypothesis, H a , may be correct.
If α ≤ p -value, fail to reject H 0 . The results of the sample data are not significant. There is not sufficient evidence to conclude that the alternative hypothesis, H a , may be correct.

After you make your decision, write a thoughtful conclusion in the context of the scenario incorporating the hypotheses.

NOTE: When you “do not reject H 0 ,” it does not mean that you should believe that H 0 is true. It simply means that the sample data have failed to provide sufficient evidence to cast serious doubt about the truthfulness of H o .

When using the p -value to evaluate a hypothesis test, the following rhymes can come in handy:

If the p -value is low, the null must go.

If the p -value is high, the null must fly.

This memory aid relates a p -value less than the established alpha (“the p -value is low”) as rejecting the null hypothesis and, likewise, relates a p -value higher than the established alpha (“the p -value is high”) as not rejecting the null hypothesis.

Fill in the blanks:

Reject the null hypothesis when .
The results of the sample data .
Do not reject the null when hypothesis when .

It’s a Boy Genetics Labs claim their procedures improve the chances of a boy being born. The results for a test of a single population proportion are as follows:

H 0 : p = 0.50, H a : p > 0.50
p -value = 0.025

Interpret the results and state a conclusion in simple, non-technical terms.

Click here for more multimedia resources, including podcasts, videos, lecture notes, and worked examples.

Figure References

Figure 5.11: Alora Griffiths (2019). dalmatian puppy near man in blue shorts kneeling. Unsplash license. https://unsplash.com/photos/7aRQZtLsvqw

Figure 5.13: Kindred Grey (2020). Bread height probability. CC BY-SA 4.0.

A decision-making procedure for determining whether sample evidence supports a hypothesis

The claim that is assumed to be true and is tested in a hypothesis test

A working hypothesis that is contradictory to the null hypothesis

A measure of the difference between observations and the hypothesized (or claimed) value

The probability that an event will occur, assuming the null hypothesis is true

Probability that a true null hypothesis will be rejected, also known as type I error and denoted by α

Finding sufficient evidence that the observed effect is not just due to variability, often from rejecting the null hypothesis

Significant Statistics Copyright © 2024 by John Morgan Russell, OpenStaxCollege, OpenIntro is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License , except where otherwise noted.

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A Summary and Analysis of Saki’s ‘The Open Window’

By Dr Oliver Tearle (Loughborough University)

‘The Open Window’ is one of Saki’s shortest stories, and that’s saying something. Few of his perfectly crafted and deliciously written tales exceed four or five pages in length, but ‘The Open Window’, at barely three pages, outstrips even ‘ The Lumber-Room ’ or ‘ Tobermory ’ for verbal economy.

It is so brief it has almost the air of a parable about it, except that it’s far from clear what the ‘moral’ of the story is, or even if there is one. Saki uses language so deftly and to such effect, that it is worth unpicking and analysing ‘The Open Window’ (which can be read in full here ) a little.

Although on first glance it seems different from some of Saki’s better-known stories, such as his classic werewolf tale ‘Gabriel-Ernest ’ and his story about a polecat worshipped as a god, ‘Sredni Vashtar’ , ‘The Open Window’ follows the same essential setup as many of Saki’s other stories, in having an adolescent character whose supposed innocence (supposed by the adult character, that is) turns out to be guile, cunning, and the mischief in disguise.

But whereas Nicholas in ‘The Lumber-Room’, Conradin in ‘Sredni Vashtar’, or Gabriel-Ernest actively seek to cause harm to their adult antagonists (or, in the case of Nicholas, to refuse to help an aunt who has got herself trapped in the water tank), Vera’s only weapon is her imagination. Yet this alone suggests that she shares some kinship with Conradin in ‘Sredni Vashtar’, whose cousin and guardian dislikes her ward’s imaginative streak.

‘The Open Window’: plot summary

What happens in ‘The Open Window’, in summary, is this: a man, who has the glorious name of Framton Nuttel, has newly arrived in a ‘rural retreat’, to help him settle his nerves. His sister, worried that he will hide himself away there and ‘mope’, thus making his nerves worse, has given him the names and addresses of all the people she knows in the area, and told him to go and introduce himself to them. (His sister had stayed at the rectory four years earlier.)

‘The Open Window’ takes place at the house of one of Framton’s sister’s contacts, a woman named Mrs Sappleton and her 15-year-old niece, Vera, whom Framton has gone round to visit so he might introduce himself.

While Mrs Sappleton is upstairs making herself ready to meet their new guest, Vera entertains Framton. After she learns that Framton knows barely anything about her aunt, Vera tells him that three years ago Mrs Sappleton’s husband and her two brothers went out through the French window on a shooting trip, and never returned. They drowned in a ‘treacherous piece of bog’ and their bodies were never recovered. The spaniel they took with them was lost, too.

Vera tells Framton that her aunt has kept the French window open ever since, in the belief that her husband and brothers are going to walk back through the open window any moment, alive and well.

Mrs Sappleton then arrives from upstairs and apologises for being late coming down. She mentions the open window and explains that her husband and brothers are out shooting but will be back any minute. They exchange small talk about shooting and birds, and Framton iterates that he has been told to have complete rest and avoid ‘mental excitement’, when Mrs Sappleton announces that her husband and brothers are returning home.

Framton looks with horror at the sight of three men and a ‘tired brown spaniel’ approaching the open window – he sees that Vera shares his look of shock. Believing he is seeing three ghosts (four if you include the dog!), he picks up his hat and coat and runs from the house as fast as he can.

Back at the house, Mrs Sappleton remarks that Mr Nuttel was an odd man – all he could do was talk about his ailments, and then he ‘dashed off’ as soon as the men arrived. Vera suggests that he was scared of dogs, and the sight of the spaniel caused him to run off. The final sentence of the story refers to Vera: ‘Romance at short notice was her speciality.’

‘The Open Window’: analysis

‘The Open Window’ is an amusing little story; but is it more than this? Closer analysis of Saki’s tale reveals that the devil is in the detail. Note that Framton is not presented as a gullible fool, and if he is, we as readers are encouraged to be gulled, too, for we are supposed to be taken in by Vera’s lie about the dead husband and brothers as well.

But as Framton is wondering whether Mrs Sappleton is married or widowed, he senses a male presence in the house: ‘An undefinable something about the room seemed to suggest masculine habitation.’ His first instinct is correct, but Vera’s entirely fabricated narrative leads him to believe he was mistaken about the ‘masculine’ atmosphere.

And she convinces him that she should be believed by a number of subtle details: the spaniel that accompanied the men on their apparently ill-fated trip, for instance, and the white waterproof coat which the husband was carrying over his arm when they left. Vera obviously saw the men leaving with the dog and coat, and weaves them into the narrative she feeds to Framton, so that when the men return – with the dog and the coat, as described – the idea that Framton is seeing dead men walking is all the more powerful.

Vera’s look of horror when they see the men returning to the house is also a nice touch. Of course, being still technically a child, female, and named Vera (meaning literally ‘truth’), all help, too. But you can never trust children in Saki, those ‘feral ephebes’ in Sandie Byrne’s memorable phrase.

But does ‘The Open Window’ mean anything else beyond itself? That is, can it be analysed as a commentary on anything other than lying teenage girls? Well, the story does raise questions which, we might argue, prefigure the concerns of the modernist writers who were active a few years after Saki, in the immediate post-WWI period.

There is no absolute truth or absolute reality, writers such as James Joyce and Virginia Woolf suggest, because everything is mediated through personal human experience, and we cannot know everything. Virginia Woolf’s first great novel, Jacob’s Room (1922), is a good example of this: no one character fully knows or understands the title character, and everyone gets a slightly different glimpse of who he is. Framton has only Vera’s word to go on about Mrs Sappleton’s husband and brothers.

But, conversely, Mrs Sappleton, unaware that her niece has been spinning their guest a web of lies, has a different perception of him, too, believing him to be an odd man who has an excessive reaction to the sight of her male relatives. Vera, the fiction-master (and thus the author-surrogate in the story), is the only one who knows both sides and can enjoy playing these two characters, with their partial glimpses of the whole story, off each other.

Although Saki’s style and approach are very different from someone like Virginia Woolf, the preoccupation with ‘fiction’ and ‘perception’ is the same – only Saki’s take on this issue is funnier.

Vera’s lie in ‘The Open Window’ about three members of one family – all of them male – going off together on a shooting trip and never returning, leaving the female characters at home to grieve for them, seems eerily to prefigure the events of a few years later, when hundreds of thousands of Englishmen – including, in many cases, every single man in a particular family – would go off to fight in the First World War and never come back. (When we consider that, in Vera’s fictional account, the three men meet their end by drowning in boggy mud, and their bodies are never recovered, the foreshadowing of the Western Front becomes downright spooky.)

Saki himself would be one of them, killed in action in 1916. With him, and many like him, the Edwardian way of life that Saki so ruthlessly skewers in his stories would die, too. But ‘The Open Window’ remains more than a window (to reach for the inevitable metaphor) onto a vanished world. It is a timeless tale about truth and fiction, and, yes, a parable without a moral. For that reason, it deserves to be revisited, analysed and studied, discussed, and celebrated.

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1 thought on “A Summary and Analysis of Saki’s ‘The Open Window’”

I love the ending to this story – the irony and surprise packed into a single sentence reminds me a lot of O. Henry’s works…

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REVIEW article

Debunking the myth of exercise-induced immune suppression: redefining the impact of exercise on immunological health across the lifespan.

$\r\nJohn P. Campbell*$

Department for Health, University of Bath, Bath, United Kingdom

Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory—referred to as the “open window” hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1–2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances—rather than suppresses—immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.

Introduction

Lifelong physical activity 1 is a potent means of reducing the risk of non-communicable diseases including cancer, cardiovascular disease, and other chronic inflammatory disorders ( 1 ). Evidence also shows that a physically active lifestyle diminishes the risk of contracting a range of communicable diseases including viral and bacterial infections ( 2 – 6 ). In contrast to the widely accepted long-term health benefits that are achieved by regular physical activity, which imply that immune competency and regulation are improved by frequent exercise bouts, the effect of a single bout of exercise on immune function remains hotly disputed. Undeniably, acute vigorous exercise has a profound effect on the phenotypic makeup and functional capacity of the immune system. Indeed, the behavior of almost all immune cell populations in the bloodstream is altered in some way during and after exercise ( 7 , 8 ). However, for decades, it has been widely accepted that these changes result in a temporary decline in immune competency in the hours following exercise. In the first part of this review, we re-interpret these data and strive to dispel the misconception that an acute bout of exercise is detrimental to immunological health. In the second part of this article, we demonstrate that rather than suppressing immunity, contemporary evidence shows that an acute bout of exercise improves immune surveillance, for example leading to enhanced antibacterial and antiviral immunity. Finally, in the third part of this article, we summarize recent data suggesting that regular physical activity and frequent exercise, which reduces systemic inflammatory activity and improves aspects of immune function, also leads to alterations in classical biomarkers of an aging immune system. These changes could be interpreted as limiting or delaying immunological aging ( 9 – 13 ).

