Exercise immunology - L4

Question 1

Describe characteristics of upper respiratory tract infections (URTIs).

Answer 1

• Most common ones include: coughs and colds, influenza, sinusitis, tonsilitis, middle ear infections, sore throat.
• Most are due to an infection with a virus (or bacteria).
• The average adult has 2-4 URTIs each year and young children have twice as many.

Question 2

In what kind of athletes are URTIs more common (i.e. higher incidence)?

Answer 2

Endurance athletes and competitive prolonged exercise (e.g. marathon).

Atheletes are most susceptible to picking up infections close to competition.

Question 3

In what other population is a higher incidence of URTIs observed?

Answer 3

In sedentary individuals

Question 4

From low intensity to high intensity sports: which intensity is associated with reduced symptoms of URTIs? And which immune cells increase their activity after this level of intensity?

Answer 4

• Moderate intensity training (5x/wk, 45-min, 60% VO2 max, brisk walking).
• NK actitivity increases after moderate training (especially the first 6 weeks)

Question 5

In what population are URTIs reduced?

Answer 5

In physically fit adults

Question 6

Why does moderate exercise protect against infection?

Answer 6

A bout of moderate aerobic exercise causes:

• an increase in blood levels of NK cells, neutrophils and antibodies
• a transient (within 3 hours) increase in NK cells and neutrophils
• Short improved immune function, but still a decreased risk of infection.

Question 7

Explain the J-shaped curve in regard to the risk of URTIs and exercise intensity.

Answer 7

• Sedentary people have an (average) increased risk of URTIs.
• Moderate intensity exercise is associated with a reduced risk of URTIs.
• High intensity exercise is associated with an even greater risk of URTIs compared to sedentary people.

If you put this in a graph, with intensity on the x-axis and risk of infection on the y-axis, this results in a J-shaped curve.

Question 8

Explain the open-window theory.

Answer 8

This theories proposes that the increased risk of URTIs observed in high intensity athletes is due to the fact that 3-72h after exercise, there is an open window of altered immunity. In the case of intense exercise, the immune system is suppressed during this open window, which is associated with an excessive risk of clinical infection.

Question 9

Answer the following questions in regard to cortisol:

• When is cortisol released?
• Does it suppress or stimulate the immune system?
• Which cytokines are inhibited by the release of cortisol?
• Which cytokines are stimulated to be expressed by the release of cortisol?

Answer 9

• Released with stress and low blood-glucose.
• Supresses immune response (used to treat B-cell overactivity).
• Inhibits production of IL-12, INF-g, IFN-a, and TNF-a.
• Stimulates the expression of IL-4, IL-10, and IL-1 (anti-inflammatory cytokines).

Question 10

Explain how high intensity (severe) exercise can lead to both increased risk of viral infection and reduced risk of chronic disease.

Answer 10

Severe exercise leads to:

• increased expression of epinephrine, cortisol, and IL-6.

This leads to:

• decreased macrophage and Th1 cell cytokine production

Which leads to:

• impaired cell mediated immunity and inflammation

Ultimately leading to:

• increased risk of viral infection
• reduced risk of chronic disease

Question 11

Explain which systems are influenced by increased cortisol expression.

Answer 11

Cortisol leads to:

• Decreased production of inflammatory cytokines by macrophages.
• Reduced production of CRH by CRH -secreting neurons -> less stimulation of pituitary gland to produce ACTH -> less stimulation of adrenal glands to produce cortisol.
• Reduced production of ACTH from the pituitary gland -> less stimulation of adrenal glands for the production of cortisol (negative feedback loop).
• Reduced expression of mediators of inflammation.

Question 11

Is cortisol expression dependent on exercise intensity?

Answer 11

Cortisol is elevated by acute exercise in an intensity and duration dependent manner:

• mild-moderate exercise leads to a reduction in cortisol by increasing elimination and supressing secretion.
• intense exercise increases cortisol by increasing secretion.