Part A: Is it Time to Close the Shutters on the “Open-Window” Hypothesis? A bout of Exercise Does Not Suppress Immune Competency

A prevailing myth has formed in the literature that participating in an acute bout of aerobic exercise, particularly if it is vigorous and prolonged, can be detrimental to immune competency. The foundations of this belief lay in research publications emanating from the 1980s and 1990s, reviewed extensively elsewhere ( 7 , 8 , 14 ). Findings from these early studies led to three principles of exercise immunology being formed, which have, until now, generally been unchallenged in the literature: (i) infection risk is increased after an acute bout of prolonged and vigorous aerobic exercise; (ii) acute bouts of vigorous exercise can lead to a temporary reduction to salivary IgA levels culminating in a higher risk of opportunistic infections; and (iii) transient decreases in the number of peripheral blood immune cells, which occurs in the hours following vigorous exercise, represents a period of immune suppression. Over the years, these collective observations have coalesced and led to the creation of the so-called “open-window” hypothesis, which purports that the immune system is compromised in the hours after vigorous exercise, leading to an increased risk of opportunistic infections in the days thereafter. To this day, the “open window” hypothesis continues to be discussed ( 15 ), despite the existence of contradictory evidence. Here, in the first part of this review, we aim to dispel the “open-window” hypothesis by revisiting key research studies and highlighting that limited evidence exists to support each of the three pillars that lay its foundation.

Exercise and Opportunistic Infections

It has been speculated for over a century that participation in physical activity heightens the risk of opportunistic infections ( 16 ). However, deeper investigation into the relationship between exercise and infection susceptibility did not take place until the end of the twentieth century. At this juncture, the principle focus of many of these studies in the late 1980s and early 1990s was to determine whether infection incidence was increased in elite and recreational athletes in the weeks following mass participation distance running events. One of the first studies from this era found that one third of 150 runners participating in the 1982 Two Oceans 56 km ultramarathon in Cape Town South Africa self-reported symptoms of upper respiratory tract infections (URTIs; symptoms = runny nose, sore throat, sneezing) within 2 weeks of the race ( 17 ). The control group, who were age matched and shared a home with another of the race competitors, reported only half the amount of URTIs in the same period ( 17 ). Similar observations were made in an often-cited larger study of the 1987 Los Angeles Marathon ( 18 ). Of 2,311 respondents who had completed the marathon and whom did not report an infection in the week prior to the race, 12.9% reported an infection in the week after the race compared to only 2.2% of individuals who withdrew from the race for reasons other than illness (odds ratio of infection in runners versus non-runners = 5.9). A separate study conducted around the same time found that shorter duration running events, such as 5, 10 km, and half-marathons (21 km) did not appear to elicit an increased incidence of self-reported URTIs ( 19 ), thereby suggesting that URTI symptoms are increased only when the duration of the exercise is long.

A fundamental limitation of each of the aforementioned studies is that none of the self-reported infections were clinically confirmed by laboratory analyses (e.g., molecular or microbiological techniques, such as polymerase chain reaction or bacterial cultures). As a consequence, it was questioned whether the self-reported URTIs in these studies represented genuine infections. Clarifying this issue, a study employing nasopharyngeal and throat swabs in athletes who reported URTI symptoms over a 5-month period—including periods of competition—found that few of the self-reported infections were of bacterial, viral, chlamydial, or mycoplasmal nature ( 20 ). Indeed, of 37 episodes of URTI reported by athletes in this study, only 11 of these (30%) had a positive laboratory diagnosis. These findings place the previously discussed marathon studies in a different light ( 17 , 18 ) and open the possibility that many of the URTIs reported were a symptom of other non-infectious causes. Indeed, of the of the non-infectious “URTIs” reported by Spence et al. ( 20 ), and likely captured elsewhere ( 17 , 18 ), it is proposed that these symptoms are a result of other causes, including allergy and asthma, non-specific mucosal inflammation, or airway epithelial cell trauma due to increased ventilation or exposure to cold air ( 21 ). In the few cases of clinically confirmed URTIs, these appear to be from viruses—in particular rhinoviruses (i.e., the “common cold”)—rather than bacterial infection ( 20 , 22 ), which is in line with the typical incidence and etiology of infections at the population level ( 23 ).

In the previously discussed clinical laboratory study of infection incidence in athletes ( 20 ), it is notable that the proportion of athletes with a confirmed infection during the 5-month period was as follows: 2/20 controls (10%), 3/31 (10%) recreational athletes, and 6/32 (19%) elite athletes. Although this study was small, these data appear to align with observations from earlier self-report studies which found that the incidence of URTI symptoms was higher in those with the fastest race time and those who had completed a greater training volume pre-race ( 17 , 18 ). These early observations contributed to the formulation of the “J-shaped curve” ( 24 ). This hypothesis infers that those who undertake an excessive volume of exercise, over a period of weeks and months, sometimes referred to as “over-training” or “intensified training” ( 25 , 26 ), are at a greater risk of infections ( 24 ). In this scenario, other factors present prior to an acute bout of exercise, such as psychological stress and anxiety ( 27 – 29 ), or nutritional deficiencies ( 30 ) which are known to impact immune regulation, are likely to impact immune competency and contribute to the risk of genuine URTIs, rather than the acute and transient immune changes that arise after the acute bout of exercise itself; these acute immunological changes arising after acute exercise are discussed later in this article (see Part A: “Is it Time to Close the Shutters on the “Open-Window” Hypothesis? A Bout of Exercise Does Not Suppress Immune Competency”; and see “Exercise and Salivary IgA and Changes to Lymphocyte Frequency and Functional Capacity in the Hours After Acute Exercise”).

Moreover, we contend that attendance at any mass participation event—whether it is a marathon or otherwise—is likely to increase the risk of acquiring novel infectious pathogens, which are in abundance due to the mass gathering of people. For example, it has been shown that around 40% of individuals attending the Hajj—a crowded religious event in Saudi Arabia—self-report an URTI ( 31 ). In this study, there was a greater risk of infection among those with the longest exposure to crowds ( 31 ). Thus, it is important to consider that other underlying factors, often not measured in the context of exercise and illness studies, likely play a greater role in infection risk than exercise participation per se . For example, recently, it has been demonstrated that air travel is a significant predictor of illness symptoms in athletes ( 32 ). Infections linked to air travel are exacerbated by long-haul flights crossing multiple time zones, implicating many other factors known to influence immune function, including exposure to hypobaric hypoxia, radiation, temperature changes, sleep disruption, fatigue, altered or inadequate diet, dehydration, and psychological stress ( 32 – 34 ).

Contrary to the aforementioned reports that exercise heightens infection incidence, it is often overlooked that other studies indicate that exercise participation may in fact reduce the incidence of infections. For example, a recent prospective cohort study of 1,509 Swedish men and women aged 20–60 years found that higher physical activity levels were associated with a lower incidence of self-reported URTIs ( 35 ). A much smaller but very detailed analysis of illness records kept by 11 elite endurance athletes over a period of 3–16 years showed that the total number of training hours per year was inversely correlated with sickness days reported ( 36 ). Similarly, another study of swimmers monitored for 4 years found that national level athletes had higher incidence of infections than more elite international level athletes ( 37 ). Finally, studies of ultramarathon runners, who undertake the largest volume of exercise among athletes, have shown that these individuals report fewer days missed from school or work due to illness compared to the general population. For example, the mean number of sickness days reported over 12 months was 1.5 days in a study of 1,212 ultramarathon runners and 2.8 days in a study of 489 ultramarathon runners ( 38 , 39 ). These studies compared their findings to data from the United States Department of Health and Human Services report in 2009, showing that the general population report on average 4.4 illness days each year. Thus, a number of studies challenge the “J-shaped curve,” indicating that athletes undertaking the largest training loads, become ill less frequently than athletes competing at, and training at, a lower level. These findings have previously been conceptualized by extending the “J-shaped curve” into an “S-shaped curve,” thereby suggesting that very elite athletes are better adapted to the demands of their training ( 40 ). Given the nature of their design, very few of these reports—akin to many of the aforementioned studies showing increased infection risk among athletes following mass participation endurance events—used appropriate laboratory diagnostics to confirm an infection. However, despite their limitations, it is important to highlight that there are as many epidemiological studies showing that regular exercise reduces infections as there are studies showing exercise increases infections, and that these studies are often overlooked in the exercise immunology literature.

It should also be considered whether the commonly reported “increased frequency” of illness symptoms among athletic populations or those taking part in sporting events is indeed more frequent than among the general population. For example, large studies have reported that approximately 7–10% of athletes competing in the Olympic Games report symptoms of illness during the competition weeks ( 41 , 42 ). However, accumulating evidence suggests the incidence of infection among athletes is not substantially different to other populations. For example, in a telephone survey of 2011 adults considered to represent the general population in the USA, 24% experienced a cold during a 4-week period, which is a similar timeframe to many international sporting competitions ( 43 ). In another telephone survey of 4,051 adults in the USA, 72% experienced at least 1 non-influenza related URTI over 12 months, and on average, experienced 2 infections annually ( 44 ). In a year-long Internet-based monitoring study of 627 individuals over 14 years of age in Germany, weekly acute respiratory illness rates were 2.7–8.2%, manifesting in 1.3–3.2 episodes annually ( 45 ). Thus, evidence suggests that the frequency of illness episodes in athletic communities is similar to the general population annually.

In the context of exercise participation in older age, it would appear to be counterintuitive that the incidence of URTI symptoms appears to be inversely correlated with age: it has been shown that URTI symptoms are more common in younger rather than older runners ( 18 ). While, once more, this aforementioned study did not confirm infections by laboratory analyses, it is notable that if acute exercise does suppress immune competency, it might be expected that older adults—whom typically have inferior immune function—would be at greatest risk of exercise-induced immune suppression. Rather than exercise per se , again, a more likely explanation for differences in illness symptoms between groups of athletes are other factors present before competing, such as fatigue, nutritional deficiency, psychological stress, or environmental exposures. On the other hand, proponents of the “open-window” hypothesis could portend that experienced athletes have higher tolerance of the symptoms associated with URTI, and/or have developed coping methods or strategies to reduce symptoms. Alternatively, experienced athletes may have evolved strategies to reduce infection risk by adopting good practice (e.g., sleep, diet, hygiene) before, during and following attendance at a mass participation event.

Separately, it has also been questioned whether illness symptoms—even if confirmed to be infectious—are a result of encountering a novel pathogen. For example, over a decade ago, some studies suggested that reactivation of latent viruses—such as Epstein Barr Virus which had most likely infected the host during childhood—was responsible for illness symptoms after exercise ( 46 , 47 ). Although these studies suggest new pathogens were not to blame, it was interpreted that exercise-induced immune suppression had resulted in loss of viral control. However, herpes viruses can reactivate even with a fully functioning immune system, for example, in response to adrenergic activity, reactive oxygen species and inflammatory cytokines ( 48 – 50 ), all of which increase during exercise. Moreover, recent evidence appears to discount herpes virus involvement in causing symptoms of illness, by showing that individuals previously infected with Cytomegalovirus , or those infected with both Epstein Barr Virus and Cytomegalovirus , exhibited a lower incidence of illness symptoms than individuals not latently infected ( 51 ).

Taken together, evidence that participation in an acute bout of vigorous exercise leads to heightened infection incidence remains spurious. If symptoms of URTI are observed after a bout of vigorous exercise, the cause is unlikely to be infectious. However, if infection or immune impairment is confirmed, their trigger is more likely to be the physical, nutritional, and psychological wellbeing of the individual prior to undertaking the single bout of acute vigorous exercise. In the context of mass participation sporting events, it is likely that increased exposure to pathogens, or the influence of environmental factors that can affect immune function (e.g., travel, sleep disruption) most likely explain genuine infections. Thus, we conclude that it is unlikely that vigorous and prolonged exercise heighten the risk of infections and should not be considered a deterrent to those seeking to become more physically active.

Exercise and Salivary IgA

A second mainstay of exercise immunology that has received considerable attention over the last three decades is the assessment of exercise-induced changes to mucosal immunity, principally via measurement of IgA levels in saliva ( 52 ). Given that IgA is the most abundant immunoglobulin in mucosal secretions and that its principle role is the inhibition of invading pathogens, isolated changes to salivary IgA following exercise has been considered of some importance in light of the purportedly higher risk of infections among athletes ( 7 , 8 ).

One of the earliest and most cited papers in this research area found that IgA was reduced by 20% after 2–3 h of cross-country skiing ( 53 ). Another study found that this effect is transient, whereby salivary IgA concentrations decreased immediately after 2 h of intensive cycling exercise, and remained low in samples collected 1 h post-exercise, but returned to normal levels within 24 h ( 54 ). A criticism of these studies at that time was that the absolute IgA levels reported did not adequately control for the amount of saliva produced, and thus these results may misrepresent IgA secretion. Although some studies measuring IgA secretory rate (IgA protein concentration multiplied by saliva flow rate) support the early findings with IgA concentration, others have shown profoundly contradictory results. For example, in alignment with prior observations, it was found in trained runners that IgA secretion rate decreased by 25% from pre-marathon to 90 min post-marathon ( 55 ). Likewise, in a separate study, a 20% reduction in IgA secretion rate was observed in elite athletes after a 2-h rowing exercise session ( 56 ). Several other studies of similar design reported analogous findings ( 57 – 59 ); however, contradictory findings are also in abundance but are much less cited in the literature. Indeed, an elegant study exploring the effects of different exercise intensities, including moderate- and high-intensity exercise to exhaustion, found that although saliva flow rate decreased, IgA secretion rate actually increased in response to both of the exercise bouts. In the words of the authors, exercise to exhaustion has an “ effect on the quantity of saliva, but not the quality of saliva ” ( 60 ). Many other studies have also reported that exercise does not elicit a decrease in IgA secretion rates following exercise ( 61 – 66 ).

Any subtle isolated changes to IgA that occur after exercise appear to be clinically insignificant as it would appear that the increased incidence of URTI symptoms that has been purported following vigorous and prolonged exercise is unrelated to salivary immunoglobulin status. A longitudinal field study of participants in the Comrades Marathon (86.5 km ultramarathon) in South Africa found that salivary IgA levels in the 4 weeks prior to the race, and 2 weeks following the race, were unrelated to the incidence of self-reported URTI ( 67 ). In the aforementioned study, it was found that symptoms of URTI were highest 4 weeks prior to the marathon, and URTI symptoms seemed to re-appear within many of the same athletes 1 or 2 weeks post-marathon. This study did not confirm the re-emergence of infections by laboratory testing, but if this was indeed demonstrated in future studies, it again shows that acute exercise participation per se does not heighten risk of opportunistic infections. In this case, an underlying infection, not resolved prior to exercise participation, or some other idiosyncrasy, is perhaps to blame. Such conclusions appear to be supported by evidence from athletes who report the most frequent illness symptoms. For example, these individuals exhibit mostly anti-inflammatory cytokine responses when whole blood, collected at rest, is cultured ex vivo with antigens from diphtheria, tetanus, acellular pertussis, poliomyelitis, and hemophilus influenza type b ( 68 , 69 ). These findings suggest the immune system may be functionally altered by underlying illness, or is already different in these “illness-prone” athletes prior to infection, rather than exercise affecting immune function per se .

A flaw in studies investigating the link between mucosal immunity and purported exercise-induced infection risk is that oral health status is rarely adequately evaluated. Salivary IgA is heavily involved in host-bacterial ecology and mucosal homeostasis ( 70 , 71 ). As optimal oral health is rare in adults—with nearly all exhibiting caries, gingivitis or periodontitis—profound between-person IgA variation has been reported, which is dependent on oral health status ( 71 ). Moreover, periodontal diseases are complex and multifactorial, and as a result, studies report large fluctuations in IgA levels relative to disease status between persons, probably due to the bespoke ecological makeup of different host mucosa ( 71 ). In addition, oral disease is a common problem in athlete populations ( 72 ), which is likely to be caused by high volume and frequent carbohydrate consumption, and in some, a neglect of oral hygiene, perhaps due to practical constraints. Thus, changes to oral inflammatory status has not been adequately considered, and emerging salivary biomarkers of oral inflammation, such as immunoglobulin-free light chains ( 73 ), may offer a means of controlling for this confounder. As highlighted elsewhere ( 70 ), salivary IgA is also highly vulnerable to short-term variation, in particular, due to circadian rhythms, typically peaking in the morning, and falling thereafter ( 74 ). As salivary IgA secretion is controlled by the parasympathetic and sympathetic nervous system, psychological stress also plays a powerful role in regulating IgA levels ( 75 ). Animal models suggest that salivary IgA levels could vary up to 27-fold within the same host over a short period of time ( 76 ). Salivary IgA levels are also affected by factors such as sex differences ( 77 ), diet, ethnicity, disease, medications, tobacco, and phase of the menstrual cycle, as reviewed elsewhere ( 71 ). To overcome some of these variations in salivary IgA, it is often the case that studies evaluate only secretory IgA (sIgA; i.e., IgA containing the secretory component) as this represents IgA produced by local mucosal plasma cells, and not IgA from the bloodstream transported via crevicular fluid. While this approach may reduce some confounding error, most IgA in saliva contains the secretory component and is, itself, subject to large variation; extensively reviewed elsewhere ( 78 ). Given these many considerations, we propose that longitudinal measurement of salivary IgA, as an isolated measure of immune competency within a single host, and even more so between persons, depicts too confusing a picture, and it is ambitious to say that any subtle changes to salivary IgA following exercise reflects immune suppression and a heightened risk of opportunistic infections. Given the limitations of salivary IgA measurement, research is being undertaken to explore mucosal IgA in other biofluids, and a recent study has shown links between reduced tear IgA levels and infection incidence ( 79 ). Others have moved toward more comprehensive oral immunity panels ( 80 ), and such strategies could benefit further from an integrative approach that, in addition to immune parameters, incorporates full dental examination, oral inflammation biomarkers, and host mucosal ecology.

Changes to Lymphocyte Frequency and Functional Capacity in the Hours After Acute Exercise

One of the most reproduced findings in human exercise physiology is the profound and transient time-dependent change that arises to the phenotypic composition and functional capacity of lymphocytes in the peripheral bloodstream in response to a single bout of exercise ( 8 ). During vigorous aerobic exercise, it is commonly observed that peripheral blood lymphocyte frequency—and, concomitantly, the functional capacity of the lymphocyte pool—is dramatically increased, leading to the concept that, during exercise, exercise appears to “stimulate” the immune system. On the other hand, in the hours following exercise, it is typically observed that total peripheral blood lymphocyte frequency—and the functional capacity of the lymphocyte pool—is decreased below pre-exercise levels, leading some to propose that exercise induces a short-term window of immune suppression (termed the “open-window” hypothesis). The purpose of this part of our review is to outline that it is a misconception to state that the “reductions” to lymphocyte frequency and function, that arise in the hours following acute exercise, reflects immune suppression, and instead we emphasize that during this post-exercise period, the immune system is in a heightened state of immune surveillance and regulation.

Transient Changes to Blood Lymphocyte Frequency in the Hours Following Exercise

The classic biphasic response of lymphocytes to acute steady state vigorous exercise lasting for around at least 45–60 minutes, is first characterized by a dramatic lymphocytosis. This response is typified by a dramatic influx of natural killer cells, which rise by up to 10-fold, and CD8 + T cells which increase to a lesser—but still profound—extent by approximately 2.5-fold ( 81 ). This exercise intensity-dependent mobilization is driven in part by increased shear forces and blood pressure during exercise causing a non-specific flushing of the marginal pools ( 82 ) but, moreover, is principally governed by adrenergic stimulation of beta-2-adrenergic receptors on the surface of lymphocytes, arising from adrenaline released during exercise, causing endothelial detachment and subsequent recirculation of lymphocytes into the bloodstream ( 83 – 85 ). Indeed, the lymphocyte mobilization response observed during exercise appears to broadly mirror the differential expression of beta-2 adrenergic receptors on lymphocytes: natural killer cells > CD8 + T cells > B cells > CD4 + T cells, including regulatory T cells ( 81 , 86 – 88 ). Upon exercise cessation, the classic biphasic exercise response is next characterized by a dramatic decrease in the frequency of lymphocytes in the bloodstream. This nadir is typically observed approximately 1–2 h post-exercise when the lymphocyte numerical count is lower than pre-exercise levels; lymphocyte frequency normally returns to pre-exercise levels within 24 h ( 87 , 89 , 90 ). The lymphopenia that occurs 1–2 h later is exercise intensity dependent and the most profound reductions during this period are typically observed among natural killer cells and CD8 + T cells ( 90 ). Akin to purported reductions to salivary IgA, discussed earlier, it was perceived that the numerical decline of blood lymphocytes that arises during this time represented “double jeopardy” ( 89 ), temporarily exposing an individual to impaired immune competency and concomitantly providing an “open-window” for opportunistic infections ( 91 , 92 ).

Rather than suppressing immune competency however, a more contemporary viewpoint is that this acute and transient lymphopenia 1–2 h after exercise is beneficial to immune surveillance and regulation. Indeed, in what appears to be a highly specialized and systematic response, it is widely proposed that exercise redeploys immune cells to peripheral tissues (e.g., mucosal surfaces) to conduct immune surveillance. Here, these immune cells are thought to identify and eradicate other cells infected with pathogens, or those that have become damaged or malignant, termed the acute stress/exercise immune-enhancement hypothesis ( 93 ). A seminal study by Kruger and colleagues, using fluorescent cell tracking in rodents, found that T cells are redeployed in large numbers to peripheral tissues including the gut and lungs, and to the bone marrow following exercise ( 84 , 94 ). In line with Dhabhar’s theory, it is hypothesized that this redistribution reflects heightened immune surveillance in sites where pathogens are likely to be encountered during and after exercise (i.e., lungs, gut). This response has also been proposed to maintain immune homeostasis via augmented regulatory activities ( 12 ). In this context, evidence implies that bone marrow homing and subsequent apoptosis of senescent T cells stimulates the production or mobilization of new progenitor cells into the periphery ( 95 ), which has been hypothesized as an exercise-induced means of maintaining a younger immune system ( 12 ), discussed later in Part C “Does Exercise and Regular Physical Activity Influence Immunological Ageing.” Links between exercise-induced apoptosis and lymphopenia have in the past been interpreted as detrimental, with speculation that apoptosis could be responsible for the fall in lymphocyte number in the hours after exercise ( 96 , 97 ). Other studies have reported increased lymphocyte apoptosis immediately after exercise (i.e., as a result of the large mobilization of cells) but not in the hours following exercise during lymphopenia ( 98 – 100 ). Although the magnitude of lymphocyte apoptosis reported in studies is dependent on the measurement technique, typically <10% of lymphocytes undergo post-exercise apoptosis ( 96 , 97 ). Given the 30–60% decrease in lymphocyte numbers post-exercise ( 89 , 101 , 102 ), apoptosis could be a small contributor to exercise-induced lymphopenia, but this process of cell death is likely to be beneficial given the stimulation of progenitor cells from the bone marrow ( 95 ).