Question 12

What is the effect of acute carbohydrate ingestion during exercise?

Answer 12

Carbohydrate ingestion during exercise leads to increased blood sugars (i.e. serum glucose, fructose, insulin). This leads to a decrease in stress hormones (i.e. cortisol, epinephrine) and to a reduction in inflammation (reduced neutrophilia, monocytosis, cytokines). The reduction in stress hormones also reduces inflammation.

Question 13

Describe how the following environmental factors during exercise influence the immune system:

• Exercise in heat
• Exercise in cold
• High altitude - low oxygen tension

Answer 13

• Exercise in heat -> more circulating leukocytes during recovery (due to higher core temperature).
• Exercise in cold -> hypothermia may lead to suppressed immune function and increased URTI incidence.
• High altitude - low oxygen tension -> associated with depressed immune function and increased URTI symptoms, but likely due to stressors like low PO2, sleep disorders and mountain sickness.

Question 14

Explain the S-shaped curve in regard to the risk of URTIs and exercise intensity.

Answer 14

• Sedentary people have an (average) increased risk of URTIs.
• Moderate intensity exercise is associated with a reduced risk of URTIs.
• High intensity exercise is associated with an even greater risk of URTIs compared to sedentary people.
• But in elite sporters, the risk of URTIs seems to be reduced compared to high intensity sporters.

If you put this in a graph, with intensity on the x-axis and risk of infection on the y-axis, this results in a S-shaped curve.

Question 15

What is the effect of acute exercise on leukocytes/leukocytosis?

Answer 15

Acute exercise leads to an increase in leukocytes.
* Higher response after prolonged exercise, compared to high-intensity exercise.
* Neutrophils make up 50-70% of all leukocytes.

Question 16

Explain why there is an increase in circulating neutrophils during/after exercise.

Answer 16

Due to (among others) increase in blood pressure during exercise, there is demargination of leukocytes from the vascular endothelium.

Question 17

Does chronic exercise have an effect on neutrophils?

Answer 17

• No, when neutrophil counts were compared between athletes and age-matched healthy controls, no difference was observed.
• But, chronic exercise appears to reduce neutrophil function at rest. Therefore, athletes partcipating in endurance events, may have lower numbers of neutrophils.

Question 18

Name the cause of the following in the context of exercise:

• immediate leukocytosis
• delayed leukocytosis (i.e. elevated white blood cell count)
• lower resting leukocytes in trained individuals

Answer 18

• immediate leukocytosis due to demargination of leukocytes from the endothelium during/after exercise
• delayed leukocytosis (i.e. elevated white blood cell count) due to actions of cortisol
• lower resting leukocytes in trained individuals due to possible immunosuppression

Question 19

What is the effect of acute exercise on NK cells?

Answer 19

There is a pronounced increase in NK cells, especially after high-intensity exercise.

Question 20

What happens to NK cell levels after exercise?

Answer 20

It quickly returns to baseline

Question 21

What is observed regarding NK cell activity after 15 weeks of moderate-intensity training in previously sedentary subjects?

Answer 21

Increased NK cytolytic activity

Question 22

Answer the following questions regarding the relationship between exercise and NK cell activity/count:

• Does acute exercise result in an increase or decrease of NK cell number and activity in proportion to exercise intensity and duration?
• What happens to NK cell number and activity after 1-6 hours after prolonged intense exercise?
• What is found to be associated with changes in NK cell number and activity?
• Does endurance training result in an increase or decrease in NK cell number and function?
• Does intense training result in an increase or decrease in NK cell number and function?

Answer 22

• Acute exercise leads to an increase of NK cell number and activity.
• NK cell number and activity decreases below baseline 1-6 hours after prolonged intense exercise
• Changes in NK cell number and activity are associated with hormonal changes (such as adrenaline, cortisol, growth hormone and beta-endorphin).
• Endurance training increases NK cell number and activity.
• Intense training may decrease NK cell number and activity.