While it has not been shown in humans that exercise—in line with rodent models—causes the redistribution of immune cells to peripheral tissues, further support for a coordinated, exercise-induced immune surveillance response elicited by lymphopenia, is revealed by studying the phenotypic characteristics of the cells that preferentially mobilize and subsequently extravasate out of the circulation after exercise. With regard to natural killer cells—the most exercise-responsive lymphocyte subset—CD56 dim cells are preferentially redeployed rather than their CD56 bright counterparts ( 81 ). CD56 dim cells are a mature subset of natural killer cells which have exclusive migratory potential for non-lymphoid tissue and potent effector capabilities, including the capacity to produce high amounts of perforin and granzyme, whereas CD56 bright cells are a more immature regulatory cell subset ( 103 ) and reside in secondary lymphoid organs, typified by their cell-surface expression of CD62L and CCR7 ( 104 ). CD56 dim natural killer cells can be further dissected, into cells with highly potent effector function based on loss of NKG2A and expression of killer immunoglobulin-like receptors and CD57 ( 105 , 106 ). In a recent study, it was shown that these natural killer cells, which are capable of rapid effector functions, are preferentially redistributed after exercise ( 107 , 108 ). Synergistically, T cells also appear to exert heterogeneous but highly coordinated responses to acute exercise. Indeed, it is consistently observed that discrete populations of CD8 + but not CD4 + T cell subsets are redeployed by exercise. For some time, there was confusion pertaining to the exact behavior of CD8 + T cells in response to exercise. Rather than losing or gaining markers of adhesion or activation—as evaluated elsewhere ( 8 )—these changes represent a uniform redeployment of a preferentially mobilized group of memory cells. In a flurry of studies about a decade ago, it was shown that exercise selectively mobilizes memory CD8 + T cells with a phenotypic propensity for homing to peripheral tissues—typified for example by CD11, and not CCR7 or CD62L expression—and the distinctive capacity to mount rapid effector functions ( 81 , 109 – 111 ). This response presumably facilitates the detection and elimination of neoplastic, stressed or infected cells in synergy with natural killer cells, as proposed elsewhere ( 112 ). Aligned with the immune surveillance theory of Burnet and Thomas, reviewed elsewhere ( 113 ), these results imply that sentinel cells of the immune system are redeployed by exercise-induced perturbations to stress hormones, to exert effector functions against neoplastic, stressed, or infected cells in the hours following exercise. This process, which occurs daily in a natural diurnal process ( 114 ), orchestrated subtly by stress hormones ( 115 , 116 ), appears to be primed in response to exercise, leading to enhanced immune surveillance ( 117 ). Principles of the acute stress/exercise immune-enhancement hypothesis continue to be investigated. For example, it has recently been shown that acute exercise does not preferentially mobilize CD8 + T cells and natural killer cells with the capacity for skin-homing ( 118 ). However, skin-homing in this context is a role that may be fulfilled by exercise-responsive mucosal-associated invariant T cells ( 119 ); but further work is needed in this area.

A key example illustrating how exercise-induced immune cell redistribution is beneficial to host health can be found in the rapidly emerging field of exercise oncology. Indeed, a recent seminal study demonstrated inhibition of tumor onset and disease progression across a range of tumor models in voluntarily active rodents ( 112 ). In this work, natural killer cell infiltration was significantly increased in tumors from active versus inactive rodents, leading to the conclusion that the presence of natural killer cells (but perhaps also T cells) in tumor sites, redeployed by adrenaline during exercise stress, “provides a spark” for tumor elimination, in what could be considered a form of “exercise immunotherapy” ( 112 , 120 ). Importantly, administration of propranolol—a beta 2 adrenergic blocker—abolished the adrenaline-induced redistribution of immune cells, and nullified the anti-tumor effect of exercise on neoplastic growth ( 112 ). While these studies are limited to rodents, there is growing evidence that exercise may promote anti-cancer effects in humans. For example, in a key study recently conducted in humans, it was shown that natural killer cells with a highly mature effector phenotype are preferentially redistributed after exercise, and have the capacity to exert augmented cytotoxicity against myeloma and lymphoma cells in vitro ( 107 , 108 ). In light of these results, research is now being conducted to harness the beneficial impact of acute exercise on lymphocyte kinetics for the purposes of cancer immunotherapy ( 121 ). It is beyond the scope of this review to discuss other findings in this exciting field and we briefly conclude that the aforementioned studies imply that exercise-induced lymphocytosis, and the lymphopenia that follows, is beneficial to the immune system’s capacity to identify and neutralize damaged and neoplastic cells in peripheral tissues. Furthermore, in the context of neoplastic growth, this process may be directly responsible for reduced incidence of cancer among physically active people across the lifespan ( 122 ). Further comprehensive discussion of the role of exercise and lymphocyte kinetics in anti-tumor responses can be found elsewhere ( 117 ). Clearly more research is needed in this area, and a shift in focus toward investigating the benefits—rather than purported detrimental effects—of exercise on health, is no doubt underway and will be a key focus for exercise immunologists in the coming years.

Transient Changes to Blood Lymphocyte Function in the Hours Following Exercise

A common misinterpretation, brought about by the exercise-induced reductions to blood lymphocyte frequency in the hours following exercise, is the observation that the functional capacity of immune cells in the peripheral blood is reduced in the hours following vigorous exercise. As measurements of cell function in peripheral blood are entirely dependent on the cells present at the time of sampling, a change to the composition of the cells in blood in the hours after exercise—as outlined in the section; “Transient Changes to Blood Lymphocyte Frequency in the Hours Following Exercise”—will consequently lead to parallel changes in overall cell function, indicated by the performance of the sampled cells being assayed. For example, among CD8 + T cells, subsets that exhibit strong effector function (e.g., CD45RA + CD27 − CD28 − CCR7 − CD62L − CD57 + ), substantially increase during exercise ( 81 , 123 ). Thus, during exercise, blood is predominantly occupied by cells capable of responding strongly (i.e., IFN-gamma production) to in vitro stimuli, and therefore, many studies have shown an increase in IFN-gamma production by cells isolated close to the exercise stimulus. In the hours following exercise, the same effector CD8 + T cells are subsequently redeployed to peripheral tissues, and, as such, this results in the blood having fewer cells capable of responding strongly to in vitro stimuli, thus explaining the commonly reported decrease in cellular function post-exercise. These effects have been neatly demonstrated approximately two decades ago when it was shown that IFN-gamma production by stimulated CD8 + T cells is reduced 2 h after completing a prolonged 2.5 h bout of cycling ( 124 ). Importantly, it was shown that this reduced capacity to produce IFN-gamma was due to a reduced number of IFN-gamma-positive CD8 + T cells in peripheral blood at the same time-point ( 124 , 125 ).

The same principles apply to other cell functions, such as in vitro proliferation in response to mitogenic stimuli. However, with this measurement in particular, the commonly reported increase in T cell proliferation immediately after acute bouts of exercise is also strongly influenced by laboratory processes and in vitro assay conditions (e.g., blood processing, temperature, mitogen selection) ( 126 ). A recent meta-analysis of 24 studies concluded that lymphocyte proliferation is suppressed following acute bouts of exercise, and that a greater magnitude of suppression is caused by exercise lasting longer than 1 h, regardless of exercise intensity ( 127 ). However, this meta-analysis did not examine the most important determinant of cell function following exercise: the time-dependent changes in the cellular composition of the samples assayed. Thus, findings such as these should be interpreted with caution if analyses did not differentiate between studies collecting samples immediately after exercise or in the hours following.

As with research focusing on T cells, a similar group of studies citing reductions to natural killer cell cytotoxicity following acute exercise, reviewed elsewhere ( 128 ), did not always take into account dramatic shifts in the constitutional makeup of the natural killer cell compartment, which is known to change in response to exercise ( 81 ). Once more, changes to the functional capacity of the total natural killer cell pool are likely to have been misrepresented, given that many of these cells, with potent effector functions, are redistributed to peripheral tissues following exercise cessation. The principles discussed herein regarding lymphocyte function are also broadly applicable to the assessment of function in other cells, such as neutrophils and monocytes; the response of these cells to exercise is beyond the scope of this article and is reviewed elsewhere ( 8 ).

Taken together, it is important to emphasize that statements such as “ acute intensive exercise elicits a depression of several aspects of acquired immune function ” and “ prolonged bouts of heavy exertion reduce the normal functioning of all major immune cell subtypes ” mentioned elsewhere ( 8 , 15 ) should be interpreted with caution. We conclude that the results of studies exploring the effects of acute exercise on cell function must be considered very carefully in light of the time-dependent changes in the cellular composition of blood that typically arise following a vigorous bout.

Summary: Exercise Induces Lymphocyte Immune Surveillance Not Immune Suppression

In summary, strong evidence implies that a reduction in the frequency and function of lymphocytes (and other immune cells) in peripheral blood in the hours following vigorous and prolonged exercise does not reflect immune suppression. Instead, the observed lymphopenia represents a heightened state of immune surveillance and immune regulation driven by a preferential mobilization of cells to peripheral tissues. As such, nutritional interventions, which have been employed to dampen the magnitude of exercise lymphopenia ( 124 , 129 ) are unlikely to reduce the incidence of infections, but interventions that augment exercise-induced lymphocyte trafficking may provide benefits ( 130 ).

Part B: Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan

Contrary to a commonly held belief—outlined in Part A “Is it Time to Close the Shutters on the “Open Window” Hypothesis? A Bout of Exercise Does Not Suppress Immune Competency?”—that acute vigorous exercise can suppress aspects of immune function, an increasingly large body of research indicates that both single bouts of exercise, or frequent participation in regular exercise, can act as an adjuvant to stimulate the immune system. Numerous methods exist to assess the effects of behavioral interventions on immunity ( 131 ) but arguably the optimal means of evaluating global immune competency at a systems level is via assessment of the immune response to in vivo challenge, ideally with a novel and clinically recognized pathogen, for example via vaccination ( 132 ). Thus, here, in the first section of Part B “Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan,” we focus on the influence that exercise has on immune responses to antigenic challenge, which requires a coordinated response from most, if not all, innate and adaptive immune system components. In light of the age-associated decline in immune competence with aging—caused in part by underlying changes to the numerical, phenotypic, and functional capacity of almost all innate and adaptive immune cells—the second section of Part B “Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan,” will evaluate the impact aging has on the immune benefits that can be attained from exercise throughout the lifespan. A detailed discussion of immunological aging processes and the influence that an active lifestyle has on established biomarkers of an aging immune system is covered in Part C “Does exercise and Regular Physical Activity Influence Immunological Ageing?” of this article.

Exercise and Immune Responses to Experimental In Vivo Challenge Across the Lifespan

In a research context, the most clinically relevant model to assess in vivo challenge in a controlled manner is via vaccination. Vaccine administration assesses the integrated capacity of the immune system to recognize and process antigen, leading to antigen neutralization. In a clinical research context, vaccination responses are principally quantified clinically in two ways, either via antibody production from antigen-specific plasma cells or via cytokine responses—typically IFN-gamma production—from T cells stimulated with cognate antigen.

Vaccination: Effects of a Single Exercise Bout

Evidence from an array of studies, evaluated recently in a comprehensive review elsewhere ( 9 ), indicates that a single acute bout of exercise appears to enhance immune responses to vaccination in both younger and older individuals. The majority of studies to date have examined muscle-damaging upper arm resistance exercise performed close to the time of vaccination which is administered shortly after the regimen into exercised muscle. However, other modes of exercise, including acute bouts of whole body aerobic activity, have also been investigated. Six of the eight trials identified in the aforementioned review indicated a statistically significant exercise-induced enhancement of immune responses against constituent antigens contained within the vaccine administered ( 133 – 138 ). It is notable that in five of these studies, statistically significant benefits were found where the vaccine strains appeared to have lower immunogenicity ( 9 ). For example, it was shown in a trial of 133 young adults, approximately 20 years of age, receiving either a full- or half-dose Pneumovax-23 (a pneumococcal vaccine), that those who exercised at the time of receiving the half-dose vaccine had heightened responses to five of the eleven pneumococcal strains contained in the vaccine, whereas no differences were observed for the other six strains; and no benefits of exercise were observed for the full-dose vaccine ( 137 ). As such, given the potential effectiveness of exercise as an adjuvant in situations where vaccine immunogenicity is low, studying the effects of exercise on antibody responses in older adults—whom typically exhibit impaired responses—has received considerable attention. In one recent study, it was found that antibody responses in women 55–75 years of age, were significantly improved when moderate-intensity aerobic exercise was performed immediately prior to vaccination; however, no beneficial effects were found in men ( 138 ). Another trial reported no benefits of a single 45-min bout of moderate-intensity walking exercise on the immune response to influenza and pneumococcal vaccination in women around 47 years of age ( 139 ). Finally, a very recent study found no effect of a bout of resistance exercise on antibody responses to influenza vaccination in adults approximately 73 years of age ( 140 ). It is possible that a number of factors including immunological aging, biological sex and variations in sex hormone levels, and perhaps latent infections (e.g., herpes viruses) ( 141 – 143 ) limit the immunostimulatory effects of exercise, and many studies have not adequately controlled for these factors. Alternatively, in light of the mechanisms proposed in the acute stress/exercise immune-enhancement hypothesis ( 93 ), it is plausible that more intensive exercise may be needed to elicit enhanced vaccine responses. Despite null findings, it is important to point out that few, if any, studies investigating the effects of acute exercise on vaccination responses have reported exercise-induced impairment to immune responses, and rather, these studies report that exercise has no effect, or in some cases a beneficial effect, on the immune response to vaccination in older adults.

Vaccination: Effects of Frequent Exercise Bouts

Data from vaccine studies exploring the effects of regular physical activity or frequent exercise training on the immune response to vaccination provides robust support for the argument that exercise enhances, rather than suppresses immunity. Indeed, at least eight studies have demonstrated heightened vaccination responses in older adults, typically over 60 years of age, who are physically active ( 144 – 151 ). For example, an early study categorized adults aged 62 years or older, into one of three groups: active (undertaking at least 20 min of vigorous exercise three or more times per week), moderately active (undertaking regular exercise but with lower intensity, frequency, and/or duration), or sedentary (non-exercisers). Two weeks after influenza vaccination, it was shown that serum anti-influenza IgG and IgM titers were higher in active versus sedentary adults, and so too were peripheral blood mononuclear cell responses to antigen-specific stimulation ( 144 ). In addition, a recent study has shown that men aged 65–85 years, who regularly undertook moderate or vigorous exercise training, exhibited higher antibody responses compared to inactive controls in response to an influenza vaccine ( 151 ). Data linking habitual levels of physical activity to enhanced immune competency in humans are supported by evidence from animal studies, and show that the immunological benefits of exercise may be particularly beneficial in enhancing otherwise poor responses in older age ( 152 ).

Interpreting Data From Vaccine Trials

A major criticism of vaccine and exercise trials conducted in humans is that many solely focus on the maximal antibody titer following vaccination, and it is not practical to follow-up with investigations into infection incidence as a gauge of protection status following vaccination ( 153 ). As such, it is unknown whether differences observed with absolute antibody titers, or the amount of IFN-gamma produced from stimulated T cells, between exercise and control groups, is representative of clinically meaningful benefits in terms of protection from infections. Three elegant studies in rodents imply that benefits, beyond antibody titer, may be brought about by acute exercise. In one of these studies, it was found that antibody responses to influenza exposure were lower in rodents that exercised around the time of exposure, compared to those that did not exercise, yet, exercised mice were still protected and did not exhibit any signs of infection upon re-exposure to the virus ( 154 ). Moreover, in an earlier study by the same authors, it was found that mice undertaking an acute bout of exercise before being expose to influenza exhibited a lower severity of infection and had enhanced viral clearance and lower inflammation in the lungs in the days following ( 155 ). Thus, it may be the case that exercise enhances immune responses, beyond those captured using maximal antibody titer as an endpoint. In accordance with this view, an elegant rodent study conducted by an independent group ( 156 ) found that mice exercised for 20–30 min at moderate intensity 4 h after intranasal influenza exposure had a substantially higher survival rate (18 of 22 survived; 82%) when compared to mice that did not exercise after influenza exposure (10 of 23 survived; 43%).

Contact Sensitivity Reactions and Acute Exercise Bouts

More recent studies have examined the effects of acute exercise on immune competency using other in vivo models of immune challenge that, in principle, also assess the coordinated efforts of immune system components. These studies have employed contact-sensitivity reactions by topically applying to skin, the dendritic cell and T cell stimulant (or attractant) diphenylcyclopropenone (DPCP), and the non-specific inflammatory stimulant, croton oil ( 157 , 158 ). For example, in studies of young adults (approximately 20–30 years of age), by applying a primary sensitizing dose of DPCP 20 min after 2 h of moderate-intensity treadmill running, and assessing recall challenge 4 weeks later, it has been concluded that this form of exercise impairs both the induction of T cell immunity and the memory response ( 159 , 160 ). Thirty minutes of moderate- or vigorous-intensity running had no effect, and no forms of exercise modulated the non-specific inflammatory challenge in response to croton oil ( 159 , 160 ). Although these findings are biologically interesting, the clinical relevance of exercise-induced change is unclear, in part, because the process of DPCP-induced immune modulation is not well defined ( 158 ) unlike the immune response to antigen administration by vaccination.

Summary: Exercise Enhances Immune Responses to In Vivo Antigenic Challenge

We conclude that there is growing evidence from a powerful array of studies in humans and rodents, indicating that exercise enhances, or at least does not suppress immune responses to in vivo challenge in younger and older individuals. These observations—which contradict those predicated by the “open-window” hypothesis—support the contention that an acute bout of exercise has no detrimental immune consequences for health. Thus, exercise should be encouraged, particularly for older adults who are at greatest risk of infections and who may obtain the greatest exercise-induced benefits to immune competency; an overview of the impact of aging on the immunological benefits that can be attained from exercise is described next.

Does Aging Influence the Immunological Benefits of Exercise and Regular Physical Activity?

Effect of a single exercise bout.

Research investigating the effects of exercise on immune function has sought to establish whether the observed benefits, as outlined earlier in young adults, such as exercise-induced immune cell mobilisation, that has been implicated in protection against cancer, is also applicable to older adults. For example, it has been reported that the magnitude of T cell mobilization in response to acute vigorous exercise is smaller in older (65 ± 1 years) compared to younger (22 ± 1 years) adults ( 161 , 162 ). However, in this study, it was also shown that following exercise, the magnitude of T cell proliferation in response to mitogens was smaller in young adults, whereas a similar exercise-induced stimulation of natural killer cell cytotoxicity was observed for both groups ( 161 , 162 ). It is beyond the scope of this review to fully critique investigations examining the influence of single exercise bouts on the function of different immune cells, with comparisons made between younger and older individuals across the lifespan; we refer the reader to comprehensive reviews on this topic ( 163 – 165 ). Nevertheless, it is important to point out that many studies in this area are difficult to interpret: at the time of their publication, the influence of Cytomegalovirus infection on the magnitude of exercise-induced immune responses was not known and was therefore not considered ( 123 , 166 ). Moreover, while the magnitude of change to lymphocyte kinetics is likely to be important for detecting and eliminating viral and bacterial infections and neoplastic cells, this process is complex to study, and comparisons between younger and older people is difficult, partly due to other age-associated changes that influence the physiological response to exercise, such as the decline in fitness (e.g., sarcopenia, cardiorespiratory fitness) with age. It is likely that some, or all of these factors impact upon on the efficacy of exercise as an adjuvant to vaccination responses in older adults, outlined earlier in the section “Exercise and Immune Responses to Experimental In Vivo Challenge Across the Lifespan.” In light of the challenge interpreting the clinical relevance of the aforementioned lymphocyte kinetics studies, from here onward, we briefly evaluate the impact of regular physical activity or frequent exercise bouts on immune competency across the lifespan, using measurements in samples collected from participants at rest.

Frequent Bouts of Exercise

Immune competency at rest has been assessed in cross-sectional studies, comparing elderly individuals differentiated by physical activity level or cardiorespiratory fitness, or by examining immune function before and after structured exercise training interventions. For example, it has commonly been reported among the elderly, that the most active participants, compared to those who are least active, show the highest T cell proliferation and cytokine production in response to mitogens ( 163 – 165 ). Fewer studies have assessed innate immune competency, but higher natural killer cell cytotoxicity has been consistently shown among the elderly who are active compared to less active age-matched controls ( 163 – 165 ). Recent studies have expanded measurements into other innate immune cells such as neutrophils. For example, a recent cross-sectional study of 211 elderly adults, showed that neutrophils from the 20 most active participants, compared to the 20 least active participants, migrated toward interleukin (IL)-8 with greater chemotactic accuracy, but there were no differences in chemotactic speed ( 167 ). In addition, a recent exercise training study has shown in both young and middle-aged adults, that 10 weeks of moderate-intensity continuous cycling training, or high-intensity interval cycling training, improve neutrophil and monocyte phagocytosis and oxidative burst irrespective of age ( 168 ). Improvements in these common measurements of immune competency, however, are not always consistent in longitudinal studies employing exercise training interventions, with around half of studies reporting improvements, and half reporting no change ( 163 – 165 ). One reason for this could be because the dramatic effects of Cytomegalovirus on driving immunological aging was not considered by most of these studies, and it is feasible that results would be different when examining individuals who are latently infected compared to those who are seronegative. Importantly however, no studies report impaired immune competency from increased participation in structured exercise. Altogether, we conclude that despite declines in fitness and immune competency, aging does not appear to negate the immunological benefits that can be attained from exercise, and indeed, frequent participation in exercise across the lifespan may lead to immune benefits, even in older age.

Part C: Does Exercise and Regular Physical Activity Influence Immunological Ageing?