Question 23

The effect of acute exercise on macrophages is related to macrophage function rather than cell count.

• What is observed regarding macrophage function after moderate acute exercise?
• What is observed regarding macrophage function after exercise to exhaustion?

Answer 23

• Improved macrophage function is seen after moderate acute exercise.
• Inconclusive for exercise to exhaustion -> macrophage function can be improved or reduced.

Evidence mostly based on animal studies.

Question 24

Does Toll-like receptor (TLR) expression increase or decrease after 90 min exercise at moderate intensity? And what does this increase or decrease reflect?

Answer 24

TLR expression reduces, which reflects reduced inflammatory state.

Question 25

Mice with induced obesity show a reduced inflammatory state after chronic exercise. Name two macrophage-related processes that explain this.

Answer 25

Reduced inflammatory state that can be explained by:
* supressed macrophage infiltration of adipose tissue
* accelerated phenotype switching from M1- to M2-type macrophages.

Question 26

Macrophages can differentiate into two different phenotypes: M1 and M2 macrophages. Explain the difference in phenotype.

Answer 26

• M1 macrophage: pro-inflammatory, microbicidal, tumoricial, Th1 response, antigen presentation capacity, killing of intracellular pathogens, tissue damage, etc.
• M2 macrophage: anti-inflammatory, clearance of parasites, tumor promotion, Th2 response, immunoregulation, tissue remodeling, angiogensis, matrix deposition, etc.

Question 27

Don’t know how to form a question.

Short-term functional overreaching (3 days, 2.5 h/day) was associated with significantly more muscle damage and systemic inflammation in runners than cyclists.

Answer 27

In 17 professional cyclists increases in pro- and anti-inflammatory acute phase proteins were observed during the Vuelta a Espana, indicating an acute phase/inflammatory response.

Question 28

Name characteristics of C-reactive protein.

Answer 28

• Acute phase protein present in blood
• Rises in response to inflammation
• Binds to phosphochiline expressed on the surface of dead or dying cells to activate the complement system.

Question 29

What is a myokine?

Answer 29

A peptide or protein secreted or released by skeletal muscle cells in response to muscular contractions.

Question 30

What is observed in amateur athletes of triathlon performance in extreme conditions?

Answer 30

• Generally: it has an impact on pro- and anti-inflammatory responses in these athletes.
• This illustrates an acute release of myokines by the muscle in response to the triathlon performance in extreme conditions.
• Systemic levels of IL-8, IL-6, and IL-10 were found to return to baseline 12 h after the competition.

Question 31

What is one of the most important myokines/cytokines that is associated with physical exercise?

Answer 31

IL-6. Increases in IL-6 >100 times above resting values have been found after exhaustive exercise such as marathon races,
moderate exercise (60–65% VO2max) and after resistance exercise, and may last for up to 72 h after the end of the exercise.

Question 32

What is cell-mediated immunity?

Answer 32

An immune response that does not involve antibodies but rahter involves the activation of macrophages and NK-cells, the production of antigen-specific cytotoxic T-cells and the release of various cytokines in response to an antigen.

Question 33

What is the effect of acute exercise (i.e. prolonged stenuous exercise) on T cells?

Answer 33

Prolonged strenuous exercise decreased total number of circulating T cells in trained male runners.

Question 34

Is there a difference in the effect of acute exercise between different types of T cells?

Answer 34

Th1 cells decreased after prolonged strenuous exercise, but not Th2 cells.

This was found in endurance-trained males and in trained male runners.

Question 35

What cytokine associated with T cell immunity was also found to be decreased in endurance-trained males (acute exercise)?

Answer 35

IFN-y

Question 36

Name a potentially underlying mechanism of the observation that circulating Th1 cells, IFN-y, but not Th2 cells decreased after acute exercise.

Answer 36

These effects may be related to underlying increases in adrenaline, cortisol, and IL-6.
* Epinephrine is found to increase from the start of treadmill running untill after. IL-6 is also found to increase during treadmill running.