Since the first exercise immunology research in the early 1900s, and the substantial increase in scientific interest from the late 1980s and early 1990s ( 169 ), studies examining interaction between immune function and lifestyle factors such as exercise and physical activity have become common. Although a few exercise studies published in the last 10–15 years have investigated some immunological processes relevant to aging, health, and disease, the theme of exercise-induced “immune suppression” continues to influence the design of new studies or at least features in the interpretation of findings and is often justified or contextualized with relevance to self-reported illness symptoms among athletes. As outlined in Part A “Is it Time to Close the Shutters on the “Open-Window” Hypothesis? A Bout of Exercise Does Not Suppress Immune Competency,” there is limited reliable evidence to show that exercise heightens risk of opportunistic infections, but there is, however, a growing body of evidence to show that exercise enhances, rather than suppresses, immune competency, as summarized in Part B: “Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan.” The beneficial effects of exercise on immune function are likely to be greatest for elderly people exhibiting the age-associated deterioration of immune competency, also referred to as immunosenescence. Moreover, preliminary evidence suggests that physical activity and regular structured exercise may even limit or delay immunological aging. Here, in Part C: “Does Exercise and Regular Physical Activity Influence Immunological Ageing?” we evaluate whether an active lifestyle influences immunosenescence.

The Aging Immune System

Aging is associated with profound changes to the numerical, phenotypic, and functional capacity of almost all innate and adaptive immune cells, resulting in altered immune responses. Some innate immune cells exhibit numerical, phenotypic, and functional alterations with aging, whereas others appear to be less affected ( 170 ). For example, the numbers and functions of eosinophils, basophils, and mast cells appear to be largely unchanged with aging, or at least, there is not a clear effect of age based on the limited current literature ( 170 ). Neutrophil numbers often increase with aging, but these cells exhibit diminished phagocytosis and impaired chemotaxis, although chemokinesis is maintained ( 170 ). Natural killer cells increase with aging, driven by an accumulation of cytotoxic CD56 dim cells but a decline in regulatory CD56 bright cells, and overall, cytokine production and cytotoxicity are less on a per cell basis ( 170 ). Other innate lymphocytes, such as invariant CD1d-restricted natural killer T cells (iNKT cells), which represent <1% of the T cell pool, decline in number but age-associated changes to their function have not been established ( 171 ). Monocyte numbers are stable with aging, but classical cells (CD14 ++ CD16 − ) decline, and intermediate (CD14 + CD16 + ) and non-classical (CD14 + CD16 ++ ) cells increase, but overall, monocyte cytokine production is impaired ( 170 , 172 ). These changes with blood monocytes are thought to be mirrored by tissue-resident macrophages, whereby classically activated M1 cells decline, and alternatively activated M2 cells accumulate ( 173 ). However, alterations in tissue-resident cells with advancing age are very likely to be a result of adipose tissue accumulation and dysfunction that also occurs in parallel with aging ( 174 , 175 ). Indeed, inflamed adipose tissue attracts macrophages with cell-surface characteristics similar to M2 alternatively activated cells—often assumed to be anti-inflammatory. However, despite their cell-surface phenotype, these cells are potent producers of inflammatory cytokines in adipose tissue, and likely drive age- and obesity-associated inflammation ( 176 – 179 ). Thus, the M1/M2 paradigm for macrophages is likely to be an over-simplification ( 180 , 181 ). It is unknown if other, primarily tissue-resident cells, are affected by adipose tissue dysfunction, but with aging, the number and function of dendritic cells have been reported to decrease in the skin and mucosal membranes ( 170 ). There is also an age-associated increase in myeloid-derived suppressor cells—a heterogeneous population of granulocytes, macrophages, and dendritic cells—that may impair aspects of immune function by producing reactive oxygen species and inhibitory cytokines ( 182 ).

Within the adaptive immune system, there are substantial changes to the numbers, function, and phenotype of T cells with aging. Among the broad population of CD4 + T-helper cells, aging is associated with a predominance of Th2 (i.e., IL-4 and IL-10), and Th17-producing cells (i.e., IL-17-producing cells that are associated with autoimmune disease), whereas there is a decline in cells with a Th1 profile [i.e., IFN-gamma- and tumor necrosis factor-alpha (TNF-alpha)-producing cells] ( 183 , 184 ). With aging, the numbers and proportions of antigen-inexperienced CD4 + and CD8 + T cells decreases (e.g., CD27 + CD28 + CD45RA + CD57 − CD62L + CCR7 + KLRG1 − naïve cells) ( 185 , 186 ). In parallel, the numbers and proportions of antigen-experienced CD4 + and CD8 + T cells increases (e.g., CD27 − CD28 − CD45RA + CD57 + CD62L − CCR7 − KLRG1 + memory cells), and these cells are potent producers of inflammatory cytokines ( 185 , 186 ). These changes are driven by lower hematopoietic stem cell numbers, thymic involution resulting in reduced output of antigen-naïve T cells, and infection with latent viruses, in particular Cytomegalovirus ( 185 , 187 ). With aging, T cells that express natural killer cell-associated cell-surface proteins (NKT-like cells) also accumulate, exhibiting similar changes to their phenotype, functional properties, and specificities as with the broader population of CD4 + and CD8 + T cells ( 171 ). There is an age-associated decline in the total number of γδ T cells; however age per se , in the absence of chronic infections, is associated with a decline in Vδ2 cells (60–80% of γδ T cells), whereas Vδ1 (15–20% γδ T cells) remain stable ( 188 ). Some evidence suggests that γδ T cell proliferative responses are impaired with aging, perhaps due to increased susceptibility of Vδ2 cells to apoptosis ( 189 , 190 ). Natural regulatory T cells increase with aging whereas inducible regulatory T cells decrease, but it is unclear if their function is affected ( 191 ). As with T cells, aging is associated with a decline in the numbers and proportions of naïve B cells, an accumulation of memory B cells with limited specificities, and impaired plasma cell antibody production ( 192 ).

Several robust and accepted hallmarks of immunosenescence have been established, especially within the adaptive immune system. For example, low numbers and proportions of naïve T cells (in particular CD8 + T cells) and high numbers and proportions of memory T cells (especially late-stage differentiated CD8 + T cells) are well established biomarkers ( 185 , 186 , 193 , 194 ). In addition, a cluster of parameters, revealed in longitudinal studies of octogenarians and nonagenarians from an isolated population in Sweden, have been referred to as the immune risk profile ( 195 – 197 ). Biomarkers included low numbers and proportions of B cells, high numbers and proportions of late-stage differentiated CD8 + T cells (i.e., CD27 − CD28 − ), poor T cell proliferation in response to mitogens, a CD4:CD8 ratio of <1.0, infection with Cytomegalovirus and high plasma IL-6, which together, predicted greater all-cause mortality at 2-, 4-, and 6-year follow-up ( 195 , 197 – 200 ). Indeed, the age-associated increase in systemic inflammation, referred to as “inflammageing” is another principle observation among aging and longevity studies ( 201 , 202 ). Subsequently, high levels of IL-6, TNF-alpha, and C-reactive protein, have been associated with shorter survival ( 203 – 205 ). Overall, it is well established that elderly individuals exhibit impaired immune responses to in vivo challenge with novel antigens ( 143 , 206 , 207 ) and these individuals are subsequently thought to be at increased risk of infection. Encouragingly however, as outlined in Part B: “Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan” exercise can be a potent stimulus of immune function, including the response to vaccination, and some evidence suggests that exercise might delay or limit the age-associated decline in immune competency.

Relationships Between Exercise and Regular Physical Activity With Hallmarks of an Aging Adaptive Immune System

As summarized in Part B: “Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan” many studies have examined the influence of regular physical activity or frequent structured exercise on the function of the adaptive immune system with aging ( 163 – 165 ). Here, we focus on recent studies that have examined relationships between exercise, physical activity or cardiorespiratory fitness, and the numbers and proportions of CD4 + and CD8 + naïve and memory T cells, as hallmarks of immunosenescence. Indeed, a small number of studies have investigated whether the characteristics of the T cell pool are influenced by an active lifestyle. There is a larger body of evidence in young adults, typically between 18 and 30 years, compared to older adults, hereafter considered as being over 40 years of age due to the characteristics of studies published to date. If an active lifestyle can be linked with a smaller accumulation of memory T cells, and a smaller decline in naïve T cells, then in young adults, one interpretation might be that exercise prevents, or at least delays immunosenescence, whereas in older adults, these associations could be interpreted as countering or limiting the development of an age-associated immune profile.

Experimental Evidence in Young People: Can Exercise Prevent or Delay Aging of the Adaptive Immune System?

The characteristics of the T cell pool have been examined in 16 young adults (50% male; 18 ± 2 years) classified as being very active (well-trained soccer players self-reporting 9–12 h of exercise per week) and compared to 16 young adults (50% male; 19 ± 2 years) classified as being untrained (individuals self-reporting 2–3 h of exercise per week). Untrained individuals showed the highest proportions of CD4 + and CD8 + memory T cells, and the lowest proportions of CD8 + naïve T cells, defined on the basis of CD57 and CD28 expression ( 208 ). Although these results suggest that regular exercise might limit the age-associated accumulation of memory T cells and decline in naïve T cells, the effects were strongly influenced by sex: only untrained males exhibited high proportions of memory T cells and low proportions of naïve cells compared to trained males, and these effects were driven by changes in the CD4 + T cell pool ( 208 ). Extending these findings by examining a female-only population of young adults, the same authors compared 13 well-trained soccer players (self-reporting around 12 h of exercise per week; 20 ± 2 years) to 13 untrained controls (self-reporting around 3 h of exercise per week; 21 ± 2 years) ( 209 ). Trained females exhibited a greater proportion of CD8 + naïve T cells compared to untrained females, but these associations did not remain statistically significant after controlling for body fat percentage (trained 21.7 ± 4.0 versus untrained 25.1 ± 4.1%, p < 0.05) ( 209 ). Indeed, very few studies have considered whether relationships between an active lifestyle and markers of an aging immune system could be influenced by other factors, such as body composition. Recently, a very small study of 15 males aged 30 ± 4 years, categorized participants using a combination of gold standard methods for measuring physiological and lifestyle variables ( 210 ). Three groups were formed (sedentary, active, and very active) on the basis of objectively assessed habitual physical activity, directly measured cardiorespiratory fitness, and body composition assessed with dual energy X-ray absorptiometry ( 210 ). This work showed that sedentary individuals had higher proportions of memory CD4 + T cells expressing CD45RO and PD-1, supporting the results of other published studies that have not taken body composition into consideration.

It should be emphasized, that among younger adults in particular, mixed results have been reported when investigating links between an active lifestyle and hallmarks of an aging immune system. Most investigations have been cross-sectional in design, or have made observations between groups over short periods. For example, one study has shown that national standard triathletes (age range 18–36 years, n = 19), appear to exhibit impaired thymic output, assessed by T cell receptor excision circle levels ( 211 ). Among CD4 + and CD8 + T cells, these athletes had lower absolute numbers of naïve cells and higher absolute numbers of memory cells compared to age-matched less active controls ( n = 16), as shown by CD45RA, CD45RO, and CD27 expression ( 211 ). Similar observations have been made by examining individuals in the third decade of life, showing that endurance athletes, compared to less active controls, appear to exhibit slightly larger accumulations of memory T cells and slightly fewer naïve T cells, defined by CD45RA and CCR7 expression ( 212 ). Thus, it appears that among younger individuals (i.e., less than 40 years of age), if exercise is undertaken at very extreme volumes, such as more than 5–10 times the amount of physical activity recommended each week (i.e., 12–25 h per week), this might contribute toward a small decline in naïve T cells and a small increase in memory T cells. It is possible that these changes are due to reactivation of latent viruses, which could be independent of immune function, and driven by exercise-induced adrenergic activity, oxidative stress and inflammatory cytokines ( 48 – 50 ). However, these results might also be explained by fluctuations in cell numbers and cell sub-populations in peripheral blood over time. Such changes have been interpreted as being linked to exercise training load ( 213 , 214 ), but it is also conceivable that these changes occur due to seasonal variation, as has been shown in non-exercise contexts ( 215 , 216 ).

Experimental Evidence in Older People: Can Exercise Limit or Counter Aging of the Adaptive Immune System?

Although most studies have examined associations between biomarkers of an aging adaptive immune system in young adults, other studies have made measurements across a broader range of ages. For example, one study examined 102 men ranging in age from 18 to 61 years (mean 39 ± 6 years) ( 217 ). It was shown that the proportion of the CD4 + and CD8 + T cell pool comprising of memory cells (defined as KLRG1 + CD57 + or KLRG1 + CD28−) was inversely correlated with cardiorespiratory fitness, which is largely indicative of an active lifestyle ( 217 ). The age-associated decrease of naïve T cells (defined as KLRG1 − CD57 − or KLRG1 − CD28 + ) and increase in memory T cells did not withstand statistical adjustment for cardiorespiratory fitness, but remained significant after adjusting statistically for body composition and Cytomegalovirus infection ( 217 ). Thus, it was concluded that fitter individuals exhibit a smaller age-associated decline of naïve T cells and a smaller accumulation of memory T cells.

As with work examining relationships between an active lifestyle and hallmarks of an aging adaptive immune system in young and middle-aged adults, similar associations have been shown in an older population of 61 men aged 65–85 years ( 218 ). In this study, participants self-reported to be “untrained” ( n = 15), or to lead a “moderate” training lifestyle ( n = 16; taking part in team sports or running less than 6 km two to three times per week), or an “intense” training lifestyle ( n = 15; running approximately 10 km at least 5 days per week). These categories were confirmed with a validated physical activity questionnaire and by measurement of cardiorespiratory fitness. Both training groups exhibited a lower proportion of CD4 + and CD8 + memory cells (defined as CD45RA + CCR7 − ), but these associations were largest and only statistically significant among men leading an “intense” training lifestyle, suggesting a dose–response effect of exercise. Although findings were less clear when examining other cell subpopulations based on CD45RA and CCR7 expression, and there were no effects of exercise when examining CD28 − cells, men in the “trained” groups had T cells with the longest telomeres ( 218 ). Another recent study compared 125 adults (55–79 years of age) who maintained a high level of cycling throughout life to 75 age-matched inactive controls ( 219 ). Within the CD4+ and CD8+ T cell pool, the frequency of naive cells (defined as CD45RA+) was greater, and the frequency of memory cells (defined as CD45RA-) was lower among cyclists. Extended phenotyping revealed that CD4+ and CD8+ CCR7-CD45RA+ accumulation was less among cyclists, but no differences were found for CD28-CD57+ cells. Cyclists also exhibited higher frequencies of recent thymic emigrants and regulatory B cells, lower Th17 polarization, and in plasma, higher IL-7 and lower IL-6 ( 219 ). Despite these findings, suggesting a beneficial effect of leading an active lifestyle on immunosenescence among older adults, there is some inconsistency in the literature. For example, comparing elderly athletes ( n = 12, approximately 74 years of age) to less active age-matched controls ( n = 26), there were no differences in thymic output, the proportions of naïve or memory CD4 + and CD8 + T cells (defined with CD45RA and CCR7 expression), or T cell activation in response to anti-CD3 stimulation ( 212 ). Most investigations of T cell immunosenescence and lifestyle among healthy elderly adults have had cross-sectional study designs. Longitudinal studies, or randomized and controlled trials of exercise training are lacking and might yield promising results. For example, one study has compared 6 months of exercise training in men and women ( n = 28, aged 61–76 years) to a similar group who maintained their current lifestyle ( n = 20, aged 62–79 years) ( 220 ). Using a simple immunophenotyping strategy, the results showed that the proportion of CD4 + T cells expressing CD28 increased in the exercise group after 6 months, but not in those who maintained their lifestyle ( 220 ).

Summary of Experimental Evidence

In summary, evidence shows that the characteristics of the T cell pool appear to be influenced by leading an active lifestyle, determined by exercise training, physical activity level, or cardiorespiratory fitness. It seems that among both the young and elderly, an active lifestyle is generally linked to lower numbers and proportions of memory T cells and higher numbers and proportions of naïve T cells ( 10 ). This summary is partly supported by a recent systematic review, concluding that regular structured exercise increases the number of naïve T cells in peripheral blood at rest ( 221 ). Altogether, findings from recent studies examining relationships between an active lifestyle and the characteristics of the T cell pool—as robust and accepted biomarkers of immunosenescence—support observations from some cross-sectional and longitudinal studies, showing that other measures of immune competency, which typically decline with aging, can be improved with physical activity or regular structured exercise ( 163 – 165 ). However, further research is needed in this area that employs precise lifestyle measurements (e.g., using wearable technology to assess physical activity, and dual energy X-ray absorptiometry to measure body composition) and more robust measurements of immune competency (e.g., absolute cell counts rather than proportions, measurements of cell function, and in vivo antigen challenges) while controlling for factors that drive immunosenescence (e.g., inflammation and Cytomegalovirus infection).

Links between a physically active lifestyle with lower numbers or proportions of memory T cells, and higher numbers or proportions of naïve T cells, have been hypothesized as being driven by the acute effects of exercise bouts. For example, it has been suggested that repeated bouts of exercise might prevent or delay immunological aging by limiting the accumulation of CD4 + and CD8 + antigen-experienced memory T cell clones, repopulating blood with antigen-inexperienced naïve T cells ( 11 , 12 ). In this hypothesis, it is proposed that memory T cells are frequently mobilized into blood during regular bouts of exercise, followed by an extravasation to peripheral tissues, where these cells are exposed to pro-apoptotic stimuli, such as reactive oxygen species, glucocorticoids, and cytokines ( 11 , 12 ). Subsequently, it is proposed that the number of naïve T cells increases as part of a negative feedback loop governing the number of naïve and memory cells in the immune system, which is bolstered by exercise-induced thymopoiesis and extrathymic T cell development ( 11 , 12 ). Supporting the mechanisms proposed in this hypothesis, many investigations have shown that memory T cells are mobilized into the circulation during exercise, followed by extravasation out of the bloodstream in the hours following ( 81 , 123 ). In addition, studies in mice show that lymphocyte apoptosis occurs post-exercise in tissues thought to be the homing destination of mobilized cells ( 222 ). Although some T cells mobilized by exercise might be resistant to apoptosis, given that Cytomegalovirus -specific CD8 + T cells express high levels of Bcl-2 ( 223 ), other work has shown that Cytomegalovirus -specific CD8 + T cells, are equally as susceptible to Fas-induced apoptosis as the total pool of CD8 + T cells ( 224 ). Further, irrespective of virus specificity, studies have shown that T cells expressing cell-surface proteins such as CD57 and KLRG1 are more susceptible to H 2 O 2 -induced apoptosis than total lymphocytes and naïve T cells ( 225 , 226 ). Thus, the concept of exercise directly countering memory T cell accumulation is supported by evidence from human and animal studies.

It is unknown whether triggering apoptosis among expanded clones of memory T cells specific for viruses such as Cytomegalovirus is advantageous. For example, in a transplant setting, Cytomegalovirus disease occurs when T cells fail to provide antiviral control ( 227 ) and a robust pro-inflammatory response to Cytomegalovirus has been associated with longer survival in the elderly ( 228 ). However, it remains to be determined what proportion of the T cell pool needs to be specific for Cytomegalovirus to limit viral reactivation. Infection with Cytomegalovirus results in approximately 10% of the CD4 + and CD8 + T cell pool becoming specific for this virus ( 229 ), although large inter-individual differences exist. For example, it has been reported that 23% of the CD8 + T cell pool can become specific for a single Cytomegalovirus epitope ( 223 ). Traditionally, it has been considered disadvantageous for such a large proportion of the T cell pool to be specific for one virus. This view is linked to another age- or infection-associated change that occurs in parallel—a fall in the numbers and proportions of naïve cells—which has been interpreted as limiting capacity to engage novel antigens. These interpretations are based upon two assumptions. First, there is an upper limit to the size of the immune system, and second, thymic output is negligible after adolescence ( 230 ). Thus, it has been proposed that antigen-inexperienced naïve T cells could be “used up” due to ongoing differentiation into antigen-experienced memory T cells that “fill up” immunological “space” ( 230 ). It has also been proposed that this accumulation of antigen-experienced memory T cells leads to “squeezing out” of T cells targeting less dominant viruses leading to loss of viral control ( 231 ). This concept of a fixed amount of immunological space has since been debated ( 232 , 233 ) and thymic output is now known to persist, albeit reduced, up until around 70 years of age ( 234 ). However, even if removal of some memory T cells is not essential for maintaining an effective T cell pool, assuming these cells contribute to systemic inflammation, their removal might limit “inflammageing” ( 230 ). Despite uncertainties over the susceptibility of memory T cells to undergo apoptosis, or whether it is advantageous to stimulate their removal, it seems that exercise-induced immune cell death in the tissues has relevance to other processes. For example, apoptotic cells and cell debris stimulates hematopoietic stem cell mobilization into blood ( 95 ) perhaps promoting trafficking to the thymus or extrathymic sites facilitating output of naïve T cells ( 235 ). Additional support for exercise stimulating production of naïve T cells is provided by work showing that contracting skeletal muscle produces IL-7 ( 236 ) which might increase thymic mass and function ( 237 ).

A physically active lifestyle might also counter T cell immunosenescence indirectly, perhaps by limiting adipose tissue accumulation and dysfunction that occurs with aging and obesity ( 174 , 238 , 239 ). Indeed, obesity has been linked with impaired lymphocyte proliferation ( 240 ), shorter leukocyte telomere length ( 241 ), and a skewing of the T cell pool toward a regulatory and Th2-phenotype ( 242 ). In addition, large expansions of differentiated αβ T cells and γδ T cells have been shown among people with obesity, with γδ T cells exhibiting impaired antiviral function ( 243 – 245 ). It is generally accepted that repeated stimulation with antigens from Cytomegalovirus drives immunosenescence ( 185 , 186 , 193 , 194 ). With obesity, adipose tissue is the primary source of pro-inflammatory cytokines and reactive oxygen species ( 174 , 246 ) which can reactivate Cytomegalovirus directly ( 48 , 49 ). Thus, exercise might limit T cell immunosenescence by decreasing visceral and subcutaneous adipose tissue ( 238 ), providing a potent anti-inflammatory and anti-oxidative stimulus ( 247 , 248 ). In turn, lower systemic inflammation and better redox balance might limit viral reactivation, reducing stimulation with antigens from viruses such as Cytomegalovirus . In addition, T cell dysfunction might also be prevented, in part, by limiting reactive oxygen species production ( 249 ).