Question 37

Considering that epinephrine, adrenaline, and IL-6 are involved in the anti-inflammatory effects of (acute) exercise, describe how the brain and muscle interact/react to exercise.

Answer 37

• Brain: HPA-axis (responsible for cortisol production) and sympathetic-adrenal-medullary axis (responsible for epinephrine production) are activated and stimulate the adrenal glands to produce adrenaline and cortisol. Adrenaline and cortisol lower the amount of TNF produced by monocytes.
• Muscle: the most important myokine produced by the muscle in response to exercise is IL-6. IL-6 is known to increase adrenaline and cortisol production, to lower TNF production and increase IL-1RA production by monocytes, and to increase IL-1RA and IL-10 production by macrophages.

Question 38

What else was found regarding the effects of acute exercise on T-cells (besides decreased Th1 cells and TNF-y)?

Answer 38

Reduced proliferation of lymphocytes (both CD4+ and CD8+) post-exercise.

Question 39

Complete the sentence.

T cell numbers increase or decrease in response to exercise but increase or decrease below baseline 1-4 hours post-exercise.

Answer 39

T cell numbers increase in response to exercise but decrease below baseline 1-4 hours post-exercise.

Question 40

Which of these findings discussed previously (T cells, NK cells, soluble factors, etc.) explains or supports the open window theory?

Answer 40

It is speculated that there is impaired T-cell function following exercise, which could explain the increased risk for URTIs in high intensity exercise.

Question 41

What is the effect of chronic exercise on T cells?

Answer 41

It is associated with an increase in lymphocyte concentration. Resistance training in college women showed increases in lymphocyte concentrations in upper and whole-body resistance training.

Question 42

Is there a difference in lymphocyte count between athletes and age-matched healthy controls?

Answer 42

No, lymphocyte counts are not much different between athletes and age-matched healthy controls.

Question 43

What was found in running mice (strenuous exercise) regarding T cell cytokines?

Answer 43

That IFN-y production decreased, but IL-4 did not compared to other exercise conditions.

Question 44

Have changes in antibodies following resistance exercise been reported (in trained/untrained individuals)?

Answer 44

No

Question 45

What type of exercise does result in an increase in antibodies?

Answer 45

• Antibodies slightly increase in sedentary women following 45-min low-intensity walk.
• Resistance training in chronic exercise (resistance training in college women) showed increases in lymphocyte concentrations, including B cells.

Question 46

What was found in professional athletes regarding B-cells and its antibodies?

Answer 46

They showed a lower salivary IgA, especially prior to URTI.

Question 47

In professional athletes, IgA was negatively found to be correlated with…?

Answer 47

training load. Thus: if training load increased, IgA decreased.

Question 48

What does this negative correlation between IgA and training load in professional athletes imply?

Answer 48

Lower (salivary) IgA (at baseline) predicts the athlete’s risk for URTIs.

Question 49

Comparing a healthy females that exercise with bedrest vs. bedrest only: what was observed regarding antibody production?

Answer 49

That there was a higher antibody production (IgG/IgM) against a bacteriophage in women who exercised with bedrest compared to the women with bedrest only. Therefore, a faster primary antibody production was observed in women who exercised in combination with bedrest. The secondary antibody production was similar in both groups, but was still higher in the group with women who exercised in combination with bedrest.

Question 50

Describe the Th1/Th2 balance.

Answer 50

Th1- and Th2-cells direct different immune responses. Th1 cells drive cellular immunity to fight intracellular pathogens. Th2 cells drive humoral immunity and up-regulate antibody production to fight extracellular pathways. Here, overactivation of one of the two pathways can cause disease, and either pathway can downregulate the other (counter-regulation).

Question 51

How does exercise intensity influence survival after viral infection?

Answer 51

It is (sort of) consistent with the open windown theory:
* Sedentary: survival rate below 40%
* Moderate exercise: highest survival rate around 80%
* Prolonged/high intensity: lowest survival rate around 30%