In summary, leading a physically active lifestyle appears to limit the age-associated changes to the cellular composition of the adaptive immune system, but the mechanisms are yet to be determined. Exercise might counter the expansion of memory T cells directly, which is desirable assuming these cells contribute to systemic inflammation and not all are required to control latent viruses. Limiting the expansion of memory T cells also assumes the “size” of the immune system is fixed, the capacity to produce antigen-naïve T cells is limited, and these constraints contribute to immune decline in the elderly. However, exercise might affect memory T cell accumulation indirectly, by reducing viral reactivation, or preventing T cell senescence, by controlling adipose tissue deposition and dysfunction that drives inflammation and oxidative stress with aging and obesity.

Concluding Remarks

Contemporary evidence from epidemiological studies shows that leading a physically active lifestyle reduces the incidence of communicable (e.g., bacterial and viral infections) and non-communicable diseases (e.g., cancer), implying that immune competency is enhanced by regular exercise bouts. However, to this day, research practice, academic teaching, and even physical activity promotion and prescription continues to consider a prevailing myth that exercise can temporarily suppress immune function. We have critically reviewed related evidence, and conclude that regular physical activity and frequent exercise are beneficial, or at the very least, are not detrimental to immunological health. We summarize that (i) limited reliable evidence exists to support the claim that exercise suppresses cellular or soluble immune competency, (ii) exercise per se does not heighten the risk of opportunistic infections, and (iii) exercise can enhance in vivo immune responses to bacterial, viral, and other antigens. In addition, we present evidence showing that regular physical activity and frequent exercise might limit or delay immunological aging. We conclude that leading an active lifestyle is likely to be beneficial, rather than detrimental, to immune function, which may have implications for health and disease in older age.

Author Contributions

JC and JT contributed equally toward literature searching and retrieval, the ideas and interpretation of the studies described, drafting and revision of the manuscript, and approval of the final version to be published. JT and JC both agreed to be accountable for the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^ “Physical activity” refers to activities undertaken during leisure time, at home, as part of employment, or for transport purposes. “Exercise” is a component of physical activity within the leisure time domain and refers to physical activities that are planned, structured, repetitive, and undertaken for the purpose of improving or maintaining components of physical fitness and/or sporting performance. When individuals are referred to as being “active” or “inactive,” the description infers that these people undertake (or fail to undertake) a defined level of exercise or physical activity (e.g., age-specific physical activity recommendations, such as those published by the World Health Organisation). In this review, the term “exercise” will generally be used to describe the effects that active behaviours have on immune competency. Individuals described as being “sedentary” accumulate prolonged periods of behaviour eliciting low energy expenditure (e.g. sitting and lying).

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Keywords: exercise, physical activity, upper respiratory tract infections, open window hypothesis, infection susceptibility, ageing, immunosenescence, immune competency

Citation: Campbell JP and Turner JE (2018) Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan. Front. Immunol. 9:648. doi: 10.3389/fimmu.2018.00648

Received: 19 November 2017; Accepted: 15 March 2018; Published: 16 April 2018

Reviewed by:

Copyright: © 2018 Campbell and Turner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: John P. Campbell, j.campbell@bath.ac.uk ; James E. Turner, j.e.turner@bath.ac.uk

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Analysis Plot structure of the Open Window The
The open window hypothesis states that the immune system is compromised
The Open Window
PPT
Open-Window theory proposed by Pendersen and Ullum explains the
Design of the "open window" theory.

COMMENTS

The open window of susceptibility to infection after acute exercise in
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). Many studies have indicated a decrease in immune function …
The open window of susceptibility to infection after acute exercise in
Introduction: The "open window" theory describes the purported short-term suppression of the immune system following an acute bout of endurance exercise, which may lead to an increased susceptibility to upper respiratory illness (URI). Although many studies have found evidence of a decrease in immune function after intense exercise, these studies have not documented the changes in immune ...
Exercise: A Protective Measure or an "Open Window" for COVID-19? A Mini
Thus, individuals are recommended to perform short exercise sessions (≤1.5 h) at moderate or low intensity. Physicians are also recommended to include in the patient record if any exercise session was performed prior to the COVID-19 infection in order to provide further data to examine the "open window" theory. Go to:
Open window hypothesis
Quick Reference. The proposition that for a period (typically 3-72 h) after a bout of intense exercise (e.g. a marathon run) the immune system is suppressed, making the exerciser more susceptible to infection. From: open window hypothesis in The Oxford Dictionary of Sports Science & Medicine ». Subjects: Medicine and health — Clinical ...
Debunking the Myth of Exercise-Induced Immune Suppression: Redefining
In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory—referred to as the "open window" hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity ...
Exercise-induced immune system response: Anti-inflammatory status on
The "open-window" hypothesis suggests that an impairment of the immune system after vigorous exercise increases the risk of contracting an upper respiratory system infection [3,8,32]. The immune system activation is a response to a stressor, aiming to restore cellular homeostasis.
Exercise and Immunity
This hypothesis states that low and very high exercise loads increases the infection odds ratio, ... The "open window" theory means that there is an 'open window' of altered immunity (which may last between 3 and 72 hours), in which the risk of clinical infection after exercise is excessive [34, 35]. This means that running a marathon or ...
Exercise and the Regulation of Immune Functions
The "open-window" hypotheses adapted from the original model proposed by Pedersen and Ullum. 54 A single bout of exercise is associated with an initial enhancement in immune function that is quickly ... With regard to exercise "dose," the generally accepted hypothesis is that prolonged periods of intensive exercise training can depress ...
PDF Exercise and Immunity: Beliefs and Facts
27, 28]. For almost three decades, the J-curve and open- window hypothesis have provided the theoretical framework to explain how exercise can apparently exert both enhancing and suppressive effects on the immune system and alter sus-ceptibility to disease [18, 29]. However, contemporary evi-dence has recently challenged the idea that any form of
Demystifying roles of exercise in immune response regulation against
The open window hypothesis was established after several studies were conducted separately with different settings and methodological approaches. It became debatable since it was declared. Selected reports are summarized in Table 1 to illustrate recent studies supporting or contradicting the open window hypotheses.
The open window theory. Pedersen & Ullum, 1994
The "open window" theory means that there is an 'open window' of altered im- munity (which may last between 3 and 72 hours), in which the risk of clinical infection after exercise is excessive [34 ...
Open window hypothesis
"open window hypothesis" published on by Oxford University Press. The proposition that for a period (typically 3-72 h) after a bout of intense exercise (e.g. a marathon run) the immune system is suppressed, making the exerciser more susceptible to ...
The ''open window theory''. Moderate exercise causes mild immune
Hypothesis testing using α = 0.05. The results and conclusions of the study stated that the normal diet had no effect on the variables of sprint running speed, SOD and TNF-α levels.
Exercise-induced immune system response: Anti ...
The "open-window" hypothesis suggests that an impairment of the immune system after vigorous exercise increases the risk of contracting an upper respiratory system infection [3, 8, 32]. The immune system activation is a response to a stressor, aiming to restore cellular homeostasis.
Design of the "open window" theory.
Most observations led to the "open window" hypothesis ( Figure 1 ), which is a decrease in the protection of the immune system for some time after intense the following days [12,13]. Some ...
Open window hypothesis
The proposition that for a period (typically 3-72 h) after a bout of intense exercise (e.g. a marathon run) the immune system is suppressed, making the exerciser more susceptible to ...
5.5 Introduction to Hypothesis Tests
When using the p-value to evaluate a hypothesis test, the following rhymes can come in handy:. If the p-value is low, the null must go.. If the p-value is high, the null must fly.. This memory aid relates a p-value less than the established alpha ("the p-value is low") as rejecting the null hypothesis and, likewise, relates a p-value higher than the established alpha ("the p-value is ...
The "Open Window" theoretical concept associated with immune responses
Download scientific diagram | The "Open Window" theoretical concept associated with immune responses to acute exercise (abbreviation: h = hours). from publication: Clinical management of ...
A Summary and Analysis of Saki's 'The Open Window'
Saki himself would be one of them, killed in action in 1916. With him, and many like him, the Edwardian way of life that Saki so ruthlessly skewers in his stories would die, too. But 'The Open Window' remains more than a window (to reach for the inevitable metaphor) onto a vanished world. It is a timeless tale about truth and fiction, and ...
The open window of susceptibility to infection after acute exercise in
Introduction: The "open window" theory describes the purported short-term suppression of the immune system following an acute bout of endurance exercise, which may lead to an increased susceptibility to upper respiratory illness (URI). Although many studies have found evidence of a decrease in immune function after intense exercise, these studies have not documented the changes in immune ...
Frontiers
In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory—referred to as the "open window" hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity ...
The open window hypothesis states that the immune system is compromised
The open window hypothesis states that the immune system is compromised 3 to 72 hours after strenuous exercise, leading to an increased risk of opportunistic infections in the following days.
The Open Window Flashcards
Study with Quizlet and memorize flashcards containing terms like In "The Open Window" why is Framton Nuttel spending time in the countryside?, How does Framton Nuttel's sister attempt to help him during his visit to the country?, While waiting for Mrs. Sappleton, what part of the room does the Mrs. Sappleton's niece Vera bring to Framton's attention? and more.

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Exercise and Immunity

Current Issues in Sports and Exercise Medicine

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1. Introduction

2. The immune system

2.1. The innate immune system

2.2. The acquired immune system

3. C-Reactive Protein (CRP)

4. Cytokines

5. Free radicals

6. Antioxidants

7. Physical activity and antioxidant supplementation

8. Different methods for detection of free radicals and antioxidants

9. Effect of exercise on immunity

9.2. The S-curve

10. The open window theory

11. Physical activity – A stimulator and an inhibitor to the immune system

12. Summary

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Introduction

Part A: Is it Time to Close the Shutters on the “Open-Window” Hypothesis? A bout of Exercise Does Not Suppress Immune Competency

Exercise and Opportunistic Infections

Exercise and Salivary IgA

Changes to Lymphocyte Frequency and Functional Capacity in the Hours After Acute Exercise

Transient Changes to Blood Lymphocyte Frequency in the Hours Following Exercise

Transient Changes to Blood Lymphocyte Function in the Hours Following Exercise

Summary: Exercise Induces Lymphocyte Immune Surveillance Not Immune Suppression

Part B: Regular Physical Activity and Frequent Exercise Augment Aspects of Immune Competency Across the Lifespan

Exercise and Immune Responses to Experimental In Vivo Challenge Across the Lifespan

Vaccination: Effects of a Single Exercise Bout

Vaccination: Effects of Frequent Exercise Bouts

Interpreting Data From Vaccine Trials

Contact Sensitivity Reactions and Acute Exercise Bouts

Summary: Exercise Enhances Immune Responses to In Vivo Antigenic Challenge

Does Aging Influence the Immunological Benefits of Exercise and Regular Physical Activity?

Frequent Bouts of Exercise

Part C: Does Exercise and Regular Physical Activity Influence Immunological Ageing?

The Aging Immune System

Relationships Between Exercise and Regular Physical Activity With Hallmarks of an Aging Adaptive Immune System